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ADVANCES IN CANCER RESEARCH VOLUME 52
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ADVANCES IN CANCER RESEARCH Edited by
GEORGE F. VANDE WOUDE NCI-Frederick Cancer Research Facility Frederick, Maryland
GEORGE KLEIN Department of Tumor Biology Karolinska lnstitutet Stockholm, Sweden
Volume 52
ACADEMIC PRESS, INC. Harcourl Brace Jovanovlch, Publishers
San Diego New York Berkeley Boston London Sydney Tokyo Toronto
COPYRIGHT 0 1989 BY ACADEMIC PRESS. INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER
ACADEMIC PRESS, INC . San Diego, California 92101
United Kingdom Edition published by
ACADEMIC PRESS LIMITED 24-28 Oval Road. London NWI 7DX
LIBRARYO F CONGRESS CATALOG
ISBN
0-12-006652-1
CARD
(alk. paper)
PRINTED IN THE UNITED STATES OF AMERICA 89909192
9 8 7 6 5 4 3 2 1
NUMBER:52-13360
CONTENTS
................................ ..................................
CONTRIBUTORS TO VOLUME5 2 . ..... PREFACE ...............................
ix xiii
Primary Chromosome Abnormalities in Human Neoplasia
HEIMAND FELIXMITELMAN Introduction ............. ............................ Cytogenetic Nomenclature . ........... SVERRE
I. 11. 111. IV. V. VI. VII. VIII. IX. X. XI. XII.
Data Base in Cancer C Acute Nonlymphocytic Leukemia . . ..................... Myelodysplastic Syndromes ............................. Chronic Myelopmlifera Acute Lymphoblastic Leukemia (ALL) ............................ Chronic Lymphoproliferative Disorders ... ................ Malignant Lymphoma .................................... .......................... Solid Tumors........ Oncogenes, Antioncogenes, an rrations ................... .................. Summary and Conclusions . .................. References ........................
2 4 9
18 22 24 27 30 37 38
T Cell Receptor and Immunoglobulin Gene Rearrangements in Lymphoproliferative Disorders M. D. REIS, H. GRIESSER,AND T. W. MAK I. 11. 111. IV. V. VI.
Introduction .......................................................... B Cell Antigen Receptor Structure, Function, and Gene Organization ......... T Cell Antigen Receptor Structure, Function, and Gene Organization. . . . . . . . . Clinical Applications of the Analysis of Immunoglobulin and T Cell Receptor Gene Rearrangements in Hematological Neoplasias . . . . . . . The Simultaneous Occurrence of the T Cell Receptor and Immunoglobulin Genes in Lymphoproliferative Disorders ................ Chrumowmal Translocations Involving the T Cell Receptor Genes . . . . . . . . . . . . References ............................................................ Note Addedin Proof .................................................... V
45 46 49 57 69 72 75 80
vi
CONTENTS
Structure. Function. and Genetics
of Human B Cell-Associated Surface Molecules
EDWARD A . CLARKAND JEFFREY A . LEDBETTER 1. Introduction . . . . . . . . . . . . . . ........................................ I1 . Major B Cell Differentiation gens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Other Biochemically Defined Surface Molecules ............................ on Pre-Band/or B Cells . . . . . . . . . . . . . . . . IV. Receptors on B Cells for Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Other Surface Molecules Expressed on Activated B Cells . . . . . . . . . . . . . . . . . . . . . VI . Surface Molecules Found on T Cells and Subsets of B Cells . . . . . . . . . . . . . . . . . . VII . Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ........................ ............................
82 89 116 125
127 132 134 135
Adenovirus Proteins and MHC Expression SVANTE PAABO. LIV SEVERINSSON. MATS ANDERSON. INGRID MARTENS.TOMMY NILSSON. AND PER A . PETERSON I. I1 . I11 . IV.
V.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ Adenoviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adenovirus Gene Products Modulating MHC Cell Surface ression . . . . . . . . . . Functional Consequences of Adenovirus-Induced Modulation of MHC Class I Expression . . . . . . . . . . . . . . ........................ Summary and Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
151 152 154
157 160 161
Multidrug Resistance
ALEXANDER M . VAN DER BLIEKAND PIETBORST I. I1 . 111. IV. V.
VI . VII . VIII .
IX. X. XI . XI1 .
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs Affected by MDR . . . . . . . . . . . . . . . . . . . . . . . . . . . . What Happens to the Drugs in MDR Cells? . . . . . . . . . . . Pharmacological Reversal of MDR . . . . . . . . . . . . . . . . . . . Alterations in MDR Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . P-Glycoprotein Overproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amplified Genes in MDR Cell Lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Central Role of P-Glycoprotein Genes in MDR . . . . . . . . . . . . . . . . . . . . . . . . . P-Glycoprotein Structure Deduced from Sequence Comparisons . . . . . . . . . . . . . . . Diversity of P-Glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mutated P-Glycoprotein Genes with Altered Drug Transport Properties . . . . . . . . P-Glycoprotein Expression in Normal Tissue and Its Regulation . . . . . . . . . . . . . .
172 174 175
178 180 185 188 189
CONTENTS XIII. XIV. XV.
Coamplified Genes and Alterations Elsewhere in the Genome . . . . . . . . . . . . . . . . M D R i n t h e Clinic ..................................................... Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vii 192 194 195 197
Glutathione Transferases as Markers of Preneoplasia and Neoplasia
KIYOMISATO I. 11. 111.
IV. V. VI.
Introduct' .................................................... Marker E Preneoplasia ................................... Molecular Forms of Glutathione rases. . . . . . . . . . . . . . . . . . . . Glutathione Transferases as Preneoplastic Markers . . . . . . . . . . . . . . . Role(s) of Glutathione Transferases in the Mechanisms Underlying Multidrug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . ................................................... .... ........... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
205 207
241 242 243
Aberrant Glycosylation in Tumors and Tumor-Associated Carbohydrate Antigens
SEN-ITIROH HAKOMORI I. 11.
111.
IV.
V. VI. VII. VIII. IX. X.
XI. XII.
Introduction and Brief Historical Background (1929-1975) . . . ...... Tumor-Associated Glycolipid Antigens in Experimental Tumors . . . . . . . . . . . . . . . Tumor-Associated Carbohydrate Antigens in Human Cancers: Classification, Mosaicism of Expression, and New Procedures for Generation of Antibodies . . . . . . . .............................. Oncogenes and Aberrant Glycosylatio .............................. Antigens .......... Normal and Oncofetal Features of G1 Carbohydrate Glycoprotein Antigens . . . . . . . . . . . . . . . . . . . . . . . . . . Alteration of Histo-Blood Group and Heterophile Antigens Expressed in Human Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aberrant Glycosylation in Preneoplastic Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . Requirements for Tumor-Associated Carbohydrate Antigens: Density of Antigens and Organizational Framework in Membranes . . . . . . . . . . . . Diagnostic Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor-Associated Carbohydrate Antigens as Targets for Therapeutic Applications ............................................ Summary and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
258 260
262 264
292 297 298 302 309 316
....................................... ....................................
318 331
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
333
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CONTRIBUTORS TO VOLUME 52 Numbers in parentheses indicate the pages on which the authors' contributions begin.
MAT^ ANDERSON,Department of Cell Research, University of Uppsala, S-75124 Uppsala, Sweden (151) PIET BORST, Department of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, T h e Netherlands (165) EDWARDA . CLARK, Department of Microbiology, University of Washington, Seattle, Washington 981 95 (81) H . GRIESSER,Ontario Cancer Institute, Toronto, Ontario, Canada M4X l K 9 (45) SEN-ITIROHHAKOMORI,T h e Biomembrane Institute, Seattle, Washington 98119 and Departments of Pathobiology, Immunology, and Microbiology, University of Washington, Seattle, Washington 98195 (257) SVERREHEIM,Department of Clinical Genetics, University Hospital, S-221-85 Lund, Sweden (1) JEFFREY A. LEDBETTER,Oncogen Corporation, Seattle, Washington 98121 (81) T. W. MAK, Ontario Cancer Institute, Toronto, Ontario, Canada M4X l K 9 and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada (45) INGRIDMARTENS,Department of Medical Virology, University of Uppsala, S-75124 Uppsala, Sweden (151) FELIXMITELMAN, Department of Clinical Genetics, University Hospital, S-221-85 Lund, Sweden (1) TOMMY NILSSON, Department of Immunology, Research Institute of Scra$@s Clinic, La Jolla, Cali&ornia 92037 (151) SVANTEPAWBO, Department of BiochemistTy, University of Calqornia, Berkeley, Calqornia 94720 (151) PERA. PETERSON, Department of Immunology, Research Institute of Scn3ps Clinic, La Jolla, California 92037 (151) M . D. REIS, Ontano Cancer Institute, Toronto, Ontano, Canada M4X 1K9 (45) ix
X
CONTRIBUTORS TO VOLUME 52
KIYOMISATO,Second Department of Biochemisty,Hirosaki University School of Medicine, Hirosaki 036, Japan (205) LIV SEVERINSSON, Ludwig Institute for Cancer Research, Uppsala Branch, BMC, S-75123 Uppsala, Sweden (151) ALEXANDER M. VAN DER BLIEK,Department of Molecular Biology, The Netherlands Cancer Institute, 1066 C X Amsterdam, The Netherlands (165)
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SIDNEYWEINHOUSE
PREFACE
This volume marks the retirement of Sidney Weinhouse from his dedicated work as Editor for Advances in Cancer Research. He assumed this post in 1961 when he edited Volume 6, together with Alexander Haddow. He has been responsible, first with Haddow and later with myself, for the subsequent 45 volumes. It is with much gratitude and true regret that I must accept Sidney’s decision to retire from the task that he has performed with so much circumspection and distinction. He always took the lion’s share of the work. Sidney Weinhouse can look back on a long and very distinguished career in biochemistry and cancer research. It started at the University of Chicago. where he received his Ph.D. and carried out wartime scientific activities. H is early research was on lipid metabolism. He was a pioneer in the use of isotopically labeled fatty acids and in the biosynthesis of amino acids in yeast. These studies led him to apply isotope methods to the study of tumors and to pursue his interest in the oxidative metabolism of glucose and other sugars. As this work progressed, Weinhouse obtained increasing evidence that conflicted with the views of Otto Warburg on the role of aerobic glycolysis in cancer cells. His publications in this area, including his G. H. A. Clowes Award Lecture of 1972 on “Glycolysis, Respiration and Anomalous Gene Expression in Experimental Hepatomas,” were largely responsible for the development of a more realistic view in a field that has suffered from both emotionalism and authoritarianism (see also Sidney Weinhouse: “The Warburg Hypothesis Fifty Years Later,” Guest Editorial, 2. Krebsforsch 87, 115-126, 1976). In the course of his work, Weinhousebecame interested in the minimal deviation hepatomas developed by H. P. Morris. He undertook an extensive series of investigationson these tumors, leading to important advances in carbohydrate metabolism as well as in the behavior of isozymes and their alterations in neoplastic cells (S. Weinhouse: “What Are Isozymes Telling Us about Gene Regulation in Cancer?” Guest Editorial,J. Natl. Cancer Znst. 68, 343-349, 1982). The results of these studies convinced Weinhouse of the great importance of aberrations in gene expression in the pathogenesis of cancer. His work forms a major part of the foundation of this now widely held view. In more recent years, Weinhouse has studied the metabolism of chemical carcinogens and started an investigation of inorganic pymphosphatase, believing that this key enzyme in cellular metabolism might play an important role in cancer. He has also turned his attention to a relatively new field for him, the possible role of nutrition in human cancer, on which he has prepared a special report for the American Cancer Society. xiii
XiV
PREFACE
The numerous contributions of Sidney Weinhouse have been recognized by many awards and distinctions of which only the most outstanding will be mentioned here. In biochemistry, he has been chairman of the Division of Biological Chemistry of the American Chemical Society and of the Committee on Biological Chemistry of the Division of Chemistry of the National Academy of Sciences-National Research Council. In cancer research, he has received the G. H. A. Clowes Award of the American Association for Cancer Research, the Papanicolau Award, and the National Achievement Award of the American Cancer Society. His election to the National Academy of Sciences confirms his stature as a truly outstanding scientist. He has assumed many editorial responsibilities, including the editorship of Cancer Research, the journal of the American Association for Cancer Research. He served on the editorial boards of numerous distinguished journals. He has also played a major role in the administration of scientific research in the United States. His positions include the Directorship of the Fels Research Institute at Temple University in Philadelphia, life membership on the Board of Directors of the American Cancer Society, and membership, often as chairman, on many national advisory bodies. I first met Sidney during my first 4 months in the United States as a predoctoral fellow at the Institute of Cancer Research, Fox Chase, Philadelphia, in 1950. Sidney headed the Department of MetabolicChemistry.The problemfocused scientific interest of Sidney and some others on the scientific staff, combined with an intense personal warmth, made a lasting impression that decisively influenced my own early scientific development and had similarly motivating effects on many other students and co-workers. It was a pleasure and a privilege to work with Sidney for more than a quarter of a century as co-editor of these Admances. His benevolent, soft-spoken personality will remain with us for many years to come. Sidney Weinhouse is succeeded by George Vande Woude as co-editor of Advances in Cancer Research. It is with great satisfaction that I see Sidney’s legacy deposited in such competent hands. I would like to extend my warmest welcome to George. GEORGE KLEIN
PRIMARY CHROMOSOME ABNORMALlTl ES IN HUMAN NEOPLASIA Sverre Heim and Felix Mitelman Department of Clinical Genetics, University Hospital, S-221-85 Lund. Sweden
I. Introduction 11. Cytogenetic Nomenclature 111. Data Base in Cancer Cytogenetics-An Overview IV. Acute Nonlymphocytic Leukemia A. inv(3)(q21q26) B. t(6;9)(p23;q34) C. t(8;21)(q22;q22) D. t(9;11)(~21-22;q23) E. t(15; 17)(q22;ql1-12) F. inv(16)(p13q22) G. +8 and Other Numerical Aberrations V. Myelodysplastic Syndromes A. Refractory Anemia without Excess of Blasts (RAWEB) B. Refractory Anemia with Ringed Sideroblasts (RARS) C. Chronic Myelomonocytic Leukemia (CMML) D. Refractory Anemia with Excess of Blasts (RAEB) and Refractory Anemia with Excess of Blasts in Transformation (RAEBT) VI. Chronic Myeloproliferative Disorders A. Chronic Myeloid Leukemia (CML) B. Polycythemia Vera (PV) C. Idiopathic Myelofibrosis/Agnogenic Myeloid Metaplasia D. Essential Thrombocythemia VII. Acute Lymphoblastic Leukemia (ALL) A. t( 1 ;19)(q23;p 13) B. t(4;11)(92 1 ;q23) C. del(6q) D. t(9;22)(q34;qll) E. Rearrangements of 14q32 and B Cell ALL F. Abnormalities Associated with T Cell ALL VIII. Chronic Lymphoproliferative Disorders A. Chronic Lymphocytic Leukemia (CLL) B. Prolymphocytic Leukemia (PLL) C. Hairy Cell Leukemia (HCL) D. Adult T Cell Leukemia (ATL) IX. Malignant Lymphoma A. Burkitt’s Lymphoma (BL) B. Non-Burkitt’s Non-Hodgkin’s Lymphoma (NHL) C. Hodgkin’s Disease (HD) X. Solid Tumors
1 ADVANCES IN CANCER RESEARCH, VOL. 52
Copyright 0 1989 h y Academic Press, Inc. All rights of reproduction in any form reserved.
2
SVERRE HEIM AND FELIX MITELMAN
A. Mixed Tumors of the Salivary Gland B. Small Cell Lung Cancer C. Renal Cell Carcinoma D. Bladder Carcinoma E. Uterine Leiomyoma F. Lipogenic Tumors G. Alveolar Rhabdomyosarcoma H. Synovial Sarcoma I. Meningioma J. Ewing's Sarcoma XI. Oncogenes, Antioncogenes, and Chromosome Aberrations A. Antioncogenes B. Oncogenes XII. Summary and Conclusions References
I. Introduction
The importance of karyotypic rearrangements in neoplasia has been the subject of heated debate ever since cellular pathologists, toward the end of the last century, described irregular cell divisions in tumors. These early observations were forged in 1914 into a systematic conceptual model by Theodor Boveri in what has become known as the somatic mutation theory of cancer. According to this hypothesis, nuclear changes, in particular chromosomal aberrations, are causative events in the transition from normal to neoplastic cell proliferation. Technical limitations prevented critical testing of the central idea in Boveri's reasoning until the 1950s. By that time, methodological improvements such as tissue culture techniques, hypotonic treatment of cells arrested in metaphase, and the air-drying method (excellent reviews of the historical background have been provided by Hsu, 1979, and Sandberg, 1980) opened up new possibilities for cytogenetic studies in oncology. The first spectacular breakthrough was not long in coming: Nowell and Hungerford in 1960 described the first characteristic neoplasia-associated karyotypic abnormality in man, the Philadelphia (Ph') chromosome, in patients with chronic myeloid leukemia (CML). This discovery seemed to perfectly epitomize the core concept of the somatic mutation theory: a distinctive chromosomal abnormality specifically associated with a particular malignant disorder. The decade following the Ph' discovery, however, did not see the expected steady increase in the reported number of tumor-specific abnormalities. The accumulated evidence instead indicated that CML might well be exceptional. Other malignancies were apparently not
CHROMOSOME ABNORMALITIES I N NEOPLASIA
3
characterized by consistent chromosomal changes; instead quite different aberrations were detected in what by all conventional criteria seemed to be indistinguishable neoplasms. Furthermore, the karyotypes were often very complex, containing numerous unidentifiable changes. As a consequence of these setbacks, the enthusiasm for a direct, causal role of primary chromosome abnormalities in human neoplasia waned, with many researchers taking the view that chromosome abnormalities in cancer and leukemia were probably randomly occurring epiphenomena of no direct pathogenetic importance. Such skepticism is seldom voiced today. Since the development of banding techniques around 1970, the discovery of which allowed unequivocal identification of individual normal and rearranged chromosomes, the evidence for an essential role of chromosomal changes in the pathogenesis of neoplastic lesions has been considerably strengthened. It is now established beyond doubt that most human tumors have karyotypic changes detectable with existing cytogenetic techniques. This conclusion is not restricted to malignant neoplasms; many benign tumors, too, are now known to contain characteristic karyotypic abnormalities. Furthermore, although the changes may vary from case to case and at times are quite complex, the overall aberration pattern is undoubtedly nonrandom, with some genomic sites involved in aberrations much more often than others. Of particular importance is the realization that many abnormalities are associated with distinctive disease variants, often revealing a cytogeneticmorphologic specificity that is fully comparable to the consistency seen between the Phl marker and CML. To these purely cytogenetic data implicating specific genetic changes in carcinogenesis may now be added the growing evidence of molecular specificity emerging from recombinant DNA studies. It appears that both currently known classes of directly cancer-relevant genes, the dominant oncogenes and the recessive antioncogenes, are located at just those genomic sites that are visibly involved in cancer-associated rearrangements. Hence, the last few years have witnessed a beginning understanding at the molecular level of the essential effects of cytogenetic changes in neoplasia. The sheer complexity of cytogenetic abnormalities in neoplastic cells has unquestionably added to the confusion regarding their importance in tumorigenesis. Greater clarity may be obtained if it is kept in mind that any chromosome aberration in a tumor cell can in principle be referred to one of the three following categories:
1. Primary abnormalities. These are essential in establishing the
4
SVERRE HEIM AND FELIX MITELMAN
neoplasm, and probably represent rate-limiting steps in tumorigenesis. They may occur as solitary cytogenetic changes, and are as a rule strongly correlated with tumor type. 2. Secondary abnormalities. The genomic instability of the tumor predisposes to further chromosomal mutations, leading to genetic and secondarily phenotypic variability within the tumor cell population. Darwinian selection invariably results, with the more fit subclones eventually outgrowing the others. Secondary abnormalities are thus important after the tumor has been established, in tumor progression, and reflect the clonal evolution during this disease phase. 3. Cytogenetic noise. Most chromosomal mutations confer no evolutionary edge on the cells, but may nevertheless be temporarily detectable as nonclonal aberrations. When the chromosomal instability in a tumor cell population is very pronounced, such noise abnormalities may obscure the pathogenetically important changes and completely dominate the karyotype. We shall in the present review concentrate on the primary abnormalities of human neoplasia. T h e types and importance of secondary aberrations have been the topic of several recent reviews, for example, Heim and Mitelman (1986a) and Nowell (1986).Before surveying the specific abnormalities known today, however, we shall recapitulate some of the basic conceps in cytogenetic nomenclature, and also briefly present an overview of the data on which all conclusions regarding chromosome changes in cancer are based. 11. Cytogenetic Nomenclature
A schematic illustration of the normal, male, G-banded human chromosome complement is presented in Fig. 1. The nomenclature of chromosome classification has been standardized at repeated international conferences, each of which has resulted in revised and improved recommendations to ensure a uniform cytogenetic terminology. The most recent and authoritative document in this regard is “An International System for Human Cytogenetic Nomenclature (1985),” or ISCN (1985), which incorporates all major decisions reached at previous conferences. The following descriptions are all based on the ISCN proposals. Transverse banding of chromosomes may be accomplished by any of numerous available methods. Each chromosome is seen as consisting of a continuous series of dark and light bands; thus no “interbands” exist. These bands define, together with regions, arms, and
5
NEOPLASIA
5
4
6
7
8
13
14
15
19
20
10
9
21
12
I1
22
X
Y
FIG. 1. Schematic illustration (idiogram) of the 24 different human chromosomes as they appear in G banding.
6
SVERRE HEIM A N D FELIX MITELMAN
chromosome number, any position that may be discerned with the resolution currently obtainable in cytogenetics. To describe a given chromosomal position, the chromosome number (see Fig. 1)is stated first. Then the chromosome arm (“p” for the short arm, “q” for the long arm) is given. This is followed by the region in which the position is located. Regions, which are chromosomal areas delimited by distinctive landmarks, are numbered consecutively from the centromere outward. The band is provided last. There may be one or several bands within each region, and again numbering is consecutive from the centromere outward. When highresolution techniques (Yunis, 1981) are utilized, subbands may be obtained within the bands seen with standard methodology. These are described by punctuation followed by numbering after the standard band has first been identified. Thus four items of informationchromosome number, arm, region, and band-are needed to define a position on a chromosome. For example, 9q34 means chromosome 9, the long arm, region 3, band 4.At the high-resolution level, subband 3 within 9q34 is written 9q34.3. The usefulness of these nomenclature rules is demonstrated when structurally rearranged chromosomes are described. Structurally abnormal chromosomes are defined by their breakpoints, which are specified within parentheses immediately following the description of the type of rearrangement and the chromosome(s) involved. The following rearrangements will be encountered in this chapter. Translocation, abbreviated “t,” means that material is transferred between chromosomes. Deletion, abbreviated “del,” means the loss of chromosome material. Inversion, abbreviated “inv,” means that a segment has rotated 180” within a chromosome. For example, t(8;21)(q22;q22) means that a translocation has occurred between chromosomes 8 and 21. The breakpoint in chromosome 8 is in q22 and the breakpoint in chromosome 21 is in q22 of that chromosome. The chromosomal segments distal to the two breakpoints have been swapped. An additional example illustrates the description of deletions: de1(5)(q13q33) means that the segment between the breakpoints 5q13 and 5q33 has been lost. Plus (-t)and minus (-) signs are placed before the chromosome number to indicate gain or loss of whole chromosomes. They are placed after the symbol to indicate an increase or decrease in the length of a chromosome, a chromosome arm, or a region. A marker (mar) is a structurally abnormal chromosome. When the banding pattern is recognized, it may be adequately described using
CHROMOSOME ABNORMALITIES IN NEOPLASIA
7
the standard nomenclature; in other instances it remains as mar in the karyotvpe description. The possibility of detecting clonal karyotypic changes in any sample is naturally dependent on the size of the respective clones and on how many metaphases are analyzed. The minimum operational requirements for accepting an aberration as clonal are two cells with the same structural rearrangement or additional chromosome, or three cells with the same missing chromosome. Ill. Data Base in Cancer Cytogenetics-An
Overview
Descriptions of numerous new cases of cytogenetically abnormal neoplasms characterized with banding techniques are added each year to the scientific literature (Fig. 2). The aberrant karyotypes thus described have been compiled and published in catalog form (Mitelman, 1983, 1985). The rapid growth of information may perhaps best be illustrated by mentioning that, whereas the first two catalogs contained, respectively, 3844 and 5345 investigated cases, the third edition, in 1988, contains 9069 human neoplasms with chromosome aberrations (Mitelman, 1988). Impressive though these figures may seem, the picture they convey of the breadth of cytogenetic knowledge in neoplasia is to some extent misleading. The data are heavily biased toward hematological malignancies. Although these disorders account for only a small fraction of human oncological morbidity and mortality, as many as 86% of all tumors investigated by mid-1987 are bone marrow (75%) or lymph
1250 1000
750
500
250 n
1973 71 75 76 77 78 79 80 81 82 83 84 85 86
FIG.2. Annual increase, from 1973 to 1986, in the reported number of human neoplasms characterized with banding technique (cytogenetically abnormal tumors). Information on more than 9000 cases is currently available.
8
SVERRE HEIM AND FELIX MITELMAN
node (11%)neoplasms. The cancers, quantitatively by far the most important neoplasias in man, contribute only 14%.The shortcomings of existing data are even more apparent when the solid tumor group is subdivided: some of the clinically most important cancers, in particular many carcinoma types (squamous cell carcinomas of the lung and uterine cervix and adenocarcinomas of the breast and prostate being but four of the most prominent examples) have karyotypic profiles that are almost totally unknown. The main reason for this is technical: solid tumors, and especially carcinomas, have proved less amenable to chromosomal investigations than have myeloid and lymphatic neoplasms. Only in the very recent past have reports of solid tumor abnormalities begun to come forth in substantial numbers. Our knowledge of the karyology of cancers has also been hampered b y the frequently low technical quality of chromosome preparations. The chromosomes are, compared to blood or bone marrow chromosomes, often contracted and fuzzy, the spreading is poor, and banding is unsatisfactory. As a consequence, structural rearrangements frequently remain undefined in such preparations, thus reducing the value of the biological inferences to be drawn from karyotype data. Finally, many solid tumor studies were undertaken very late in the disease process, often of samples from effusion material rather than primary tumors. The karyotypic changes then found are mostly quite complex, with numerous numerical and structural abnormalities. Undoubtedly many of the changes represent cytogenetic noise (see above) or secondary changes acquired during tumor progression. The primary abnormalities may be exceedingly difficult to identify in this setting. All these difficulties notwithstanding, the gradual improvements of the data base have allowed significant conclusions about the pathogenetic role of chromosome changes in solid tumors. Here, as in the more extensively studied hematological neoplasms, the chromosomal changes are distributed throughout the genome in a strictly nonrandom manner. Several primary abnormalities have been identified, some of which are correlated with particular disease entities with a specificity quite comparable to that seen in leukemias and lymphomas. In the following sections we present a brief review of rearrangements for which a primary pathogenetic role in leukemogenesis and tumorigenesis is strongly suspected. The emphasis will be on the cytogenetic and pathogenetic features of the aberrations; clinical implications have largely been omitted. A recent and more extensive
CHROMOSOME ABNORMALITIES IN NEOPLASIA
9
discussion of the importance of chromosome aberrations in neoplasia may b e found in Heim and Mitelman (1987b), which may also be consulted for more extensive referencing. IV. Acute Nonlymphocytic Leukemia
Karyotypic abnormalities have been reported in roughly 2500 cases of acute nonlymphocytic leukemia (ANLL). The frequency with which clonal abnormalities are found in unselected series varies, but in state-of-the-art investigations may be conservatively estimated at about two-thirds of all cases. Some aberrations are found with remarkable consistency, indicating that their role in disease development is primary (Table I). Several of these abnormalities are associated with particular morphological ANLL subtypes, as defined, for example, by the French-American-British (FAB) classification, which denotes acute myeloid leukemias as MI-MG, based on the morphology of cells in Romanowsky-stained blood and marrow films and certain supplemental cytochemical reactions (see Bennett et al., 1976). By definition, these primary abnormalities are often found as the sole TABLE I PRIMARY CHROMOSOME ABNORMALITIESIN ACUTE NONLYMPHOCYTIC LEUKEMIA Rearrangement
inv(3)(q21q26) +4
-5 del(5q) t(6;W(p23;q34)
-7 del(7q) +8 t(8: 16)(pll;p13) t(8:21)i q22;q22) t(9;1l)(p21-p22;q23) t(9;22)(q34;qll) del/t(l l)(q13-q23) del It( 12p) t( 15;17)(q22;q11-12 12) inv(l6)(p13q22) del(2Oq)
Hematologic characteristic Dysmegakaryocytopoiesis Secondary ANLL, mostly &I4 Abnormal megakaryocytes and thrombocytosis Mz and M4 Secondary ANLL Secondary ANLL Mz and M4with basophilia Secondary ANLL Secondary ANLL
Ms with phagocytosis Mp with Auer rods and eosinophilia M;, mostly Msa MI and Mz M4 and Ms,mostly Msa Secondary ANLL, M 4or M Zwith eosinophilia M.3
and > 1 3 ~
M 4with eosinophilia Mfi
10
SVERRE HEIM AND FELIX MITELMAN
3
inv(3Mq21926)
FIG.3. The paracentric inversion inv(3)(q21q26) is associated with ANLL, with prominent megakaryocytic and platelet abnormalities.
detectable aberration; alternatively, they may be accompanied by secondary changes. A. inv(3)(q21q26) This paracentric inversion of the long arm of chromosome 3 (Fig. 3) is found primarily in ANLL patients with prominent megakaryocytic and platelet abnormalities. Similar hematological features are associated also with t(3;3)(q21;q26), with t(1;3)(p36;q21),and occasionally with other rearrangements affecting 3q21 or 3q26 (Bitter et al., 1985; Pinto et al., 1985; Bloomfield et al., 1985; Mertens et al., 1987a); it is possible that these latter aberrations may best be thought of as pathogenetically equivalent variants of inv(3). The molecular pathology of the rearrangement is unknown. Interference with the transferrin and transferrin receptor genes, located in 3q21 and 3q26, has been suggested as one pathogenetic possibility (Le Beau et al., 1986a). B . t(6;9)(p23;q34)
This translocation has been associated with bone marrow basophilia (Pearson et d.,1985), a feature not present in all t(6;9) leukemias (Heim et al., 1986). Most patients with t(6;Q)have been quite young, the leukemia has been Mz or Mq, and often a clinically manifest myelodysplastic syndrome has preceded full-blown ANLL. The pathogenetic mechanism is unknown. Although 9q34 is affected here as in CML (see below), at subband level the breakpoint in t(6;9) is distal to
CHROMOSOME ABNORMALITIES IN NEOPLASIA
8
21
11
t(8;21)(q22;q22)
FIG.4. The rearrangement t(8;21)(q22;q22) is associated with ANLL M2, with bone marrow eosinophilia and Auer rods.
the break in t(9;22), in 9q34.3, making it unlikely that similar molecular mechanisms are involved in the two disorders. C. t(8;21)(q22;q22) This, the single most common structural rearrangement (Fig. 4) in ANLL, was found in 15% of all ANLL patients reported at the Fourth International Workshop on Chromosomes in Leukemia 1982 (1984). Although occasional cases have cells with morphology corresponding to other subgroups, the vast majority of cases are classified as M2. Auer rods are frequently prominent, as is bone marrow eosinophilia. Several variants involving structural rearrangements of either 8q22 or 21q22 have been reported (Billstrom et al., 1987); hence, it is at present unclear which of the breaks is more important in pathogenesis. The essential molecular consequences of t(8;21) are unknown, but the cellular oncogene ets2 is moved from 21q to the derivative chromosome 8 (Sacchi et al., 1986).
D. t(9;11)(p21-22;q23) The nonrandom occurrence of structural rearrangements of l l q in patients with acute monoblastic leukemia (Ms), in particular the immature Msa subtype, was first pointed out by Berger et ul., who in 1982 reported l l q abnormalities in 12 of 34 MS patients. The rearrangement most commonly seen is a reciprocal translocation between chromosomes 9 and ll (Hagemeijer et d.,1982), i.e., t(9; 1l)(p21--22;q23); the other 1l q affecting changes may represent
12
SVERRE HEIM AND FELIX MITELMAN
variants of this abnormality. The changes are not always translocations: in several cases the only recognizable abnormality is a deletion of parts of Ilq. Diaz et al. (1986) have shown that in t(9;ll) the cellular oncogene c-etsl translocates from 11423 to 9p adjacent to the interferon genes, which are split by the 9p22 breakpoint. Whether this is pathogenetically important remains unknown.
E . t(15;17)(q22;q 11- 12) This is the highly specific translocation associated with acute promyelocytic leukemia (APL), or M3 and M ~ vas , these subtypes are known within the FAB classification. With increasing cytogenetic sophistication, the t( 15;17) is being found in steadily higher pro1984), portions of APL patients, and the Chicago group (Larson et d., which has played a leading part in describing this translocation, has suggested that practically all ANLL patients of this subtype will eventually b e shown to have rearrangements of these chromosomal sites. The molecular pathology of t(15;17) is unknown.
F. inv(16)(p13q22) The marrow morphology of ANLL patients carrying this abnormality is quite characteristic: the leukemia is of the myelomonocytic (M4) subtype, and disturbances of the eosinophilic lineage are particularly prominent, with both an excess of eosinophils and abnormal eosinophilic granulation (Arthur and Bloomfield, 1983; Berger et al., 1985; Larson et al., 1986). Variant rearrangements associated with the same hematologic features, mostly del(16)(q22), t( 16;16)(p13;q22), and translocation between 16q22 and other chromosomes, have also been reported. Le Beau e t al. (1985) have offered a hypothesis regarding the pathogenetic consequences of inv( 16). They found that the metallothionein (MT) multigene family was localized in 16q22, and that the 16q22 breakpoint split the MT gene cluster. Possibly this might interfere with intracellular zinc binding or storage, and hence affect granulocyte and monocyte differentiation. Alternatively, an as yet undefined oncogene might, as a result of the rearrangement, be recombined with sequences in the M T locus, leading to structural or regulatory abnormalities of oncogene function and ultimately to leukemia.
CHROMOSOME ABNORMALITIES I N NEOPLASIA
G. + 8
AND
13
OTHERNUMERICAL ABERRATIONS
Numerical,karyotypic abnormalities (Heim and Mitelman, 1986a) are common in ANLL. Trisomy 8 is the change most often seen and is apparently not restricted to any particular FAB subgroup. It occurs as the sole abnormality in 7% of all cytogenetically abnormal cases. If leukemias with multiple aberrations are taken into consideration, +8 is found at double that frequency. The other nonrandomly occurring numerical aberrations in ANLL, i.e., +4, -5, -7, +21, and -Y, together account for another 5%. The fact that each of these is often the only change merits their inclusion among the primary abnormalities. Monosomy 5 and monosomy 7, as well as the partial monosomies brought about by del(5q) and de1(7q), are associated with secondary ANLL. V. Myelodysplastic Syndromes
Several hematopoietic dysfunction states are covered by the umbrella diagnosis, myelodysplastic syndrome (MDS); terms such as preleukemia and dysmyelopoietic syndromes have also been used synonymously. MDS thus includes entities such as refractory anemia with or without blasts, nonregenerative anemia, sideroblastic anemia, hematopoietic dysplasia, and chronic myelosis. An attempt to reach an internationally acceptable, standardized nomenclature for the various MDS subgroups has been made by the French-American-British Study Group (Bennett et al., 1982). Their proposals recognize five MDS subtypes: refractory anemia without excess of blasts (RAWEB), refractory anemia with ringed sideroblasts (RARS), chronic myelomonocytic leukemia (CMML),refractory anemia with excess of blasts (RAEB), and refractory anemia with excess of blasts in transformation (RAEBT). Clonal chromosome abnormalities have now been reported in more than 700 MDS patients (reviewed in Heim and Mitelman, 1986b). The frequency of aberrations in unselected series varies (Second International Workshop on Chromosomes in Leukemia, 1979, 1980; Nowell, 1982; Knapp et al., 1985; Tricot et al., 1985; Jacobs et al., 1986; Yunis et al., 1986), but has mostly been below corresponding frequencies obtained in ANLL. The finding of acquired karyotypic abnormalities in myelodysplastic bone marrows confirms the presently held view that MDS is a neoplastic disorder. The aberration pattern varies among subtypes
14
SVERRE HEIM AND FELIX MITELMAN
TABLE I1 FREQUENCY OF PRINCIPAL PRIMARY KARYOTYPIC ABNORMALITIES IN MDS Abnormality (70)
Disorder
5q-
-5
-7
+8
deI/t(llq)
deUt(l2p)
RAWEB RARS CMML RAEB(T)
70 30 10 pg/106 cells) for as yet undefined reasons. The apparent requirement for internalization of anti-CD23 contrasts with the results of Barsumian and co-workers, who found that IgE does not induce internalization of CD23. More recently, Guy and Gordon (1987) found that both BCGF and anti-CD23 induce decreased expression of CD23 on activated B cells, presumably by stimulating the shedding of surface CD23 into a soluble form. Since IgE and IL-4 up-regulate CD23 expression, it is possible that IL-4/ IgE and BCGF may function together to increase surface and then soluble CD23 levels, which may then function to regulate B cell growth (Gordon and Guy, 1987). Together, these studies imply that CD23 is not only (1)a receptor for IgE and (2) a soluble factor, but also
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EDWARD A. CLARK AND JEFFREY
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LEDBETTER
may b e (3) a receptor for a BCGF, which presumably has some homology with IgE Fc domains that also bind CD23. Are not too many functions being ascribed to one surface molecule? One possibility is that anti-CD23 does not in fact act directly but rather promotes, e.g., the modulation of BCGF receptors and/or the shedding of soluble CD23, which has been reported to have BCGF activity (Swendeman and Thorley-Lawson, 1987). These issues can only be decisively answered by using recombinant BCGF and recombinant soluble CD23 material. It is possible that LT may be able to modulate CD23 levels, because high levels of LT are present in partially purified BCGF (Kehrl et al., 1987b). EBV-transformed lymphoblastoid cell lines (B-LCL) can be stimulated to proliferate by autocrine growth factors (Gordon et al., 1984). Swendeman and Thorley-Lawson (1987) reported that purified soluble CD23 stimulates proliferation of B-LCL and that autocrine growth activity in supernatants of B-LCL is specifically removed with antiCD23 MAb. They propose that EBV induces B cells to make autocrine CD23, which may function in EBV-mediated cell transformation. One EBV gene product that can initiate increased expression of CD23 is EBNA-2: The EBV-BL line, Louckes, when transfected with EBNA-2 but no other EBV genes, expresses elevated levels of CD23 protein and mRNA but shows no changes in the expression of other cell surface proteins, such as C3d receptors or activation antigens (Wang et al., 1987). Thus, the EBNA-2 gene product may directly or indirectly activate CD23 gene expression. However, EBNA-2 may not always selectively activate only CD23 and can also activate other B cellassociated molecules. Calender and co-workers (1987) have found that some EBV- lymphoma lines, when infected with EBV, also show changes in expression of, e.g., CD21, C3d receptors, and the B cell activation antigen Bac-1. Furthermore, some EBV+ BL, while expressing EBNA-2, are CD23- (Rowe et al., 1987). Recently, Bonnefoy and co-workers (1988) found that CD23 and class I1 DR molecules are closely associated on the surface of normal B cells or B cell lines. Some MAb specific for DR partially blocked the binding of IgE to CD23. CD23 was associated with DR but not DQ or D P molecules. The results are particularly intriguing since class I1 MHC may function as a transduction signal in B cells (see Cambier and Ransom, 1987).
G. CDw40/BLCa: RECEPTORS FOR B CELLPROGRESSION SIGNALS Recently, we and others defined 50- to 55-kDa polypeptides expressed on both normal B cells and on epithelial-derived malignan-
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cies (Chan et aZ., 1985; Paulie et al., 1985; Clark and Ledbetter, 1986a). Two MAbs, G28-5 and S2C6, were found to recognize the same epitope and to have similar functional activity (Gordon et al., 1987a) and were assigned to form a provisional cluster group, CDw40 (Ling et al., 1987). CDw40 is found on B cells and interdigitating cells but not on a range of nonhematopoietic normal tissues (Ledbetter et d., 1987d; Ling et al., 1987), but is expressed on melanomas and a variety of carcinomas and carcinoma cell lines, e.g., from the lung, colon, or breast (Ledbetter et al., 1987d). CDw40 is an acidic glycoprotein with an pI of 3.2 and is stable at low pHs or relatively high temperatures (Braesch-Anderson et al., 1986). Recently, Stamenkovic and co-workers (1988) isolated a cDNA encoding for the CDw40 protein using the expression vector-panning method described above. The gene encodes for a polypeptide 277 amino acids long containing a 20-amino acid signal sequence at the N-terminus and a 24-amino acid hydrophobic segment typical of transmembrane segments, about 172 amino acids from the N-terminus (Fig. 4d). Paulie and co-workers (1985) independently isolated the CDw40 protein and sequenced the first 35 amino acids at the N-terminus of CDw40. Their protein sequence matches the sequence predicted by the cDNA sequence and begins 20 amino acids after the first methionine, just after the end of the first hydrophobic domain. The fact that CDw40 has an N-terminal signal sequence indicates that the N-terminal region is oriented to the outside of the cell membrane. The predicted amino acid sequence of CDw40 has a highly significant homology with human nerve growth factor (NGF) receptor and a weaker yet significant homology with human growth hormone receptor and the neu oncogene. In particular, 19 of the 20 cysteine residues of CDw40 align with the cysteine residues of NGF receptor. These similarities strongly suggest that CDw40 is a receptor for a soluble factor. T h e approximately 172 amino acids in the N-terminal external region include 20 cysteines, implying that the region is tightly folded and has two potential N-linked glycosylation sites. The overall polypeptide portion of CD40 is about 28.3 kDa, indicating that about 20 kDa of the glycoprotein may be carbohydrate. The 60-amino acid cytoplasmic tail of CD40 has six threonines and serines, but no tyrosines, as potential sites for phosphorylation, and one threonine is a potential phosphorylation site for calmodulin kinase. We have proposed that the expression of CDw40 and MHC class I1 may be under common regulation (Ledbetter et al., 1987a). First, a comparison of serial tissue sections clearly shows that expression of CDw40 and class I1 MHC is at similar levels on both B cells and interdigitating cells (Ling et al., 1987). Second, the same competence
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LEDBETTER
signals that induce increased levels of class I1 MHC on B cells also induce increased expression of CDw40 (Ledbetter et al., 1987a; Clark et al., 1988c), including TPA, anti-Ig, anti-CD20, anti-Bgp95, and IL-4. This is true even though these same competence signals have very different effects on modulating expression of CD20 and CD23 Furthermore, acute lymphocytic leukemias that (Clark et al., 1988~). express little or no GDw40 are induced by low-molecular-weight BCGF to express high levels of both class I1 MHC and CDw40 (Ledbetter et al., 1987a; Cheerva et al., 1988). Finally, normal epithelial cells do not express CDw40 (Ledbetter et al., 1987d) but activated, dividing epithelial-derived tumors do. This suggests that, like class I1 MHC, both constitutive expression and the overall level of CDw40 expression is under regulatory control. Thus, it is possible that some of the same transactivating factors that regulate class 11 MHC also regulate CDw40. MAb to CDw40 can deliver a progression signal that augments the proliferation of activated B cells (Clark and Ledbetter, 1986a,b; Ledbetter et al., 1987a; Gordon et al., 1987b). Anti-CDw40 is costimulatory with competence signals including anti-IgM, anti-CD20, anti-Bgp95, and TPA, but is not costimulatory with IL-4 or lowmolecular-weight BCGF (Ledbetter et al., 1987a; Valentine et al., 1988; Clark et al., 1988~).The effects of anti-CDw40 can be distinguished from those of low-molecular-weight BCGF. For instance, some B cell malignancies, in particular follicular center cell lymphomas, can be stimulated with anti-CDw40 but not BCGF (Ledbetter et al., 1987a; Beiske et al., 1988). The properties of anti-CDw40 suggest that CDw40 may normally function as a receptor for a cell-cell or soluble growth signal. The tissue distribution of CDw40 does not correspond to any known growth factor receptors, but the CDw40 gene has clear homology with the NGF receptor. Inui and co-workers (1988) transfected the CDw40 gene isolated by Stamenkovic et al. (1988) into a murine pre-B cell line M12. A MAb to CDw40 stimulated CDw40' cells but not CDw40- pare i t M 12 cells to stop proliferating. In this system, the cytoplasmic tail of CDw40 was required for signal transduction (S. Inui, personal communication). The responsive transformant provided us with an indicator system for testing whether any existing growth factors could stimulate the CDw40+ transformant. No soluble factor yet tested (human IL-1, IL-2, IL-3, IL-4, IL-5, GM-CSF, IFN-a, IFN-P, IFN-.)I,PHA supernatants, and neuroleukin effected the proliferation of the transformant. Thus, our working hypothesis is that CDw40 is a receptor for a soluble factor not yet described.
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BLCa: B Lymphocyte Carcinoma Cross-Reacting Antigen
About the same time that anti-CDw40 MAbs were described, Chan and co-workers (1985; Yip et al., 1987a,b) described two MAbs, MA5 and MA6, specific for human B cells and carcinomas. The MAbs were generated by immunizing mice with B-cell-associated antigens recognized by a serum from a patient with nasollharyngeal carcinoma (NPC). Anti-BLCa MAbs detect carbohydrate-associated epitopes on a 55-kDa glycoprotein. Although BLCa and CDw40 have similar molecular weights and tissue distributions, they appear to be distinct gene products (Clark et al., 1988a): (1)CDw40 is expressed on carcinoma cell lines but BLCa is not; (2) L cells and a pre-B cell line transfected with CDw40 cDNA express CDw40 but not BLCa; (3) and antiCDw40-specific MAbs or heteroantisera, unlike anti-BLCa, do not block the migration of BLCa in gels. Peptide maps should reveal how related CDw40 and BLCa are. Both anti-CDw4O and anti-BLCa can provide progression signals for B cells activated by PMA or anti-Ig, indicating that CDw40 and BLCa have related functions in B cell activation. However, anti-BLCa, unlike anti-CDw40, is not co-stimulatory with anti-CDBO, implying that the CDw40 and BLCa progression signals are distinct. In sum, CDw40 and BLCa show strong similarities in size, function, and expression, and thus may function some way together in regulating cell growth. In 1979, Wang and co-workers, using a heteroantiserum, described a 54-kDa antigen, gp54, expressed on human B cells and B lymphoblastoid cell lines. Antisera to gp54 stimulated tonsillar B cells to proliferate; however, unlike anti-CDw40 or anti-BLCa MAb, which require activation signals to have an effect, anti-gp54 serum could stimulate tonsillar B cells without additional costimulants. This is probably because activated B cells were present in the tonsillar B preparation. In their discussion, Wang et al. mention that anti-gp54, like anti-CDw40 (Ledbetter et al., 1987d), reacts with carcinoma cell lines, indicating that gp54 may indeed be related to CDw40 and/or BLCa.
H. Bgp95: A UNIQUE95-kDa GLYCOPROTEIN ANTIGENINVOLVED IN B CELLACTIVATION We recently produced an antibody, G28-8, that was classified as CD39 by the third international workshop studies (Ledbetter et al., 1987c; Ling et al., 1987). However, our own studies showed that G28-8 recognizes a 95-kDa B cell-associated antigen (designated
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EDWARD A. CLAHK AND JEFFREY A. LEDBETTER
Bgp95) that is not related to the CD39 antigen (Valentine et al., 1988). The Bgp95 antigen contains N-linked carbohydrate, since it was 70 kDa after endoglycosidase F treatment. Furthermore, Bgp95 and CD39 showed different patterns of expression on cell lines, although both markers are not expressed on most BL lines (Valentine et al., 1988). The CD19 antigen, although similar in size to Bgp95, is also distinct because of differences in expression and function (see below). In functional studies, stimulation by G28-8 MAb or its F ( a b ' ) ~ fragments was distinct from that of antibodies binding to CD20, CD19, CD39, and CDw40 proteins. Anti-Bgp95 induced increased class 11 MHC expression on B cells and a Go to GI cell cycle transition, and it was synergistic with IL-4, PMA, anti-p, or antiCDw40 in stimulating proliferation of resting B cells (Clark et al., 1988c; Valentine et al., 1988). Bgp95 also induced an increase in [Ca2+lj in a subpopulation of tonsillar peripheral blood B cells. Although the Bgp95 MAb alone induced a steady increase in [Ca2+]i detectable even 1 to 2 hr after stimulation, cross-linking the G28-8 MAb with a second MAb specific for murine K light chains induced a rapid increase of [Ca2+Iiwhich peaked at 10 to 20 min and then declined (Fig. 6). The same conditions of cross-linking which increased the kinetics of the calcium flux abrogated the proliferative response, which otherwise followed coincubation of the MAb with BCGF or PMA (Valentine et al., 1988). Thus, conditions leading to rapid [Ca"li increase may not be as effective at stimulating B cell proliferation as conditions favoring a slower prolonged [Ca2+li rise. Although the Bgp95 molecule is present on activated buoyant tonsillar B cells, it did not trigger calcium fluxes in these cells. These results suggest that the Bgp95 protein may function in early B cell activation and that its signal mechanisms are altered by the activation state of the cell. Ill. Other Biochemically Defined Surface Molecules on Pre-B and/or B Cells
A. CD10: THECOMMON ACUTELYMPHOCYTIC LEUKEMIA ANTIGEN The common acute lymphoblastic leukemia-associated antigen (cALLA/CD10) was first defined by Greaves et al. (1975), using a rabbit polyclonal antisera, and later by Ritz et al. (1980), using a MAb. The results of initial studies suggested that CALLA expression was restricted to non-T, non-B ALL cells (Brown et d . , 1975; Ritz et al.,
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Time (min)
130
223 [CO'']
338 i
FIG.6. Bgp95 cross-linking regulates calcium concentration in resting B cells. Dense E- tonsillar B cells were indo-1 loaded and analyzed (Pezzutto et al., 1987d). (4) Calcium response in the first 10 min of stimulation. The response to 10 mg of ,MAb G28-8 anti-Bgp95 added at 2 min (-) is compared to the response from 10mg G28-8 at 2 min, followed by cross-linking with 40 mg of MAb 187.1 anti-rc added at 5.5 min. (---). The response to stimulation of surface IgM [lo pg F (ab'), anti-y] added at 2 min is shown (B) Mean calcium concentration of the population at 1 hr after stimulation. Control unstimulated cells (-) compared to 10 pg F (ab'), anti-p (--.), 10 pg G28-8 anti-Bgp95 (---), or 10 p g G28-8 plus 40 p g 187.1 (--) (Valentine et al., 1988). ( e - 0 ) .
1980). Subsequent studies, however, have shown that CALLA is also expressed on the surface of a wide variety of other normal and neoplastic cells types, including fibroblasts, renal epithelium, bone marrow stroma, granulocytes, lymphomas, and nonhematopoietic tumors (Greaves et al., 1980; Braun et al., 1983; Ritz et al., 1981; Carrel et al., 1983; Keating e t al., 1983; Metzgar et al., 1981; Platt et al., 1983; Cossman et al., 1983). The expression of CALLA by these diverse cell types is unlikely to be due to passive uptake of antigen, since cultured normal fibroblasts express CALLA (Braun et nl., 1983) and normal granulocytes synthesize CALLA (McCormaek et al., 1986; Pesando et al., 1986). The CALLA antigen has been characterized biochemically as a glycoprotein of approximately 100 kDa (Newman et al., 1981). The
118
EDWARD A. CLARK AND JEFFREY A. LEDBETTER
precise molecular weight varies, depending upon the source of antigen, most likely due to variations in carbohydrate content (Braun et al., 1983; Pesando et al., 1980; McCormack et al., 1986). CALLAexpression on pro- and pre-B cells but not mature B cells has aided the characterization of early B cell differentiation in fetal liver and bone marrow (Hokland et aZ., 1983). Pro-B cells are CALLA positive, but earlier progenitors measured in colony-forming assays (CFU-GM) are CALLA negative (Hokland et al., 1983). Little is known, however, of the function of the CALLA antigen. One report has indicated that granulocyte chemotaxis was inhibited by a CALLA/ CDlO MAb, whereas no effects on aggregation or degranulation were seen (McCormack et al., 1986). In addition, CALLA readily internalizes (modulates) in response to MAb, and the rate of internalization appears to vary depending on the affinity of the antibody used (Pesando et al., 1983; Braun et al., 1983; LeBien et al., 1982).
B. CD24 The first MAb made to CD24 was BA-1 (Abramson et al., 1981), and the CD24 cluster was established with MAb developed by Tedder and co-workers (1983). CD24 is expressed on B lineage cells and granulocytes but not on T cells or monocytes. CD24 is not restricted to hematopoietic tissues and can be found on, e.g., tonsillar epithelial cells, neuroblastomas cells, and fetal kidney nephron (Platt et al., 1983; Hsu and Jaffe, 1984; Stockinger et al., 1987). Some CD24 epitopes are expressed on plasma cells, vascular endothelium, and some myeloid and T cell leukemias (Nadler, 1986; Ling et al., 1987; Stockinger et al., 1987). Nevertheless, anti-CD24 MAbs have found use in evaluating B cell tumors, since CD24 is expressed on almost all B lineage cells and malignancies, with the notable exception of hairy cell leukemias (e.g., Melink and LeBien, 1983; Nadler, 1986; Dorken and Moldenhauer, 1987). The CD24 molecule is a single-chain sialoglycoprotein that migrates on gels as a broad band at about 40 to 45 kDa (Pirruccello and LeBien, 1986), most likely because of heterogeneity in its glycosylation. Initially, CD24 was thought to be three chains of 45,55, and 65 kDa (Pirruccello and LeBien, 1985), but the two higher molecularweight bands were subsequently shown to be artifactual IgG and IgM heavy chains (Pirruccello and LeBien, 1986).The association of CD24 with Ig suggests that CD24 might be a receptor for immunoglobulin. However, anti-CD24 did not bind to 45-kDa Fc receptors isolated
B CELL-ASSOCIATED SURFACE MOLECULES
119
from B cells (Pirruccello and LeBien, 1986). CD24 is similar in size to CD37, but has a different tissue distribution (Fig. 3). One possible clue to the still unknown function of CD24 is the fact that CD24 has several epitopes with characteristic expression, for example, expression on myelomas, neuroblastomas, and S6zary cells (HB8, epitope a), expression of S6zary cells and neuroblastomas (VIBES, epitope b), and expression on neuroblastomas (VIBC5, epitope c) (Stockinger et al., 1987; Nathan et al., 1987). Epitope c is lost rapidly after B cells are activated, and MAbs to epitope c do not block differentiation or costimulate with TPA in proliferation assays. In contrast, epitope b is not lost after B cells are activated and MAbs to epitope b inhibit B cell differentiation and costimulate in proliferation assays with TPA (Engle et al., 1987; Rawle et al., 1987; Rabinovitch et al., 1987). Other MAbs to CD24, including OKB2, have also been reported to inhibit pokeweed mitogen-induced B cell differentiation (Mittler et al., 1983; Rawle et al., 1987). Further work defining more precisely the expression and regulation of CD24 epitopes should help to clarify the function of CD24. C. CD37 In the second international workshop, based on cross-blocking studies, three MAbs, H H 1 (Funderud et al., 1983),HD28 (Dorken et al., 1986b), and BL14 (Brochier et al., 1984),were clustered into a new group, but the antigen recognized was not biochemically defined (Clark and Einfeld, 1986). In the third international workshop, the above MAbs and others were used to biochemically define CD37 as a 40- to 45-kDa glycoprotein (Ling et al., 1987). This marker is strongly expressed on mature B cells, B cell lines, and most B cell malignancies tested, but is not on B cell precursor cells or plasma cells (Brochier et al., 1984; Pallensen and Hager,1987; Ledbetter et al., 1987b). In normal hematopoietic tissues, Pallensen and Hager (1987) found CD37 weakly expressed on thymocytes, neutrophils, macrophages, Langerhans cells, and Kupffer cells. It was also weakly expressed on some nonhematopoietic tissues such as astrocytes, some neurons, and bladder epithelium. Others have also reported that CD37 is weakly expressed on some T cells and myelomonocytic cells (Dorken and Moldenhauer, 1987). However, because CD37 is most strongly expressed on mature B cells, it is a useful B cell marker. Within 24 hr after B cells are activated with TPA, CD37 is lost from the cell surface (Schwartz et al., 1987), and thus appears to be a marker for mature resting B cells.
120
EDWARD A. CLARK AND JEFFREY A. LEDBETTEH
Schwartz and co-workers (1987) found that under both reducing and nonreducing conditions CD37 migrates over a broad range, from 36 to 52 kDa, depending on the cell line type. However, after treatment with endoglycosidase F to remove N-linked sugars, CD37 was reduced in size to 25 kDa and had no O-linked sugar chains. Previously, Zipf and co-workers (1983) had described a MAb 41H.16 that recognizes a 40-to 45-kDa B-cell-associated surface molecule. The epitope recognized by this MAb is different from that recognized by antiCD37 MAb and, unlike the CD37 epitope, is expressed on thymic epithelial cells and cell lines not expressing CD37 (Pallesen and Hager, 1987; Ledbetter et al., 1987b). Thus, 41H.16 may recognize a distinct epitope or antigen. The function of CD37 is not known. Some anti-CD37 MAbs weakly costimulate with anti-IgM and BCGF (Ledbetter et al., 1987b), but this effect is not dramatic. Also, anti CD-37 MAbs neither induce [Ca2'li fluxes (Rabinovitch et al., 1987) nor affect the induction of antibody-producing cells (Rawle et al., 1987). Fortunately, 1. Stamenkovic and B. Seed (personal communication) have recently isolated the cDNA encoding for CD37, which should be useful for defining the function of CD37.
D. CD39 In 1982 Rowe and co-workers described a MAb, AC2, that reacted with an 80-kDa surface polypeptide expressed principally on B lymphoblastoid cell lines but not on endemic BL lines. In the third international workshop, we found that our workshop MAb, G28-10, cross-blocked the binding of AC2 and also precipitated an 80-kDa molecule (Ledbetter et al., 1987c), enabling a new CD39 group to be formulated. Initially, MAb G28-8 was placed in the CD39 cluster, but further studies revealed that G28-8 recognizes a distinct larger surface polypeptide with similar yet distinct tissue distribution (Valentine et al., 1988; see Section 11,H). CD39 is expressed on all blood B cells, some tonsillar B cells, and weakly on monocytes. CD39' B cells are found in the follicular mantle and marginal zones of lymphoid tissues, but germinal center B cells are CD39- (Ling et al., 1987; Lueders and Feller, 1987). This restricted pattern is of particular interest since CD39, like CD23, is expressed on virtually all B-LCL but is not found on most BL lines (Rowe et al., 1982, 1987; Gregory et al., 1987a). CD39 is also found on some T cell clones, plasma cells, subepithelial macrophages, and on some smooth muscle and endothelium (Ling et al., 1987). CD39 is not expressed on pro-B leukemia, but is expressed
B CELL-ASSOCIATED SURFACE MOLECULES
121
on some pre-B leukemias and on a range of B-CLL, immunocytomas, centrocytic lymphomas, and plasmacytomas (Lueders and Feller, 1987). CD39 is a heavily glycosylated glycoprotein of about 80 kDa (Rowe et al., 1982; Ledbetter et al., 1987c) with a 55-kDa core when N-linked sugars are removed (Valentine et al., 1988);CD39 MAbs recognize an epitope expressed on the 55-kDa polypeptide. A cDNA encoding for CD39 has been recently isolated by I. Stamenkovic and B. Seed (personal communication) and is currently being evaluated. The function of CD39 is not yet known. G28-10 anti-CD39 cannot stimulate [Ca2'Ii fluxes and has little or no effect on the induction of B cell proliferation or differentiation, while G28-8 anti-Bgp95 stimulates [Ca2+Iiand increased RNA synthesis in B cells and inhibits Ig secretion in some assays (Rabinovitch et al., 1987; Rawle et al., 1987; Valentine e t al., 1988). Rowe and co-workers (1987) have found that EBNA-1' EBNA-2' BL express CD39 and CD23 and grow in clumps, while EBNA-1' EBNA-2- BL do not express CD39 and CD23 and grow as single-cell suspensions. This result implies that CD39 may be regulated by EBV genes and/or may contribute to homotypic adhesion in B cell lines. However, since markers other than CD39 and CD23 are also expressed on BL expression EBNA-2 and growing in clumps, it is also possible that CD39 and CD23 expression simply reflects a change in the overall differentiated state of the transformed B cells.
E. BLA: A GLYCOLIPID GLOBOTRIAOSYLCERAMIDE A MAb, 38.13, was produced by immunization with Burkitt's lymphoma cells and was found to react with Burkitt's lymphomas but not with normal or activated B cells or B cell CLLs or non-Burkitt's B cell lymphomas (Wiels et al., 1981, 1982).The antigen recognized was soluble in chloroform and methanol and was identified as a glycolipid globotriaosylceramide (Lipinski et al., 1982; Nudelman et al., 1983), also known as the rare blood group antigen PK(Fellows et al., 1985). The enzymatic basis for BLA expression on the cell surface is due both to synthesis by a-galactosyl transferase activity and to membrane organization controlled through interaction with sialosyl residues of a second glycoconjugate (Wiels et al., 1984a). Although normal B cells were originally thought to be negative for BLA expression, a small subpopulation of B cells in germinal centers has been identified as BLA+ (Gregory et al., 1987b; Fyfe et al., 1987). These cells have been postulated to be the normal counterpart of the
122
EDWARD A. CLARK AND JEFFREY A. LEDBETTER
Burkitt’s tumor cells (Gregory et at., 1987b). immunotoxins prepared with the 38.13 antibody using ricin A chain or gelonin are effective with extremely rapid kinetics (50% inhibition of protein synthesis in 3 hr) (Wiels et al., 198413).The BLA immunotoxin studies also showed in some cell lines that BLA- cells by conventional phenotyping methods were specifically killed by the BLA immunotoxins, most likely reflecting their expression of very low levels of BLA. The expression of BLA on Burkitt’s lymphomas was down-regulated by treatment with phorbol esters, suggesting that BLA represents a differentiation antigen for a very restricted stage of B cell differentiation (Balana et al., 1985).
F. OTHERMOLECULESEXPRESSED ON RESTINGB CELLS In this section we describe a series of interesting B cell-associated surface molecules that have not yet been given CD nomenclature and are not yet as comprehensively studied as the antigens above. We describe only those molecules that are clearly distinct from the major CD markers, and have not discussed those MAbs made to B cellassociated markers not yet biochemically defined. Common leukocyte markers and other markers strongly expressed on both B and non-B lymphocytes are also not discussed. Table I1 lists some of these antigens and their characteristic properties. A number of these markers are also summarized succinctly by Zola (1987). In 1978 Balch and co-workers described with a heteroantiserum a 65-kDa molecule expressed on human B cells. Subsequently, Wang and her co-workers described a B cell-associated polypeptide of a similar size (68 kDa), also found on immature and mature B cells but no on plasma cells (Miki et al., 1982; Knowles et al., 1983; Wang et al., 1984). Of interest was the finding that their MAb induced the B-LCL, CESS, to produce more IgG (Miki et al., 1982). B. T. Huber and co-workers have previously defined in the mouse a 68-kDa B-cellassociated surface marker, Lyb3, and have shown that anti-Lyb3, like anti-BL2, promotes Ig secretion in B cells (see Kemp et al., 1983). Thus, based on both functional and biochemical similarities, it is likely that BL2 recognizes the Lyb3 homologue in humans. Autoantibodies in serums obtained from Wiskott-Aldrich patients also have been reported to promote B cell differentiation in uitro (Brouet et al., 1980), so it would be of interest to determine whether or not these sera recognize this 68-kDa B cell marker. Wang and co-workers, using MAb BL3, have described a 105-kDa B cell-associated polypeptide that has a more restricted B cell distri-
B CELL-ASSOCIATED SURFACE MOLECULES
123
TABLE I1 HUMAN B CELL-ASSOCIATED SURFACEPOLYPEPTIDES NOT YET GIVENCD NOMENCLATURE Size (kDa)
Antibody ~~
~
Antigen expressionlcharacteristics ~~
Reference
~
B Cells, pre-B ALL Early and mature B cells, MAb
Anti-BDA" BL2
65 68
FMC7 BL3 Anti-gp54"
105 105 54
41H.16 KB6 1
39-43 35-45
FMCl OKB4 Ki-B3
95 87 431220
stimulates Ig secretion Mature subset Mature B subset B cells/weak on T cells, antiserum stimulatoly B cells, granulocytes Mantle B cells, monocytes, granulocytes, macrophages Resting/activated B cells Most mature B cells IgD+ B cell subset
L23 L26
205 30133
IgD+M' B cells Pan-B marker
Balch et al. (1978) Miki et al. (1982) Brooks et at. (1981) Wang et al. (1984) Wang et al. (1979)
Zipf et al. (1983) Pulford et al. (1986) Brooks et al. (1980) Mittler et al. (1983) Leuders and Feller (1987) Takami et al. (1985) Ishii et al. (1984)
~~
a
Heteroantiserum and not MAb.
bution than does BL2. Similarly, Brooks and co-workers (1981; Zola, 1987) have described with MAb, FMC7, a 105-kDa B cell marker that is on a restricted B cell subset. Tedder and co-workers (1985a) also have developed a MAb, HB-4, that reacts with a biochemically undefined marker on a restriction subset of B cells. It will be important to compare these MAbs in a future workshop to determine whether or not they recognize the same structure. As already mentioned, Wang and co-workers (1979) developed antiserum to a 54-kDa polypeptide, which, based on its size, tissue distribution, and possible function, is likely to be CDw40 or BLCa (see Section 11,G). Zipf and co-workers (1983)made a MAb, 41H.16, that recognizes a 39- to 43-kDa glycoprotein and has a number of properties in common with CD37 (see Section 111,C). Pulford and co-workers (1986) have also made a MAb, KB61, that also reacts with a heavily glycosylated antigen of about 35-45 kDa and that is also found on granulocytes and resting B cells not activated B cells. Given their similarities, the 41H.16 and KB61 MAbs were compared, and based on sequential immunoprecipitation analyses, have been found to recognize the same molecule (D.Y. Mason, personal communication). Brooks and co-workers (1980) were the first group to describe a
124
EDWARD A. CLARK AND JEFFREY A. LEDBETTER
MAb to a human B cell-associated marker (accepted July, 1979), which they called FMC1. The F M C l marker is expressed on mature B cells but no on pre-B cells or a pre-B ALLs. Zola (1987)reported that F M C l recognizes a 95-kDa glycoprotein, a size similar to that of both CD19 and Bgp95. CD19, unlike FMC1, is expressed early in B cell development, and Bgp95, unlike FMC1, is not expressed on BL lines. Mittler and co-workers (1983) have also described a B cell-associated marker, OKB4, of a size similar (87 kDa) to that of CD19, Bgp95, and FMC1, but without direct comparisons it is difficult to determine the relationship, if any, of these markers. Two groups have described 205- to 220-kDa polypeptides selectively expressed on B cells that share features with the murine B220 marker (Coffman and Weissman, 1981) and the common leukocyterestricted marker CD45R first described by Dalchau and Fabre (1981). The MAb Ki-B3 (Lueders and Feller, 1987) precipitates proteins 43 and 220 kDa in size expressed on IgD' B cells present in mantle zones but not in marginal zones and weakly in germinal centers (Lueders and Feller, 1987; et aE., Ling et al., 1987). Ki-B3 also reacts with monocytes and some non-T All, BL, and B-LCL, but not with mature T cells. Takami and co-workers (1985) described a MAB, L23, that reacts with a similarly sized surface marker (205 kDa) also expressed selectiveIy on mantle zone B cells and only on some BL and B-LCL (Ishii et al., 1986). It is quite possible that L23 and Ki-B3 recognize the same molecule. The Ki-B3 MAb did not induce [Ca2+lifluxes but was a strong costimulant with anti-Ig to induce B cell proliferation (Rabinovitch et al., 1987). Furthermore, Ki-B3 clearly inhibited IgG secretion by the CESS cell line (Rawle et al., 1987). Lueders and Feller claim that Ki-B3 recognizes a form of the leukocyte common family of molecules (Ralph et al., 1987; Streuli et al., 1987). This is of particular interest given that anti-CD45R MAbs also are good costimulants, albeit with anti-CD3 in inducing T cell proliferation (Ledbetter et al., 1985b). Thus, it is possible that different forms of the common leukocyte family are selectively expressed on distinct lymphoid lineages yet have some common function in regulating cell activation. Ishii et al. (1984, 1986) defined a MAb L26 that precipitates two B-cell-associated polypeptides of about the same size as CD20,33 and 30 Kda, but, unlike CD20, the L26-defined polypeptides are expressed in the cytoplasm and not on the cell surface and are expressed in pro-B ALL and in plasmacytomas (Ishii et al., 1986; Lueders and Feller, 1987).
B CELL-ASSOCIATED SURFACE MOLECULES
IV. Receptors on
125
B Cells for Cytokines
As discussed previously, it is unlikely that many of the CD markers described above are receptors for known cytokines (Clark and Ledbetter, 1986b). I n this section we discuss cytokine receptors expressed on B cells and their possible relationship and interaction with B differentiation markers that are expressed at high levels on B cells. We do not describe receptors on B cells for nutrients or hormones. We refer the reader to a review by Plaut (1987). A. IL-2 RECEPTORS
IL-2 receptors are expressed on activated B cells but not on resting B cells (Tsudo et al., 1984; Waldmann et al., 1984; Jung et al., 1984). These receptors bind anti-CD25 (TAC) MAb and radiolabeled IL-2 (Waldmann et al., 1984). The IL-2 receptors on B cells are functionally active, since anti-TAC blocks B cell differentiation in response to PWM (Depper et al., 1983), and IL-2 enhances the growth and differentiation of activated B cells (Muraguchi et al., 1985; Jung et al., 1984; Mittler et al., 1985; Suzuki and Cooper, 1985; Nakagawa et al., 1985). B cell malignancies such as hairy cell leukemia and B cell lymphomas also express functional IL-2 receptors (Korsmeyer et al., 1983b; Laurent et al., 1986). B. IL-4 RECEPTORS B-cell-stimulating factor 1 (BSF-1, IL-4) was originally characterized as a cytokine that is costimulatory with anti-IgM to augment B cell proliferation (Howard et al., 1982), but it is now known that BSF-1 has a number of biological effects on a variety of cell types other than B cells (Paul and Ohara, 1987). Using either radiolabeled recombinant (Park et al., 1987a) or natural murine BSF-1 (Ohara and Paul, 1987), the receptors for BSF-1 have been found on a broad number of tissues at levels ranging from approximately 30 to 3000 receptors/cell. More recently, Park et al. (1987b), using125I-labeled human recombinant BSF-1, have characterized human BSF-1 receptors. Radiolabeled BSF-1 bound rapidly and specifically to a single class of high-affinity receptor (100 to 2500 receptors/cell), with a K , of about 0.5-1.Ox lo-'' M . Human BSF-1 receptors were expressed on a range of cell lines, such as B cell, T cell, monocyte, or bladder-derived tumor cell lines, and also bound to normal fibroblasts and epithelial cells. Blood
126
EDWARD A. CLARK AND JEFFREY A. LEDBETTER
lymphocytes expressed low levels of BSF-1 receptors, and activation induced increased expression. Using affinity cross-linking, the human BSF-1 receptor was found to be about 140 kDa in size, which is different from the 60- to 70-kDa size reported for the murine BSF-1 receptor (Ohara and Paul, 1987; Park et al., 1987a).The reason for this difference is not clear but one possibility suggested by Park et al. (198713)is that the murine BSF-1 receptors isolated were degraded by proteases.
C. IL-6 RECEPTORS The receptor for human BSF-2 (IL-6) has also recently been characterized (Taga et al., 1987) and resembles the BSF-1 receptor in several of its features. Radiolabeled BSF-2 also bound specifically and rapidly to a single class of high-affinity receptors (80 to 11,000 sitedcell), with a K , of about 2 ~ 1 0 M - .~ BSF-2 ~ receptors were expressed at low to moderate levels on EBV-transformed lymphoblastoid cell lines but were not detectable on Burkitt’s lymphomas lines of T cell lines. A plasmacytoma cell line, U266 (22,000 sitedcell), expressed the highest level of BSF-2 receptors, and some nonlymphoid lines expressed detectable levels. Activated B cells expressed BSF-2 receptors but resting B cells did not. In contrast, resting T cells expressed more BSF-2 receptors than did activated T cells. The results suggest that for B cells BSF-2 receptors are only expressed after activation and increase as B cells mature to plasma cells. This is in accord with the known effects of BSF-2, which stimulates activated B cells to mature into antibody-producing cells (Kishimoto and Hirano, 1988). D. RECEPTORSFOR OTHERFACTORS
A number of well-defined factors such as IL-1 (Lipsky et al., 1983; Falkoff et al., 1983), IFN-a (Harfast et al., 1981; Peters et al., 1986), IFN-7 (Romagnani et al., 1986), and transforming growth factor /3 (Kehrl et al., 1987b), have been reported to modulate B cell proliferation or differentiation. High-affinity receptors for IL-1 have been detected at low levels (100-200 sitedcell) on B cells and B cell lines (Dower et al., 1985; Matsushima et al., 1986), and this receptor is about 60 kDa in size. The B cell-associated receptors for the other factors require further characterization. Maize1 and co-workers have characterized a 12-kDa BCGF and purified it to homogeneity (Mehta et al., 1985). This iodinated BCGF
B CELL-ASSOCIATED SURFACE MOLECULES
127
(low) binds to high-affinity receptors expressed on activated B cells but not on resting B cells (Mehta et al., 1986). Other interleukins, including IL-1 and IL-2, and IFN-y did not block the binding of the BCGF (low), and the BCGF (low) receptors were expressed on cells not expressing IL-2 receptors. Since both LT and TNF bind to receptors on activated B cells and have BCGF activity (Kehrl et al., 1987a,b), it is necessary to determine whether the 12-kDa BCGF of Mehta et al. is LT or TNF or binds to the same or a different receptor than LT and TNF. Ambrus and co-workers have characterized a 60-kDa BCGF produced by certain B and T cell lines (Ambrus and Fauci, 1985; Ambrus et al., 1985). This BCGF (high) bound to activated B cells but not to activated T cells or resting T or B cells, and the binding of the BCGF was specifically inhibited by BCGF but not by IL-2 (Ambrus et al., 1985). What might be the relationship between cytokine receptors and the CD receptors discussed in this review? The IL-1, IL-4, and IL-6 receptors are expressed in very low densitites and thus are probably not related to known CD antigens, which are present in higher numbers. However, the high-affinity receptor for IL-2 is composed of two chains (Smith, 1987). Thus, it is possible that some growth factor receptors have one chain expressed at high levels on resting cells, and another chain with more limited expression. Some CD receptors might function as components or subunits of this kind of growth factor receptor. However, we believe it is more likely that many of the known pan-B markers will prove to be receptors of cell surface-bound ligands, particularly since they are expressed at such high levels: high-affinity receptors for soluble factors tend to be expressed at low levels (10' to 103 sitedcell), while surface molecules involved in cell-cell interactions with cell-bound ligands have lower receptor affinities but are expressed at higher levels on cells (lo4 to lo5 sitedcell). V. Other Surface Molecules Expressed on Activated B Cells
IL-2 receptors were found on activated T cells but not on resting T cells (see Cantrell and Smith, 1984), so it was possible that receptors of B cell-stimulating factors might also be selectively expressed on activated B cells. As described above, while this is true for IL-2 and BCGF (low) receptors on B cells, this is not the case for B cell IL-1, IL-4 or IL-6 receptors. Nevertheless, a number of MAbs have been made that react selectively with structures on activated B cells (Table
128
EDWARD A. CLARK AND JEFFREY A. LEDBETTER
TABLE 111 SURFACE MOLECULESSELECTIVELY EXPRESSED ON ACTIVATEDB CELLS Antigen Antibody Early markers IgM MAb56“ B7 AB-1
Size (kDa)
60 60 Unknown
Ba
Unknown
Bac-1
Unknown
LB-2
76-85
Expression/characteristics
Activated B cells by 18 hr, IgM binding protein Activated B cells by 24 hr Rapidly expressed on activated B cells, 3-12 hr Rapidly expressed on activated B cells, 6-12 hr Activated B cells, detect at 16-24 hr Increased on activated B cells by 16 hr, I-CAM-1
Reference Sanders et al. (1987) Freedman et al. (1987) Jung and Fu (1984) Kikutani et al. ( 1 9 8 6 ~ ) Suzuki et al. (1986) Clark et al. (1984)
Late markers
B5
75
BB-1
37
BLAST-1
45
HC2
52-63
a
Activated B cells, peak of expression on day 3 Activated B cells, peak at 5-7 days after activation Activated B cells, peak at 3-4 days after activation Some resting B, elevated after activation, day 4
Freedman et al. (1985) Yokochi et aE. (1982) Thorley-Lawson et al. (1982) Posnett et al. (1984)
Various IgM monoclonal proteins bind to this marker.
111). The functions of most of these “activation” antigens are not known. It is possible they function as receptors for signals that drive activated B cells to enter S phase, divide, and/or differentiate into antibody-producing cells. Alternatively, some of these molecules may function to regulate specific adhesion and migration of activated B cells during their interactions with accessory cells of differentiation into plasma cells. In this section we have divided the activation markers into those that are expressed relatively early after B cells are activated and those that appear to be expressed somewhat later, perhaps after cells leave the S phase. It should be noted that “activation” antigen is a somewhat loosely used relative term. Class I1 MHC, CD23, and CDw40 are expressed at lower levels on resting B cells and have dramatically higher expression on activated B cells. Furthermore, many studies describing “activation” antigens not on resting B cells have used relatively insensitive detection techniques, such as cell sorter analyses incapable of detecting lo6 kDa. The DUPAN-2 antigen has been reported to be expressed in pancreatic, stomach, gall bladder, and bile duct carcinomas (Metzgar et al., 1984). Reactivity of the antibody was sensitive to both sialidase and protease, and its epitope structure was assumed to consist of both O-linked carbohydrate and peptide (Lan et al., 1987). The antibody OC 125, established after immunization with an epithelial cell line (OVCA433) isolated from a patient with serous papillary cystadenocarcinoma (Bast et al., 1981), reacted with ovarian carcinoma cell lines and cryopreserved ovarian cancer tissue (12 of 20 cases). The antigen is also susceptible to sialidase, and was claimed to be a mucin-type glycoprotein (Klug et al., 1984).Another MAb, OM-1, directed to ovarian cancer cells, defines the high-molecular-weight glycoprotein ( M , 360 kDa) antigen SGA, which is highly expressed at the surface of ovarian cancer cells and sebaceous gland epithelia (DeKretser et al., 1985). A number of MAbs defining breast cancer-associated antigens have been prepared by two methods, one utilizing breast cancer cell lines or membrane fraction prepared from metastatic breast cancer cells, the other utilizing human milk fat globule membrane as immunogen. Interestingly, antigens defined by these approaches have been identified as high-molecular-weight mucin-type glycoproteins; a part of the epitopes defined by the various antibodies could be associated
TABLE V MONOCLONAL ANrIaoDrcs DIHECTEU TO TUMOR-ASSCXIATEU G1.YCOPROTEIN CAHBOHYUIMTE CIIAINS" ~~
Antigen
Antibody
Immunogen
Tn
NCC-LU-35, NCC-LU-81
Squamous lung carcinoma LU65
Sialyl Tn
B72.3
Breast cancer mernhranc
Lung cancer pleural eihrsion
MLS 102 TKH-I, TKH-2
Colonic Ciinwr Ovinc submarillary mucin
L-6
Lung
adenocarcinomit
cells Pancreatic cancer
DUPAN-2
Pancreatic cancer
Ovarian cancer
OC125
Ovarian epithelial cell OVCA433 Ovarian cancer
OM-1
Specificity
GalNAcal + 0 + Ser/Thr (Tn antigen)
Lung, gastric colonic cancer; cross-react with A antigen Colonic and breast cancer
1
Lung? hrt:;ist,
-
SdThr
Unidentified glynoplntt:in
and
HMFG-142
115D8
D73
Human milk fat glohule membrane Human milk lilt plohiile meinbnne Bredst cilncer rnem1,rarie
~~
Knrosaka et (11. (1987); Kjeldsen et uZ. (1988)
Hcllstrorn et a!. (1986a); IIellshijrrl ut
d.(1986b)
nvarian curcinoma Pancreatic/gastric cancer Ovarian canwr
Sialidase sensitive, nnidentified Sialidase sensitive, nnidentified
Metzgar et al. (1982); L m et al. (1987) Bast et al. (1981); Hug et d.(1984); DeKretser et al.
Breast cancer
Mncin-type glycoprotein
Bnrchell et
Hrrast, colorwtd, Inng canc!cr,
MAM6 rnncin glyctipnitcin
Hilkcns et al. (1986)
-
Ovarian cancel
cell Breast cancer
Hirohashi e t al. (1985)
Johnson et al. (1986)
NeuAca2
6 C.alNAi:oI -+ 0
colon,
Reference
Structure
(1986) (11.
(1983)
Krifr ct 01. (19M)
Only muliptiant breast cancer (not benign adenoma) was positive ~~
~~~~~~
~~
" Crowreacts wcakly with some glycolipids, but major epitopc is prcscnt i n glycoprntcin (H. Kojinia, E.Nridellriari, S. Ilakonwri, I. IIellstrijiii, and K.-E. Hellstrom, unpublished observations).
GLYCOSYLATION IN TUMORS AND TUMOR ANTIGENS
289
with oligosaccharides and the other part of the epitopes could be in the protein moiety of mucin glycoproteins, although none of the epitopes has been clearly identified chemically. MAb F36122 was generated after immunization with breast tumor cells, and showed strong reactivity with adenocarcinoma of the breast and ovary. The antigen seems to be associated with a ductular lineage of breast adenocarcinoma, but occurs on a limited number of normal ductal structures (Papsidero et al., 1983). The antigen was purified from malignant effusions and was found to be a high-molecular-weight glycoprotein ( M , > 300 kDa) highly reactive with wheat germ lectin. Its antigenicity was resistant to heat and acid treatment and was insensitive to sialidase, but was highly susceptible to base treatment (Papsidero et al., 1984). The antibody B72.3, established after immunization with metastatic breast cancer cell membrane, was reactive no: only with breast cancer but also a number of other gastrointestinal tumors, particularly colonic cancer; however, it showed no significant reactivity with various norma1 tissues (Colcher et al., 1981; Nuti et at., 1982; Stramignoni et al., 1983). The ar+;gen was identified as a high-molecular-weight glycoprotein with MI 220-400 kDa ( Johnson et al., 1986), sensitive to sialidase. The epitope structure was clearly identified as sialyl 2 + 6 N-acetylgalactosaminyl (Y + O-Ser or -Thr, i.e., sialyl Tn (Kjeldsen et al., 1988). Another antibody, DF-3, was raised against the membrane-enriched fraction of a human breast carcinoma cell line, and the antigen glycoprotein (MI 290 kDa) was detectable at the cell surface of human breast carcinoma. Interestingly, the antibody clearly distinguishes malignant and benign breast lesions. Cytoplasmic staining has been observed with 40 of 51 (78%) breast carcinomas, but only 1 of 13. fibroadenoma or fibrocystic disease specimens, i.e., the expression of this glycoprotein antigen is closely related to malignancy (Kufe et al., 1984). The antibody NCRC11, raised by immunizing dissociated human mammary carcinoma cells, showed a remarkable association with breast cancer cells (positive staining of 119 of 126 tumors tested). Expression of this antigen was claimed to be of prognostic valpe. The patients whose tumors exhibited intense staining had an improved survival compared to those with less intensely stained tumors (Ellis et al., 1985). Based on biochemical similarity between actively proliferating breast epithelial cells in breast carcinoma and human milk fat globule membrane, a number of studies have been focused on the immunization of mice with human fat globule membrane followed by establishment of MAbs. Some of these antibodies showed a remarkable
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SEN-ITIROH HAKOMORI
association with human breast cancer cells. Antibodies HMFG-1 and -2 react with breast, ovarian, and other carcinomas, but not with tumors from mesenchymal tissues (Burchell et al., 1983), and are directed to a large mucin-type molecule present in human milk and lactating human mammary epithelial cells (Shimizu and Yamauchi, 1982). HMFG-2 recognized an extremely heterogeneous group of glycopi-oteins of M , 80-300 kDa, in contrast to HMFG-1, which recognized only high-molecular-weight ( M , 300 kDa) glycoproteins. Metastatic and malignant potential is closely related to expression of HMFG-2 (Burchell et al., 1983). Similarly, antibody 115D8, raised against milk globule membranes, defined an epithelial membrane marker glycoprotein, MAM-6. This antigen was also defined by other MAbs, and is associated not only with breast carcinoma but also a large variety of human malignancies such as colorectal, lung, and prostate carcinoma, melanoma, and lymphoma (Hilkens et al., 1986). A similar approach was used by the research groups of Ceriani et al. (1983) and Foster et al. (1982). The antibodies established were directed to human mammary epithelial cell membranes, and were highly reactive with an antigen closely associated with breast carcinoma. The antibody BLMRL series established by Ceriani et al. (1983) defines glycoproteins with M , 46, 70, and 400 kDa. MAbs were raised against human epidermoid carcinoma A431 cells. One of the antibodies (AR-3) defines a highly glycosylated glycoprotein antigen (CAR-3). This antigen was highly expressed in gastric adenocarcinoma, pancreatic adenocarcinoma, cervical squamous cell carcinoma, uterine endometrial carcinoma, mucinous cystadenoma, and cystadenocarcinoma. It was weakly expressed in normal epithelium from stomach and breast, but is highly expressed in normal testis. Its epitope structure appears to be carbohydrate but has not been defined (Prat et al., 1985). All these tumor-associated mucin-type glycoproteins show a tendency to be released into serum, and some of them have been claimed to have diagnostic value (see Section X). Because of the extreme complexity and heterogeneity of mucin-type glycoproteins, none of the epitope structures, except Tn and sialyl Tn, has been clearly identified. Recently, however, genes encoding core proteins of mucin-type breast cancer antigen were cloned from a cDNA library isolated from breast cancer cells, and expressed in hgtll. These core proteins without glycosylation show clear reactivities with some of the MAbs described above, e.g., DF3 (Abe et al., 1988; Siddiqui et al., 1988) and SM3 (an antibody to HMFG) (Taylor-Papadimitriou et al., 1988), and with antibodies to MAM-6 antigen (Hilkens et al., 1988).
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Undoubtedly, many MAbs defining tumor-associated mucin are directed to the protein core, yet some of the antigenic activities could be fully maintained on glycosylation. A typical example of a polypeptide epitope influenced by glycosylation is described in the following section.
E. TUMOR-ASSOCIATED PEPTIDEANTIGENSWHOSEEPITOPE BY GLYCOSYLATION STRUCTURE Is INFLUENCED Fibronectins consist of multiple isotypes showing different molecular weights and degrees of glycosylation. Plasma fibronectin (pFn) showed lower molecular weight than those released from fibroblasts to their culture media, and those present in pericellular matrix of cultured fibroblasts, which are called cellular fibronectin (cFn). Fibronectin secreted from transformed cells (tFn) showed a molecular weight similar to that of cFn, but showed a different glycosylation pattern (Murayama et al., 1984; Nichols et al., 1986). Recently, MAb FDC6, reacting specifically with cFn and tFn but not pFn, was established. This antibody did not react with fibronectins extracted from normal adult tissues, but did react with those isolated from fetal tissue, placenta, and cancer tissues. Thus, a structure or structures defined by MAb FDCG reflects oncofetal status of fibronectin, and the fibronectins reacting with this antibody were termed oncofetal fibronectins (onfFn), while those not reacting with it were termed normal fibronectins (norFn). The structure carrying the FDCG epitope has been found in the domain between “Hep2” and “Feb2,” and is within the type 111 connecting segment (IIIcs). This region was isolated and further fragmented by proteolysis, and an active fragment was isolated. The minimal structure that reacts with FDCG antibody is valyl-threonyl-histidyl-prolyl-glycyl-tyrosine(VTHPGY) 0glycosylated at threonine (T). The peptide VTHPGY, or any peptide containing this sequence, did not react with FDC-6 antibody. The structure of sugars involved in this O-glycosylation is a regular Gal01 + 3GalNAca linkage, carrying one or two sialic acid residues, i.e., ordinary short O-linked structures (Matsuura et al., 1988). Results of these studies clearly indicate that O-glycosylation is important in defining the conformational structure of a polypeptide that creates a tumor-associated antigen. It has been found that blood group M and N determinants are carried by the N-terminal region of glycophorin A, although conformation of the epitope is properly exposed by glycosylation, specifically at the terminal sialic acid. The epitope structure for onfFn defined by FDCG antibody is the first example indicating a
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SEN-ITIROH HAKOMORI TABLE VI CHANGES OF HISTO-BLOOD GROUPANTIGENSIN HUMAN CANCER
1. Deletion of A and B determinants (Masamune et al., 1952, 1953, 1960) and associated accumulation and disorganization of precursor (H and N-acetyllactosamine) (Dabelsteen et al., 1983) 2. Expression of incompatible A antigen in 0 or B tumors: a. Identification as Tn antigen (Hirohashi et al., 1985) b. Real A antigen expression (ALeb,ALed) (Clausen et al., 1986) c. Other stnichires (Forssman and fucose-less A) are of minor importance 3. Expression of incompatible PPIPkantigen in small p tumor (Levine et al., 1951; Kannagi et al., 198213; Hattori et al., 1987) 4. Change of carrier isotype in A tumor (Dabelsteen et al., 1988). Type 2 and type 3 chain A antigens are absent in normal adult colonic mucosa, but are expressed in tumors
possibility that expression of polypeptide tumor antigen is regulated by glycosylation. Such examples must be present in a large number of so-called tumor-associated polypeptide antigens whose epitope structure is as yet unknown. VII. Alteration of Histo-Blood Group and Heterophile Antigens Expressed in Human Cancer
In the preceding sections, many examples of modification of carrier structures for histo-blood group2 determinants in human cancer, particularly lacto-series carrier types, have been discussed. On the other hand, histo-blood group determinants per se are greatly altered in many human cancers, as will be discussed in this section (see also Table VI). Because this field of study has been reviewed (Hakomori, 198417; Kuhns and Primus, 1985; Feizi, 1985), only a brief overview is presented here. A. HISTO-BLOOD GROUPABH ANTIGENS Reduction of A or B determinants associated with human cancer, first discovered by Oh-Uti (1949) on a chemical basis, was confirmed by immunohistological analysis of various tumors using the red blood cell adherence test (Davidsohn et at., 1966; 1969), mixed hemagglutinin test (Kay and Wallace, 1961), and immunofluorescence test (Prendergast et al., 1968; Dabelsteen and Fulling, 1971), which The term “histo-blood group” is used to emphasize the predominance of ABII (Lewis) antigens in epithelial tissue and P antigens in mesenchymal tissue. They are minor components in blood (Clarrsen and Hakomori, 1989).
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indicated that deletion of blood group A and B antigens occurs in a large variety of tumors, as well as in preneoplastic lesions (see Section VILA). The pathobiological significance of the deletion or reduction of A and B determinants, particularly a possible correlation with malignant potential of tumors, has been debated (Grntoft e t al., 1987; 1988; see also Feizi, 1985). Incompatible A antigen expressed in tumors from 0 or B individuals has received a great deal of attention. The chemical basis of this phenomenon was initially studied with glycolipid isolated from type 0 tumor, which inhibited lectin-induced A hemagglutination. In addition, rabbit antisera against the glycolipid showed a preferential reactivity with A erythrocytes (Hakomori et al., 1967). Using anti-A immune serum (not naturally occurring anti-A isohemagglutinin), Hakkinen (1970) detected A antigen by immunofluorescence in gastric cancer of B and 0 individuals. More recently, a glycolipid fraction with blood group A activity was demonstrated in a few cases of gastric cancer (Hattori e t al., 1981) and a case of primary hepatoma (Yokota et al., 1981) from blood group 0 individuals. An A-like glycolipid with obscure reactivity was isolated from tumor of host with blood group B, and was identified as ceramide heptasaccharide with difucosylated A structure (Breimer, 1980). Forssman antigen expressed in tumors derived from Forssman-negative tissue has been a well-accepted candidate for A-like antigen, which will be discussed in Section VI1,C. With development of various monoclonal anti-A antibodies defining type 1 chain A, type 3 chain A, ALeb, and ALeY(Abe et al., 1984; Clausen et at., 1985a; 1985b), the properties of A antigen expressed in type 0 colonic cancer have been thoroughly reinvestigated. The presence of real type 1 chain A antigen, either ALed (defined by MAb AH21) or ALeb (defined by MAb HH3), has been detected in approximately 10-15% of primary colonic cancer cases from histo-blood group 0 patients. The presence of glycolipid antigen was demonstrated by TLC immunostaining, and A transferase activity was detected in typical A-expressing 0 tumors (Clausen et al., 1986). Thus, real A antigen, rather than A-like antigen, is indeed expressed in 0 or B tumors, although expression of such incompatible A antigens is observed in less than 15% of cases. Interestingly, the incidence of various human adenocarcinomas, e.g., gastric, colonic, ovarian, and parotid cancer, is higher in blood group A than in the blood group 0 or B populations (Mourant et al., 1978). Although the immunobiological basis for this epidemiological finding is difficult to explain, it is possible that primary or in situ tumors of blood group 0 and B individuals, if expressing real A antigen, were likely to be recognized
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as foreign, and were immunologically rejected. In hct, the incompatible A antigens studied by Clausen et aZ. (1986) were all from primary colonic cancers. Incidence of incompatible A antigen expression in ovarian cancer is also high, reflecting the high incidence of this disease in A individuals (R. Metoki, Y. Tsuji, and S. Hakomori, unpublished observations). Antibodies directed to Tn antigen showed a cross-reactivity with A antigen, and two anti-Tn MAbs, NCC-Lu-38 and -81, showed anti-A properties (Hirohashi et aZ., 1985). Since the incidence of Tn antigen expression is quite high (70-90%) in some tumors, it is possible that some anti-A antibodies may pick up Tn antigen. The high incidence of A expression as observed by Yuan et al. (1986) and Itzkowitz et al. (1986b; 1987) may well reflect a cross-reactivity with Tn antigen. Incompatible A or A-like antigens expressed in B or 0 tumors are therefore manifold; their detectability depends on the specificity of antibodies applied, since each antibody could recognize a variety of antigens which have aGalNAc as an epitope. Two important antigens are real A antigen and Tn antigen, both of which could have important clinical applicability in diagnosis and treatment of human cancer. Forssman antigen may also be able to contribute A cross-reacting antigen in human cancer. The quantity of Forssman expressed in human cancer is too small to be clinically significant (see Section VI1,C). Although A antigen is deleted or reduced in gastric, esophageal, oral, and bladder cancers, its expression remains in colonic cancer. With application of various anti-A MAbs that distinguish carrier type structures, it has become apparent that A antigens, carried by type 1, 2, 3, and 4 chains, are all detected in colonic adenocarcinoma and in normal fetal mucosae, in striking contrast to the absence of type 2 and type 3 chain A structures in normal adult mucosa. Type 1 chain A and ALeb were expressed in part of the normal colonic proximal mucosa (Dabelsteen et al., 1988). Thus, there are several possible mechanisms for aberrant expression of A or A-like antigen: (1)deletion or reduction of A determinant, (2) incompatible expression of A determinant in B or 0 tumor, and (3)anomalous combination of carrier type and A determinant.
B. HISTO-BLOOD GROUPP ANTIGENS An unusual case of gastric cancer involving the occurrence of incompatible histo-blood group P antigen was reported in 1951
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(Levine et al., 1951).A 66 year old female patient with gastric cancer and apparent blood group 0 was treated surgically. Blood examination before surgery revealed that her serum contained antibodies which agglutinated all random erythrocytes except her own. These antibodies were later identified as anti-PPIPk (also called anti-Tja). This was the first reported case of rare blood group p (genotype p p ) , which has an estimated frequency of 1: 100,000. In the patient’s family, however, the incidence was 1: 4, her parents were double first cousins, and her younger sister was found to also have genotype p p . The sister’s serum also contained anti-PPIPk. Before surgery, the patient received a transfusion (approximately 25 ml) of incompatible blood. This produced a severe hemolytic reaction, with fever and an increase in anti-PPIPk titer from 1: 8 to 1:512. Shortly after the transfusion reaction subsided, subtotal gastrectomy was performed; however, the tumor and metastatic region were not completely removed. The patient recovered, survived for another 22 years, and died of old age in 1973. There was no evidence of recurrence or metastasis of the tumor (for a review, see Levine, 1978). The tumor tissue obtained from the 1951 surgery was lyophilized and the powder was kept at low temperatures. Chemical analysis performed in the laboratory of the present reviewer in 1980 clearly indicated the presence of a glycolipid cross-reacting with P (globoside), i.e., GalNAcpl+ 3GalP1+ 4GlcNAcP1+ 3Galpl+ 4Glcpl+ 1Cer. P1 activity was detected in the glycolipid, as well as in the glycoprotein, fraction (Kannagi et al., 1982b). This was the first clear documentation of the presence of PPIPk antigen in cancer from a type p individual. It is suspected that the transfusion of mismatched blood induced a high level of anti-PPIPk, which actively suppressed growth of tumor remaining after the surgery. A second case of incompatible P antigen expressed in gastric cancer of a p p genotype individual was reported recently by Hattori et al. (1987). The female patient’s blood group was p, 0, Le(a-b+); her serum was reactive with all blood samples except her own, and was shown to contain anti-PPIPk antibody, as in the patient from the 1951 case. The p blood group was confirmed serologically with anti-Pl and anti-Pk. TLC immunostaining of the glycolipid fraction of the patient’s tumor tissue revealed the presence of Gb3 (Pk antigen), Gb4 (P antigen), as well as Forssman and incompatible A antigens. In contrast to the earlier case, this patient did not receive transfusions of mismatched blood. Her subsequent clinical history has not been available.
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C. FORSSMAN ANTIGENS Forssman antigen shows an allogeneic expression in man and is absent in normal lung and gastrointestinal mucosa in the majority of the human population, but is detectable in gastric and colonic cancer (Hakomori et al., 1977c) and lung cancer (Yoda et al., 1980). In the majority of lung cancers, whether squamous cell carcinoma or adenocarcinoma, activity of a1 + 3GalNAc transferase, which is responsible for synthesis of Forssman antigen, is greatly enhanced, whereas the same enzyme is undetectable in normal lung tissue (Taniguchi et al., 1981). Although these and other studies (Kawanami, 1972; Mori et al., 1983)indicate a close association of Forssman antigen expression with human malignancy (for a review, see Milgrom et al., 1973), antiForssman antibody, either monoclonal or polyclonal, does not stain tumor tissue or normal tissue (S.-M. Wang, K. Abe, and S. Hakomori, unpublished observations). Furthermore, no MAbs directed to Forssman antigen were found among various hybridomas established after immunization with human cancer. Therefore, the potential clinical usefulness of Forssman antigen as a human cancer marker is questionable. ANTIGENS D. HANGANUTZIU-DEICHER Heterophile Hanganutziu-Deicher (HD) antibodies were originally detected in sera of patients who had received therapeutic injection o f foreign immune serum, and were found to agglutinate erythrocytes of sheep, ox, horse, rabbit, and other animal species, but not human erythrocytes (Hanganutziu, 1924; Deicher, 1926). Later, patients with various diseases (including cancer) who had not received injection of foreign serum were also found to possess HD-type heterophile antibodies (Kasukawa et al., 1975). The HD antigen was identified as a ganglioside containing N-glycolylneuraminic acid (NeuGc) (Higashi et al., 1977; Merrick et al., 1978). Since sera from cancer patients occasionally contained H D antigen, an association of this type of antigen with human cancer was suspected. A series of extensive studies by Higashi, Naiki, and associates (Higashi et al., 1984; 1985; Hirabayashi et al., 1987) clearly indicated the presence of GM3, sialyl paragloboside, and other gangliosides containing NeuGc in colonic cancer, melanoma, retinoblastoma, ovarian cancer, and seminoma. Recent studies have detected the presence of GM.3
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containing 4-O-acetyl-N-glycolyl neuraminic acid in human colonic cancer (Miyoshi et al., 1986). Since the quantity of NeuGc ganglioside present in cancer is extremely low, the antibody recognition may be difficult. Since no data on immunoreactivity or antibody-dependent cytotoxicity with anti-HD antibodies are available, it is difficult to predict the clinical significance of H D antigens in human cancer. VIII. Aberrant Glycosylation in Preneoplastic Tissues
Preneoplastic cells express the same type of aberrant glycosylation as found in established tumor cells in both experimental and human cancer. Cells in preneoplastic nodules in rat liver contain fucosyl GM1 ( IV2FucI13NeuAcGg4), fucosyl asialo GMI ( IV2FucGg4), and a-galactosylfiicosyl GM (ganglio-B; IV2FucIV3aGalI13NeuAcGg4).These glycolipids are completely absent in normal rat liver but are highly expressed in rat hepatoma, although established hepatoma cell lines express the former two glycolipids (Holmes and Hakomori, 1982). The enzymatic basis for the induction of fucoganglioside synthesis in preneoplastic rat liver and hepatoma has been studied. An a1 -+ 2 fucosyltransferase specific to GM1 was induced after rats were fed 2-N-fluoroacetamide for 3 weeks (Holmes and Hakomori, 1983). Deletion or reduction of A antigen associated with accumulation of H and its precursor antigen were observed in preneoplastic dysplasia lesions of oral epithelia (Dabelsteen and Fulling, 1971; Dabelsteen et al., 1983). Ley expression in colonic polyps was found to be closely correlated with preneoplastic state of polyps. Juvenile polyps without dysplasia, having no malignant potential, did not express Ley, whereas tubulovillous and villous adenomas with severe dysplasia, which have high malignant potential, express Ley antigen (Abe et al., 1986). A similar study with antibodies directed to extended Ley (CC1 and CC2) and trifucosyl Ley (KHl) showed an even clearer correlation between the malignant potential of colonic polyps as determined by histological type, degree of dysplasia, and Ley expression rather than by AH6 antibody (Kim et al., 1986). In the majority of liver cirrhosis tissue, the FH6-defined antigen was highly expressed in a characteristic honeycomb-like pattern. The pattern was particularly remarkable in hepatitis-induced cirrhosis, which has a high potential to induce hepatoma. The FH6-defined antigen is highly expressed in hepatoma (Okada et nl., 1988).All these studies clearly indicate that premalignant lesions are characterized by the same aberrant glycosylation as found in malignant tissue.
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IX. Requirements for Tumor-Associated Carbohydrate Antigens: Density of Antigens and Organizational Framework in Membranes
Only a few tumor-associated carbohydrate antigens are known to be virtually absent in normal cells and tissues. These are incompatible histo-blood group antigens and Forssman and H D antigens. Because the incidence and degree of expression of these specific antigens in tumors are low, the antigens are clinically of minor importance, except for real A and T n antigen as incompatible A antigen. A second class of antigens has a novel structure highly expressed in tumor cells, absent in the progenitor cells, but found in unrelated normal tissues, i.e., ectopic expression in tumors. They include dimeric or trimeric Lex,trifucosyl Ley, sialyl difucosyl Lex,monosialyl and disialyl Lea, GD3 and GD2 ganglioside, and Tn and sialyl Tn antigens. The third class of antigens can be detected chemically in a wide number in normal tissues, but are found in very high levels in some tumor cells, e.g., GM3 in melanoma, Gb3 in Burkitt's lymphoma, and Lex, Ley, Lea, and Leb in a variety of human cancers. Despite the fact that antigens of the second and third class are expressed in normal cells, some antibodies directed to them are clinically useful in diagnosis and treatment of human cancer (see Sections X and XI). These antigens are not only present in high quantity, but may exist with a novel organization at the tumor cell surface. The importance of the organization of glycolipid antigens at the cell surface has been suggested by the following various data.
1. Some glycolipids are chemically present in considerable quantity but are hardly detectable by immunological methods, whereas others are present in relatively small quantity but are conspicuous by immunological methods. The restricted expression of major glycolipids present in various types of normal cells by their antibodies has been well documented; e.g., Gb4 in adult human erythrocytes (Hakomori, 1969) and hamster fibroblast NIL cells (Gahmberg and Hakomori, 1975), and GM3 in baby hamster kidney fibroblasts (Hakomori et uZ., 1968). These major glycolipids are immunologically conspicuous in fetal erythrocytes and virally transformed cells, although the chemical quantity of Gb4 or GM3 in the fetal or transformed cells is even lower than in adult or normal progenitor cells. Gb3 in ARH77 human lymphoblastoid cells was not expressed at the cell surface, although cells contained a quantity of Gb3 comparable to that in Burkitt's lymphoma, which expressed this antigen conspicuously at the cell surface (Wiels et uZ., 1984).
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2. Some antibodies are able to recognize density of glycolipid antigens at the cell surface and on solid phase; e.g., anti-SSEA-1 antibody does not react with Le" ceramide pentasaccharide on liposome lysis assay at concentrations below 10 pmol, but reacts maximally at concentrations above 12-15 pmol (Hakomori et al., 1981b). A melanoma-specific antibody M2590 reacted with GM, only when present at concentrations higher than 10 mol%; it did not react at concentrations below 8 mol% in liposome lysis assay. When melanoma cells were treated with sialidase, reactivity (as determined by immunofluorescence and by flow cytofluorometry) decreased suddenly to a minimal level, although only 10% of cellular GM3 was hydrolyzed. Further incubation of cells with sialidase, which caused increasing degradation of GMS, did not alter fluorescence intensity with anti-GM, antibody. These findings indicate that some, if not all, antibodies show a clear threshold value for reactivity in all-or-none fashion (Nores et al., 1987) (see Table VII). 3. Some glycolipid antigens are highly expressed in certain experimental tumors and are also present at lower levels in some normal cells. Administration of antibodies with the proper isotype and affinity may inhibit tumor cell growth without affecting the function of normal cells expressing the same antigen. Mouse lymphoma L5178, in which Gg, is highly expressed, was completely suppressed by administration of the anti-Gg3 IgG3 antibody DlOG11, and the animals remained healthy for an extended period of time despite the fact that Gg3 is also expressed in a few normal cells (Young and Hakomori, 1981). Similarly, growth of B16 melanoma inoculated in C57BL mice was inhibited by administration of anti-GM3 IgG3 antibody DH2, and the animals remained healthy, despite the presence of GM3 in normal cells of various tissues (Dohi et al., 1988). Differential cell surface recognition of normal versus tumor cells TABLE VII
FACTORS AFFECTING ANTIGENICITY AND IMMUNOCENICITY OF MEMBRANE GLYCOLIPIDS 1. Concentration and density of glycolipids: Glycolipid antigens organized at a concentration higher than a certain threshold value are recognized by a certain antibody. The same antigen at subthreshold concentration is not recognized (Hakomori et al., 1981b;Nores et al., 1987) 2. Membrane proteins surrounding glycolipids: Cryptic glyco-epitopes are exposed on protease treatment (for examples, see text) 3. Sialosyl glycoconjugutes surrounding glycolipids: Cryptic glyco-epitopes are exposed on sialidase treatment (for examples, see text) 4. Cerarnide composition: See Table VIII
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involves not only antibodies (Nores et al., 1987), but also secondary immune responses triggered by the antibody (Herlyn et al., 1985; Welt et al., 1987), i.e., activated effector cells, macrophages, and antiidiotype as well as anti-antiidiotype antibody responses, which are capable of recognizing the organization and density of glycolipid antigens. These secondary mechanisms may show even greater ability to distinguish organizational framework of antigens at the surface of tumor cells versus normal cells. What are the precise chemical and physical bases for organizational differences in the surface membranes of normal versus malignant cells? Current research has not yet been able to answer this question. However, the following factors are certainly involved. 1 . Glycolipid concentration and density at the cell surface menibrane. Some MAbs, showing a preferential or specific reactivity with certain types of tumor cells over normal cells, are capable of recognizing a high density of a common glycolipid organized at the tumor cell surface membrane. These antibodies react with the glycolipid antigen only at high density, in an all-or-none fashion, i.e., display a threshold reactivity. Thus, Le” glycolipid highly expressed in colonic adenocarcinoma (Hakomori et al., 1981b) and GM3 ganglioside in melanoma (Nores et al., 1987) display “tumor-specific” reactivity. It is suspected that these glycolipid antigens at high density may have conformations different than they do at low density. However, final conclusions should be based on direct NMR studies of cell membranes. 2. Crypticity of glycolipid antigens. According to the minimum energy conformation model, the axis of the carbohydrate is perpendicular to that of ceramide; glycolipids are inserted in the lipid bilayer through their ceramide moiety, and their carbohydrates are laid on and fixed to the surface of the lipid bilayer, exposing the hydrophilic surface toward the outside of the membrane (Kaizu et at., 1986; Hakomori, 1986). Considering such a model, crypticity of glycolipid antigens could be controlled by several complex factors as described below. a. Membrane Proteins Surrounding Glycolipids. Accessibility of antibody to glycolipids at the cell surface must be greatly influenced b y surrounding membrane proteins. The reactivity of Gb4 in adult human erythrocytes (Hakomori, 1969) and that of G M I in mouse lymphocytes (Stein et al., 1978) were enhanced when cells were treated with protease. Enhanced agglutinability of erythrocytes by antisera versus blood group ABH, Lewis, and Ii antigen after treat-
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ment with proteases has been known empirically. Lectin-induced agglutinability of fibroblasts and lymphocytes is also known to be enhanced by protease treatment. b. Siulosyl Glycoconjugutes Surrounding Glycolipids. Reactivities of Gg, in L5178 lymphoma (Urdal and Hakomori, 1983b) and Gb] in human lymphoblastoid cells (Wiels et ul., 1984) to their respective MAbs were greatly enhanced when the cells were treated with sialidase rather than protease, although no sialyl derivatives of Ggo or Gb3 susceptible to sialidase were present in the cells. The labeling efficiency of Ggo in L5178 cells by galactose oxidase/NaB3H4 was also greatly enhanced after sialidase treatment (Urdal and Hakomori, 1983b). In this case, GMIl, was hydrolyzed and converted to asialo GMI (Gg4). It is possible that Gg3 or Gb3 was made cryptic by the presence of adjacent GM,,, (Kannagi et ul., 1983a) or some other sialosyl glycoprotein that masks Gg, at the cell surface (Urdal and Hakomori, 1983b). c. Cerumide Composition. Another factor determining the crypticity of glycolipids is differential ceramide composition (see Table VIII). Reactivity of glycolipid is greatly affected by chain lengths of fatty acids, and the presencelabsence of the a-hydroxyl group at the fatty acid component of ceramide (Cer). Differences in Cer composition will affect the organizational state of glycolipids in cell surface membranes that modify the glycolipid crypticity to their antibodies and ligands. The two acyl chains in Cer are almost of equal length in glycolipids with short-chain fatty acids (C14 : 0 to C18 : 0), whereas two acyl chains in glycolipids with longer fatty acids (C22 : 0, C22 : 1, C24 : 0, C24 : 1) are very unbalanced; one of them is approximately 1.2-1.4 times longer than the other. This causes organizational and TABLE VIII EVIDENCE THAT CEPAMIDE COMPOSITION Is IMPORTANT FOR IMMUNOGENICITY AND ANTIGENICITYOF GLYCOLIPIDS
1. FucCer from adenocarcinoma contains C14fatty acids and Cm sphingenine and is poorly irnmnnogenic in rabbits, while synthetic FucCer containing Ce4 htty acids and CLssphingenine is skongly immunogenic (Yoshino et al., 1982) 2. Gg3 in L5178 lymphoma showed the following order of reactivity with its MAb: a-OH CL6fatty acid > Cm-C% fatty acid > C16fatty acid (Kannagi et al., 1983a) 3. LicCer with long-chain fatty acids (Cz0-C7,) showed greater reactivity with MAI) TSA7 than did LacCer with short-chain fatty acids (C14-Clx)(Symington et d., 1984;1
4. Propionibacterium grunulosum binds to LacCer with a-OH fatty acids, while Propionibacterium freudenreichii binds to LacCer with long-chain fatty acids (Hansson et d., 1983)
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stability differences of the glycolipids in the lipid bilayer. The arrangement of glycolipid antigens having hydroxylated Cer in either a-hydroxy fatty acids or 3-hydroxysphinganine must be much different in glycolipid antigens without hydroxyl function at the Cer. Although the exact mechanism is unknown, antibodies directed to carbohydrate epitopes of glycolipids showed significantly different reactivity depending on the ceramide composition. The longer the fatty acid chain length, the greater the antibody reactivity demonstrated to the same carbohydrate epitope. The reactivity and immunogenicity of liposomes containing FucCer having long-chain fatty acids and a-hydroxy fatty acids were significantly higher than those of liposomes containing short-chain fatty acids (Yoshino et al., 1982). GD3 ganglioside in human melanoma was characterized as having Cer with long-chain fatty acids, in a striking contrast to GD3 of normal brain having Cer with short-chain fatty acids. GD3 immunogenicity and antigenicity in human melanoma could be much higher than that of GD3 in normal tissue (Nudelman et al., 1982). The reactivity of lactosylceramide with C20-24 fatty acids to its MAb A5T7 was much higher than that of lactosylceramide with C16-18 fatty acids in solid-phase antibody-binding assays (Symington et al., 1984). A close correlation between antigenicity of Gg3 in mouse lymphoma L-5178Y and their Cer composition was studied. A greater antigenicity was found to correlate with the amount of a-hydroxy C16 : 0 fatty acid. It is suggested that the glycolipid becomes more exposed when Cer has a-hydroxy fatty acids (Kannagi et al., 1983a). X. Diagnostic Applications A. EARLIER STUDIES
There have been a few observations indicating that sera of patients with cancer show elevated levels of tumor antigens or antibodies. In a classic study, Tal et al. (1964) observed that sera from tumor patients and pregnant women contained autoimmune antibodies that agglutinated tumor cells in uitro. This agglutination was specifically inhibited by lactose, and it was suggested that the antigen was lactosylceramide. More recently, Jozwiak and Koscielak (1982) observed an elevated level of antibody directed to lactosyl sphingosine in a number of patients with gastrointestinal cancer. The antibody level was determined by inhibition of '251-labeledantihuman IgG to a lactosyl sphingosine-polyacrylamide conjugate. A similar inhibition was observed with the antibody binding to lactosaminyl glycolipid,
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but not to other types of glycolipid. These early studies indicate the presence of antibody directed to lactosyl or N-acetyl lactosamine glycoconjugates in sera of patients with various types of gastrointestinal cancer.
B. SERUM ANTIGENLEVELS DEFINED BY MONOCLONAL ANTIBODIES Enhanced levels of antigen in sera of patients with gastrointestinal cancer were initially observed by inhibition of MAb N-19-9 binding to colonic tumor cells (Koprowski et al., 1981) and by “sandwich” assay (Herlyn et al., 1984). The antigen was subsequently identified as 2- 3 monosialyl Lea (Magnani et al., 1982). Studies using this antibody have assessed the elevated level of the antigen in sera of patients with various types of gastrointestinal tumors (Herlyn et al., 1982; Chia et al., 1985). Of particular interest is the high incidence of antigen elevation in sera of patients with pancreatic cancer, which is otherwise difficult to diagnose in its early stages (Haglund et al., 1986; Ritts et al., 1984; Satake et al., 1985; del Favero et al., 1986). This tumor marker, however, has the drawback that the antigen is absent in sera of Le(a-b-) patients (the incidence of this trait is 1-3% in the Caucasian population), since tumors in such patients do not express a1 -+4 fucosyl transferase due to the absence of the LA gene (Brockhaus et al., 1985; Temper0 et al., 1987). Another antigen with a similar structure, sialyl Le”, defined by antibody CSLEX-1 (Fukushima et al., 1984), was also found to be elevated in several types of human cancer (including lung and breast) and showed a pattern of high elevation complementary to that of sialyl Lea (Chia et al., 1985). Sialyl Le” antigen has an advantage in that it is expressed in tumors in Le(a-b-) patients. The antigen with a similar epitope, defined by the antibody FH6, having a long-chain sialyl lactosamine with internal fucosylation (sialyl Lex-i or sialyl dimeric Le”), was also found to be elevated in patients with various types of cancer (Fukushi et al., 1985; Kannagi et al., 1986). A large-scale screening (over 3000 patients) utilizing this antibody has been performed. The antibody showed a high incidence of positivity in sera of patients with lung adenocarcinoma (86%) and pancreatic cancer (85%), but relatively low positive incidence in other human cancers (average 55%). Nevertheless, the antibody may have diagnostic value since it rarely gave false positive results (Imura et al., 1987). A high incidence of positive cases was found with another antibody, CA50, which defines the 2- 3 sialyl type 1 chain. The antibody, however, cross-reacts with 2- 3 sialyl Lea (Nilsson et al.,1985; Mansson et al., 1985; Holmgren et al., 1983).
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The antibody was able to detect monosialoganglioside in 60-90% of colorectal or pancreatic adenocarcinomas or their metastases, but was essentially unreactive with normal colonic mucosa (Lindholm et al., 1983).Antibody CA50 was able to detect enhanced level of antigen in sera of patients with various types of cancer, particularly colorectal cancer (50-75%), uterine cancer (75%), and prostate cancer (90%) (Holmgren et al., 1984). More recently, a new sialylated type 1 chain, disialyl Lea (2 + 3, 2 + 6 sialyl Lea), was isolated and characterized from human colonic adenocarcinoma, and its antibody, FH-7, which defined 2 + 6 sialyl Lea, was established (Nudelman et al., 1986a). This antibody was capable of detecting the enhanced level of characteristic antigen in various types of human cancer. The antigen level, determined by inhibition of antibody binding, was particularly high in pancreatic, colonic, and bladder cancer (including stages I and 11), although false positive results were also observed in a few patients with nonmalignant diseases such as chronic hepatitis and liver cirrhosis (Kannagi et al., 1988). An antigen with the Le" determinant was detectable in sera of patients with cancer (25 out of 49; 53%) but not in 16 healthy subjects or in seven patients with nonmalignant diseases, when anti-Le" 29-1 antibody was applied using the sandwich method (Herlyn et al., 1984). When IgGS anti-Lexantibody (SH-1) was used as the "catcher" antibody, followed by application of another IgG3 antibody (SH-2) directed to dimeric Le" and used as the detector antibody, the detectability and specificity of the Le" antigen in sera of patients was found to be as high as 7 0 4 0 % (Singhal et al., 1988). However, some other anti-Le" antibodies such as FH2 and FH3 were unable to detect serum antibody levels in patients with cancer. The level of Ley antigen defined by antibody AH6 was relatively high in sera of some patients with hepatoma (Kannagi et al., 1986). An antibody directed to gastric cancer, NCC-ST-439, established by Hirohashi et al. (1984), is capable of detecting high levels of antigen in sera of patients with pancreatic, colorectal, and breast carcinoma. In studies of sera from 19 patients with colorectal carcinoma, the antigen level decreased sharply in all cases after surgical intervention (Sugano et al., 1988). The antigen is sensitive to sialidase and seems to be a sialylated structure, but is not identical to sialyl Lea or sialyl Le". Hanai et al. (198613)established four MAbs, KM32, KM34, KM52, and KM93, directed to human lung squamous cell carcinoma and adenocarcinoma. They utilized a unique technique to enhance production of hybridoma specific to squamous carcinoma. They initially immunized newborn nude mice with normal lung tissue to which the mice were immune tolerant. The same mice, after reaching adulthood,
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were immunized with lung tumor cells, and the resulting MAbs were established. Antibody KM32, cross-reacting with blood group A, may define an A-like antigen associated with various cancers, particularly lung adenocarcinoma. It was found to be capable of detecting elevated levels of A-like antigen in sera of patients with lung cancer (Hanai e t al., 1986a). Antibody KM93 defines a sialidase-sensitive antigen, and could detect a relatively high antigen level in sera of patients with lung adenocarcinoma (Shitara et al., 1987). The antibody DUPAN-2 (Metzgar et al., 1982; 1984), defining mucin-type glycoprotein, is useful in detecting high levels of antigen in sera of patients with pancreatic and gastrointestinal cancer, and was found to be useful in monitoring patients during the course of the disease. The antibody OC125 (Bast e t al., 1981), defining mucin-type glycoprotein that is highly expressed in ovarian carcinoma, could detect high levels of the antigen in sera of patients with ovarian cancer. The antibody C-12 established by Tsuji et al. (1987), originally raised against an endometrial carcinoma cell line, could detect an antigen that is highly expressed in endometrial carcinoma (24 positive out of 25) and ovarian carcinoma (5positive out of 5). The antibody could also detect high antigen levels in sera of patients with not only gynecological cancer but also hepatoma. The high antigen level was also found in patients with liver cirrhosis, but not in normal subjects or patients with other benign diseases. The antigen is expressed in blood group 0 but not A or B erythrocytes, and is assumed to be closely related to H. However, C-12 antigen in sera showed no association with blood group 0, and is therefore distinctive from the common H antigen which is present in sera of blood group 0 subjects, but is absent in sera of blood group A and B subjects (Tsuji et al., 1987). The C-12 epitope could be an extended unbranched Ley (H) structure (H. Tsuji, H. Clausen, E. Nudelman, S. Isojima, and S. Hakomori, unpublished observations). A number of other MAbs raised against various human cancer cell lines or membranes have been found to be directed to sialidasesensitive epitopes carried by mucin-type high-molecular-weight glycoproteins (see Table V). The antigen defined by MAb B72.3, originally raised against the membrane fraction of breast carcinoma (Colcher et al., 1981), has been identified as a sialidase-sensitive epitope associated with mucin (Johnson et al., 1986). The real epitope has been identified as sialyl Tp as previously described (Kjeldsen et al., 1988). The antibody is useful for detection of the antigen present in sera of patients with colon carcinoma (Paterson et al., 1986). Another mucin-type antigen, defined by MAb KL-6, increased in sera
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from patients with lung adenocarcinoma, pancreatic cancer, and breast cancer (Kohno et al., 1987). Various antibodies directed to breast carcinoma, some of which were raised against human milk fat globule membrane (Burchell et al., 1984; Hilkens et al., 1986; Ceriani et al., 1983), and others using breast cancer cell membranes (Johnson et al., 1986; Papsidero et al., 1984; Kufe et al., 1984), displayed the ability to detect high levels of mucin-type antigens in sera of breast cancer patients, particularly those screened by the ability of antibody to recognize serum antigen elevation in sera of patients with breast cancer. Two antibodies, W1 and W9, both directed to carbohydrates of mucin-type glycoproteins, were capable of detecting 60-75% of breast cancer at stages I1 and 111, and are of high diagnostic value (Linsley et al., 1986). There are a number of carbohydrate antigens present in various tumors that are not released into the bloodstream and thus are undetectable by radiometric assay, e.g., GD3 ganglioside in melanoma, and trifucosyl Ley and dimeric Le" in various types of adenocarcinoma. These antigens may, however, be good markers for tumor imaging. The following general characteristics have been noted in antigens detected in sera of cancer patients (see also Table IX):
1. Detectability can vary widely depending on the method used, TABLE IX DIAGNOSTIC APPLICATIONOF TUMOR-ASSOCIATED CARBOHYDRATE ANTIGENS 1. Detection of serum antigens shed from tumors Target molecules: Sialyl 2 + 3 Le" (Koprowski et al., 1981; Herlyn et al., 1982, 1984; Chia et al., 1985; for others, see text) Sialyl 2 + 6 Le" (Kannagi et al., 1988) Sialyl Le" (Chia et al., 1985), sialyl Le"-i (Imura et ul., 1987; Kannagi et al., 1986) Sialyl type 1 chain (Holmgren et al., 1984), Ley (Kannagi et al., 1986) Le" (Herlyn et al., 1984; Singhal et ul., 1988) 2. Detection of antigen-antibody complex through ex oioo circulatory system Target molecule: Le" anti-Lex complex (Singhal et al., 1987) 3. Targeting of labeled antibodies for immuno-imaging Target molecules: CEA, a-fetoprotein (Keenan et al., 1985; Larson, 1985) HMFG mucin-type glycoprotein (Epenetos et a/., 19824 1986a) 17.1 glycoprotein (37 kda) (Chatal et a/., 1986; Herlyn et d., B72.3 glycoprotein, sialyl-Tn (Colcher et nl., 1984) GD2 ganglioside (Heiner et al., 1987) GM1 ganglioside (Dohi et nl., 1988)
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and on intrinsic properties of the antibodies applied. Sandwich assay is sometimes more convenient because it does not require purified antigen, which is not always available. The method shows a high detection rate for some antibodies. However, competitive binding assay (i.e., inhibition of antibody binding to purified antigen) shows a better detection rate for other antibodies. 2. Many of these antigens showing high levels in circulating blood are sialylated compounds. On gel filtration, each antigen was eluted as a high-molecular-weight glycoprotein soluble in perchloric acid and insoluble in chloroform : methanol, i.e., these antigens are mucin-type glycoproteins rather than glycosphingolipids. 3. Not all antigens with elevated levels in sera of cancer patients are the specific products of tumor tissue. Some are components of normal tissue (particularly glandular tissue), and are normally secreted exocrinously. Many of the epithelial cancers are derived from glandular tissues, and some maintain the secretory function and secrete the same antigen endocrinously. In this way, what was originally an exocrine secretion becomes an endocrine secretion in cancer tissues, and the antigen appears in high levels in circulating blood. A typical example could be sialyl Lea or disialyl Lea antigen, abundantly present in normal exocrine secretions from pancreas and salivary glands (Brockhaus et al., 1985). In pancreatic cancer, the antigen is released into the bloodstream, and the level of this antigen appears greatly elevated in the bloodstream. Production of sialyl Lea in pancreatic cancer cells is not greatly increased; its release into the bloodstream is enhanced as a result of the malignancy.
C . SERUMANTIGEN-ANTIBODYCOMPLEX The presence of anticarbohydrate antibodies in sera of patients with cancer, which was suggested in earlier studies (see Section XII,A), was further elucidated in recent studies with MAbs. Antibodies have been detected as immune complexes which can be adsorbed onto a protein A-sepharose column. Hakansson et al. (1985) obtained such immune complexes by elution from protein A-sepharose columns followed by analysis for gangliosides. They detected various types of gangliosides in the immune complex eluate and reported that ganglioside composition in immune complexes from sera of cancer patients was quite different compared to gangliosides in complexes obtained from sera of normal subjects. In an independent study, Singhal et al. (1987) demonstrated a clear qualitative as well as quantitative difference of Le" antigen in the immune complex. Using ex uiz;o circulatory
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assembly through a protein A-silica gel column, they detected the presence of an immune complex with Le" glycolipid. Remarkably, Le" glycolipid was detectable in 100% of 19 tested cases, and was undetectable in all cases tested for nonmalignant disease (0/7). Such a clear-cut distinction has not been observed in any other type of serum antigen assay. It should be noted, however, that the method was based on treatment of a large volume of ex vivo circulating blood passing through a protein A-sepharose column. In contrast, all other serum assays utilized only a minimal quantity (25 pl) of serum. A preliminary attempt to detect levels of glycolipid immune complex using a small sample of serum has been unsuccessful (Singhal et al., 1987). D. IMAGING OF TUMORS BY LABELED ANTICARBOHYDRATE ANTIBODIES Utilizing the specificity of MAbs for tumor antigens expressed at the tumor cell surface, a number of studies have been performed using radiolabeled antibodies to obtain information on tumor location. Successful radioimaging of tumors depends on (1) properties of antigens at the cell surface; (2) qualities of antibodies such as affinity, immunoglobulin isotype, and derivatized state; and (3) kinds of nuclide introduced. In the initial studies, the antigens targeted for imaging were CEA and a-fetoprotein (for reviews, see Keenan et al., 1985; Larson, 1985). The lZ51-labeled antibody HMFG-2, defining mucin-type glycoprotein (Burchell et al., 1984), has been successfully used in targeting the antibody to ovarian, breast, and gastrointestinal tumors (Epenetos et al., 1982a). The same antibody was also applied in diagnosis of malignancy in serous effusions (Epenetos et a1.,1982b). These antigens were, however, actively shedding from the tumor cell surface, and may not be ideal for targeting and imaging purposes. Nonshedding 37-kDa tumor membrane glycoproteins defined by the antibody 17.1 have been extensively used, although the epitope structure of this antibody is ill-defined (Chatal et al., 1984; 1986; Moldofsky et al., 1984; Mach et al., 1983; Herlyn et al., 1986b). Whole or F(ab)Z fragments were labeled with 1251or 1311 using various human carcinomas grafted in nude mice. Of 63 colorectal carcinoma studies, 34 showed significant accumulation of antibody by external photoscanning and tomoscintigraphy (Mach et al., 1983). Radioimmunoimaging of human tumor xenografts was much improved by a mixture of MAb F(ab)z fragments compared to using a single antibody fragment (Munz et al., 1986). For coupling of a preferable radionuclide (such as ''lIn) to an antibody, diethylenetriaminepentaacetic acid (DTPA) conjugation through cyclic DTPA an-
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hydride was useful. The reaction condition for DTPA coupling was investigated (Paik et al., 1983). For possible N M R imaging of tumors, a 19-9 antibody-gadolinium (Gd) complex was prepared through use of the DTPA conjugate, which was used in N M R of tumors to which the Gd-DTPA-antibody 19-9 complex was added. Addition of the complex decreased T1 relaxation of water protons at 90 MHz in proportion to Gd concentration. When radioactive Gd was used, scintillographic visualization of tumors in nude mice was possible (Curtet et al., 1986). The lZ5I-labeledantibody B72.3, defining sialyl Tn, was successfully used for imaging human colonic cancer xenografts in nude mice. Tumorltissue ratio of the tumor-localized antibody increased greatly during 7 days, and showed a prolonged binding activity over a 19-day period of study (Colcher et uZ., 1984). More recently, ganglioside was used for tumor imaging. Localization of human osteosarcoma grown in nude mice was targeted by whole or F (ab)2 fragments of anti-GDZ ganglioside MAb 3F8. The targeting was highly efficient and specific for the osteosarcoma, but not for Ewing's tumor, which did not express GD2 antigen (Heiner et al., 1987). Interestingly, the same GD2 antigen has been found in human neurobIastoma, melanoma, small cell lung carcinoma, and certain brain tumors (see Section V,D). The antibody 3F8, defining GD2 antigen, is therefore the common imaging reagent for these tumor types. Expression of GD2 ganglioside in normal tissues is highly restricted in humans; in mice, it is found only in the thymus. Another study involved GM3 ganglioside in melanoma as a target. An IgG3 antibody, DH2, showed significant inhibitory activity for melanoma growth in ciao and in vitro. The '251-labeIed DH2 antibody accumulates most in B16 melanoma cells, followed by blood, lung, urinary bladder, thyroid, and adjacent tissues; however, little labeling occurred in brain, bone marrow, or other tissues (Dohi et al., 1988). It is possible that these antibodies, 3F8 and DH2, will be useful for imaging of human cancer in future clinical studies. XI. Tumor-Associated Carbohydrate Antigens as Targets for Therapeutic Applications
Host immune response to tumor, particularly spontaneous tumor, is weak or undetectable. A large number of publications from the past several decades indicate that active immunization by killed or attenuated tumor cells (or antigens extracted therefrom) is fruitless. Hybridoma technology, however, has made available an essentially unlimited supply of reagents with highly specific affinity to tumor
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TABLE X THERAPEUTIC APPLICATIONOF TUMOR-ASSOCIATED CARBOHYDRATE ANTIGENS
1. Effect of systemic administration of mouse monoclonal antibodies (IgC&, IgC3) on human cancer in uiuo: activation of antibody-dependent cytotoxic cells (ADCC) and complement-dependent cytotoxicity (CDCC) Target molecule: GD:, in melanoma (Houghton et al., 1985; Herberman et d., 1985) 2. Effect of lesional application of‘antibody (IgM) on tumor Target molecule: GD2 in melanoma (hie and Morton, 1986) 3. Effect of antiidiotype or anti-antiidiotype antibodies Target molecule: 17.1 MAb (DeFreitas et al., 1985; Herlyn et al., 1986a) 4. Targeting drug conjugates (“magic bullets”) Cytotoxic drug conjugate with anti-Gg, (Urdal and Hakomori, 1980; Hakoniori et al., 1982) Cytotoxic drug conjugate with anti-globo-H (Della Torre et al., 1987) Differentiation inducer conjugate with anti-Le” (M. Otaka, A. Singhal, and S. Hakomori, unpublished data) 5. Active immunization with carbohydrate antigen Glycoprotein antigen (Adachi et al., 1988) GalPl- 3GalNAc-protein complex (Henningsson et al., 1987) Ganglioside-BCG complex (Livingston et al., 1987, 1988)
cells, through which many human tumor antigens have been chemically well defined. Thus, many possibilities have opened for suppression of human tumor growth, as discussed below (see also Table X). A.
EFFECTOF MONOCLONAL ANTIBODIESON TUMOR CELLGROWTH In Vitro AND In Vivo
MAbs defining tumor-associated antigens with suitable isotype and affinity have proved to be useful to some extent in suppressing tumor growth in vitro and in vivo, albeit the tumor growth suppression in vivo is highly variable due to multiple, as yet unidentified, factors. A number of studies performed by groups at the Sloan-Kettering Institute, Scripps Clinic, Wistar Institute, and others indicate that cytotoxic effector cells are activated by MAbs that interact through the Fc receptor of lymphocytes or macrophages in concert with classically known complement-dependent cytolysis. Furthermore, some antibodies are able to inhibit tumor growth by themselves, by an unknown mechanism that does not involve effector cells or complement. In addition, antiganglioside antibody may facilitate lymphokinedependent T cell activation. A detailed review of this area of study is not within the scope of this article, but reviews covering the material have been published (Koprowski, 1984; Baldwin and Byers, 1984; Reisfeld and Cheresh, 1985).
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Effective immunotherapy by IgG3 MAb directed to the Gg3 antigen that is highly expressed on mouse lymphoma L5178 was first described by Young and Hakomori (1981). The growth of L5178 lymphoma was completely inhibited by administration of IgG3 anti-Gg3 antibody in a dose-dependent manner. Growth of the variant lymphoma, which did not express Gg3, was not inhibited by the antibody. Growth of neither Gg3 expressor nor nonexpressor lymphoma was inhibited by the antibody directed to the same epitope with IgM isotype. Since both IgG3 and IgM antibodies directed to Gg3 showed complement-dependent cytolysis, the factor involved in this lymphoma suppression could be an antibody-dependent cytotoxic effector cell. The IgG3 mouse MAb R24, defining the GD3 ganglioside that is highly expressed on human melanoma cell surfaces (see Section V,D), activated human effector cell functions, causing lysis of melanoma cells through complement- and antibody-dependent cytotoxicity (Dippold et al., 1984). Another IgG3 MAb directed to GD3, B3.6, showed a clear antibody-mediated melanoma cell lysis (Cheresh et nl., 1985). Subsequently, a phase I clinical trial of R24 antibody in patients with malignant melanoma was carried out. Of 12 patients tested, 3 showed clear regression of tumors, and 4 patients showed a partial response (Houghton et al., 1985). Only inflammatory reactions (in the form of urticaria at the tumor lesion) were observed. GD3 is expressed highly in retina and moderately in kidney and gastrointestinal tissue, yet patients did not develop any visual, gastrointestinal, or renal disease symptoms. It is highly possible that GD3 in melanoma shows a specific organization which is susceptible to complementdependent cytolysis or to antibody-mediated effector cell attack. On the other hand, some melanoma cases showed no response to R24 antibody treatment, although GD3 was still highly expressed in melanoma of such cases; the reason for this phenomenon is not clear. Further elaborate immunobiological studies suggest that a threshold number of R24 molecules is necessary to initiate complement- and cell-mediated cytolysis; i.e., both mechanisms appear to depend on similar threshold quantities of R24 molecules (Welt et al., 1987). A similar IgG3 anti-GD3 antibody (MB3.6) has also been applied in clinical trials in melanoma patients. Of 12 patients, 3 showed partial regression of melanoma. In contrast, another antimelanoma antibody (9.2.27), directed to proteoglycan, did not show any effect upon administration of >lo0 mg of antibody (Herberman et al., 1985). Hellstrom et al. (1985) reported three mouse monoclonal IgG3 antibodies directed to GD3. All three antibodies mediated antibodydependent cytotoxicity in vitro and inhibited outgrowth of human melanoma xenografts in nude mice.
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Anti-GD3 antibody showed strong growth inhibition of melanoma cells in vitro (Dippold et al., 1984), activated IL-2 dependent natural killer cells, and potentiated mitogen-dependent T cell response in vitro (Hersey et al., 1986). IL-2 dependent proliferative and cytotoxic responses of T cell clones from melanoma patients were also activated by anti-GD3 antibody (Hersey et al., 1987). GD3 is expressed by a small subset of T cells which seems to respond to anti-GD3 antibody stimulation (Welt et al., 1987). Thus, the ganglioside GD3 expressed on human melanoma cells is an effective target in in vitro as well as in in vivo immune responses through complement-mediated and effector cell-mediated cytotoxicity by the IgG3 subclass. In more recent studies, such effect was enhanced by lymphokine IL-2. The IgG3 MAbs 14.18 and 116C4, directed against GD2 and GD3, respectively, when used in combination with human peripheral blood mononuciear cells and stimulated with IL-2, lysed melanoma and neuroblastoma cells; i.e., IL-2 displayed an “arming” effect on antibody-dependent cytotoxicity (Honsik et a&, 1986). Interestingly, however, anti-GD3 antibody R24 did not show any significant effect on human melanoma xenografts in nude mice; only a minimal effect was demonstrated at the earliest stage of melanoma development (Welt et al., 1987). This observation reinforces the important lesson that immune responses in mice are quite different from those in humans, and that the mouse model cannot always be adopted to human malignant phenomena. Melanomas, regardless of species, all express high concentrations of GM3. Antibody M2590, claimed to be specific to melanoma, was found to be directed to GM3 (see Sections V,D and IX). The IgG3 version of anti-GM3 antibody (DH2), originally directed to GM3 lactone, was growth inhibitory to mouse and human melanoma in vitm, displayed antibody-dependent cytotoxicity, and inhibited B 16 melanoma growth in syngeneic mice (Dohi et al., 1988). Thus, the DH2 antibody was similar in function to R24, but displayed a more striking effect on melanoma growth in syngeneic mice. The importance of complement-mediated cytotoxicity is fully demonstrated by the effect of human IgM MAb L72, which is directed to GD2 ganglioside. Irie and Morton (1986) injected this antibody into cutaneous metastasis of eight melanoma patients on a daily or weekly basis. Regression was seen in all tumors except those of two patients whose tumors were shown to have low GD2 expression. One patient with melanoma satellitosis, treated with L72, showed complete regression of tumor with no sign of recurrence. Furthermore, with the exception of mild erythema, no significant side effects were observed in any patient.
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B. EFFECT OF ANTIIDIOTYPE OR ANTI-ANTIIDIOTYPE ANTIBODIESON TUMOR GROWTH A second important approach utilizing MAbs is production and application of antiidiotype or anti-antiidiotype antibodies. Immunization with antiidiotype antibody may induce effective immune response to the antigen recognition site of the antibody, which mimics the antigen surface structure, i.e., the internal image of the antibody. The effective immune response is particularly true for anticarbohydrate idiotype antibody, since this could bypass a complex mechanism to cause anticarbohydrate immune response. Anti-antiidiotype antibody originally directed to a carbohydrate antigen may directly and efficiently attack tumor antigen. This is still a hypothesis, and practical application of anticarbohydrate idiotype has not been applied in inhibition of tumor cell growth in z;iz;o. So far, studies have been performed using MAbs with ill-defined antigen structure. Growing evidence in support of these approaches is again not within the scope of this article, but this area has been reviewed in connection with the antiidiotype antibody directed to the anti-17-1 MAb, which is directed to an intrinsic membrane glycoprotein (DeFreitas et al., 1985; Herlyn et al., 1986a). OF ANTIBODY-DRUG CONJUGATES TO TUMOR CELLS C. TARGETING
A third, but popular and perhaps relevant approach utilizing MAbs is based on the classical idea proposed by Paul Ehrlich (1906), who
envisioned the use of antibodies that possess the particular affinity needed to carry therapeutically active agents to specific cells. A number of studies along this line, utilizing MAbs, are being carried out; the MAbs are popularly termed “magic bullets.” Some work appears quite promising, despite the existence of a number of technical problems and pitfalls. This area of research has been reviewed repeatedly (Baldwin, 1985; Gregoriadis et al., 1986; Baldwin and Byers, 1986). An important factor in targeting antibody conjugates to tumor cells, however, is the intrinsic property of the antigen to which the antibody or its fragment is directed. The antigen (1)should be in high concentration and highly exposed at the cell surface; (2) should be sterically and metabolically stable; and (3)should not be shedding from the cell surface, but should be internalized when ligand binds to it. For this purpose, carbohydrate antigens carried by intrinsic membrane glycoproteins or bound to glycolipids are of particular importance. However, no intensive study with anticarbohydrate antibodies
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has been made. A study was published using biotinyl anti-Gga, avidin, and biotinyl neocarcinostatin as a targeting kit to kill L5178 lymphoma expressing Gg3 in vitro (Urdal and Hakomori, 1980) and in vivo (Hakomori et al., 1982). Using an avidin gold conjugate, the binding and internalization of the biotinylated antibreast cancer antibody MBr-1 in MCF-7 cells were effective. It is suggested that globo-H antigen defined by MBr-1 could be a good target for a toxin carrier agent (Della Torre et al., 1987). There are major drawbacks to the approach using immunotoxins or antibodies conjugated to drugs or liposomes, since the conjugates are rapidly taken up by cellular components of the reticuloendothelial system before they can reach the tumor cells. In addition, since antibody specificity is not highly restricted to tumor cells, the conjugates are targeted to some normal cell populations in addition to tumor cells. In view of these drawbacks, delivery of noncytotoxic differentiation inducers conjugated with anticarbohydrate antibodies seems to be an interesting approach for suppression of tumor growth. In theory, differentiation inducers could modify tumor cell growth by inhibiting malignant properties, while having little or no effect on normal cells and tissues. In an initial trial of this approach, the differentiation inducer sodium butyrate was encapsulated in liposomes covalently linked to anti-Le” IgG3antibody. The differentiation inducer was successfully targeted to human colonic adenocarcinoma cells expressing Le” antigen in uitro, as well as to in uivo cells grown in athymic nu/nu mice (M. Otaka et d., 1989).
D. ACTIVE IMMUNIZATION WITH TUMOR-ASSOCIATED ANTIGEN: EFFECTON TUMOR GROWTH Active immunization with tumor antigen to suppress tumor growth has had little success in the past. However, since tumor-associated carbohydrate antigens have been well established, the approach using purified glycolipid antigens or synthetic antigens should be reevaluated for possible tumor vaccine development. Immunization of syngeneic mice with the glycoprotein antigen of Lewis lung carcinoma purified by peanut lectin column was found to induce cytotoxic effector cells in vivo against Lewis lung carcinoma cells (as detected by Winn’s tumor neutralization assay), and reduced Lewis carcinoma lesions in the lungs after intravenous inoculation (Adachi et aZ., 1984). Because PNA receptor represents T antigen (Thomsen-Friedenreich antigen; GalPl- 3GalNAc), this epitope disaccharide coupled to
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bovine serum albumin (BSA) was used to immunize CAFl J (BALB x A/J) mice. The immunized animals showed delayed-type hypersensitivity (DTH) reaction against the disaccharide-BSA antigen (but not BSA or other carbohydrate-BSA complexes), and became resistant to growth of TA3Ha tumor cells, which show strong expression of T antigen (Henningsson et al., 1987). These two animal experiments indicate the possibility that carbohydrate antigens such as T or T-like antigens induce immune responses that can suppress tumor growth, possibly through cytotoxic T cell response, although the exact mechanism is still unknown. Recently, a similar PNA receptor glycoprotein (tumor-associated carbohydrate antigen; TCA) was purified from the gastric cancer cell line KATO-3 and was used for active immunization of more than 150 patients with various stages of cancer. Some cases showed a reduction of tumor growth (Adachi et aZ., 1988). Interestingly, the effective dose was as small as 50-200 ng of glycoprotein administered intradermally every 3 days and repeated weekly. All the cases in which the glycoprotein administration was effective showed a clear reduction of granulocytes and an increase of lymphocytes. Thus, the granulocyte/ lymphocyte ratio decreased significantly, while the cases in which the treatment was not effective did not show reduction of this ratio. No measurable antibody response nor DTH was recorded (Adachi et al., 1988). A less well-defined tumor-associated antigen (TAA) has also been used in immunotherapy trials, and Hollinshead and associates recently reported 5 years of accumulated data from a Phase I11 clinical trial. Active TAA immunotherapy was reported to be effective for successful suppression of tumors and significantly increased the survival rate of patients when the protocol was adhered to strictly. The survival rate of a total of 234 lung cancer patients in stage 1 and 2 during 5 years was 49% in the control groups, whereas the survival rate of patients receiving active immunotherapy was 70% (Hollinshead et d., 1987). Wallack and associates developed melanoma vaccines by infecting human melanoma cells grown in vitro with Vaccinia virus. The virus shed in the supernatant was pelleted (30,000 g for 2 hr), and 50-pg protein aliquots of the pellet (“Vaccinia melanoma oncolysate”; VMO) were injected intradermally in melanoma patients (Wallack et al., 1977, 1987; Bash and Wallack, 1988). Patients were divided into two groups, showing either IgM or IgG response, and the incidence of recurrence of the melanoma was correlated with the titer of antibodies directed to gangliosides. The higher the antiganglioside IgG antibody
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titer in sera of patients, the lower the incidence of recurrence (Bash et al., 1988).Therefore, the essential epitopes of VMO vaccine could be gangliosides. Morton et al. (1987)immunized 149 patients with stage I1 melanoma after surgery. Patients were treated in three groups: group 1 (surgery only); group 2 (surgery and adjuvant Bacillus Calmette-Guerin [BCG]); group 3 (surgery and adjuvant BCG with melanoma tumor-cell vaccine containing GD3, GM2 and GD2). A significant number of group 3 (but not group 1 or 2) patients developed antibodies against GD2 (IgM; two patients), GM2 (IgM; 10 patients), and GM2 (IgG; two patients). Because gangliosides GM2, GD2, and GD3 represent potential targets for immunological control of melanoma, a systematic study was performed which attempted to elicit immune response against gangliosides (Livingston et al., 1983). Bacillus Calmette-Guerin (BCG) coated with GM2 elicited anti-GMz antibody response in patients with melanoma, particularly those pretreated with cyclophosphamide. Anti-GMz antibodies in vaccinated patients were of the IgM class, and were cytotoxic for melanoma cells expressing GM2 in the presence of human complement (Livingston et al., 1987). In a preliminary followup study, tumor size was reduced and length of survival was increased in patients showing anti-GMz antibody response to vaccination, as compared with patients who did not show anti-GMz response; however, definite conclusions must await further studies (Livingston et al., 1988). XII. ,Summary and Perspectives
Aberrant glycosylation is the most common phenomenon associated with oncogenic transformation expressed in cell membranes of animal and human cancer cells. Many of the aberrant glycosylation products can be recognized by specific MAbs as tumor-associated carbohydrate antigens. Either incomplete synthesis with precursor accumulation or neosynthesis of aberrant structures results in accumulation of certain carbohydrates in high density at the tumor cell surface. They are present in the form of glycosphingolipids, or are associated with glycoproteins, particularly high-molecular-weight mucin-type glycoproteins. Those antigens whose epitope structure is clearly identified have been discussed according to the conventional classification: lacto-series type 1 and type 2, globo-series, ganglio-series. A few classes of important structures are as follows: (1) Elongated type 2 chain (i antigen) with penultimate and internal a1 - 3 fucosylated structures (Le', di-, tri-, or tetrameric Le") combined with a terminally
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a1 + 2 fucosylated structure (Leyand extended Ley) or a terminally sialylated structure (sialyl Le” or sialyl di- or trimeric Le”). (2) For type 1 chain derivatives, sialyl a2 +. 3 or 2 -+ 6 sialylated structures, with or without an a1 +. 4 fucosyl structure, are of great importance. (3) Incompatible blood group A antigen, or heterophile antigen expression, has now been clearly identified chemically and immunochemically. (4)Tn and sialyl Tn structures as tumor-associated antigens have been well defined by MAbs; the high incidence and intensity of expression of these antigens suggest potential clinical applicability. A unique possibility has been suggested based on oncofetal fibronectin: a common 0-glycosylation may induce conformational changes of polypeptides, which are recognized by specific antibodies. Many of these carbohydrate structures accumulating at the tumor cell surface are absent in progenitor cells, but may be found at low levels in other cell types. Antibodies that recognize tumor-associated antigens have the novel ability to recognize the density of antigen at the cell surface in excess of the threshold value, as well as the specific structure of the epitope. Many such antibodies are able to “ignore” subthreshold concentrations of the antigen present at the normal cell surface. Complement-mediated and effector cell-mediated tumor cell lysis may also depend on the concentration and density of carbohydrate antigen and the bound antibody at the cell surface. Variability of antigen expression can be associated with the stage of cancer development, from in situ, through actively infiltrating, to highly metastatic tumor. A tumor does not express one carbohydrate antigen exclusively; rather, most tumors express multiple tumorassociated antigens to different degrees at different loci within the tumor; this is termed “mosaicism” of antigen expression. Many anticarbohydrate antibodies have been utilized in detection of elevated tumor antigen in sera of patients with cancer, e.g., FH6 and FH7 for adenocarcinoma in general, and 19-9 for gastrointestinal tumors, particularly pancreatic cancer. Those fucosylated or fucosyl/ sialylated type 1 or type 2 chain epitopes useful in serum diagnosis are carried by mucin-type high-molecular-weight glycoproteins. Some tumor-associated glycolipid antigens, e.g., GD3 or GD2 ganglioside or 37-kDa glycoprotein (defined by 17.6 antibody), are not readily released in sera; they may be more suitable for antibody-mediated cytolysis as well as targeting by labeled antibodies or their derivatives. Imaging of tumor location through suitably labeled antibodies (or their fragments) directed to specific carbohydrate markers is another
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promising area of study. Knowledge of tumor location is of great clinical importance for effectively focused radiotherapy and surgical operations. Targeting of labeled antibodies, fragments, and their conjugates to tumors for delivery of antitumor drugs is obviously a popular and important approach. Yet carbohydrate antigens have not been utilized as the target for this approach. Extensive studies are expected to be made. Some carbohydrate antigens are strongly immunogenic if properly presented, and data from a few preliminary studies on the effect of active immunization with tumor-associated carbohydrate antigens on tumor growth are now available. Proper assembly of effective antigen in artificial membranes may produce stronger and more specific response, and may eventually lead to the development of tumor vaccines. Thus, our knowledge of the chemical structure and organization of tumor-associated antigens at the tumor cell surface, and their specific MAbs, is increasingly important for the development of more effective diagnostic methods, as well as various methods for treatment and prevention of human cancer.
ACKNOWLEDGMENTS The author wishes to thank Dr. John Magnani for providing information 011 mucintype antigens and Dr. Stephen Anderson for expert assistance during preparation of the manuscript. The author’s work has been supported by Outstanding Investigator Grant CA 42505 from the National Cancer Institute (National Institutes of Health), and b y funds from The Biomembrane Institute.
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NOTEADDED IN PROOF. Anti-LeX (SSEA-I) antibody labeled with lZ5I has been utilized for determination of antibody accumulation in tumor cells in uiuo.The labeled antibody was preferentially accumulated in various Lex-expressing human cancers grown in nude mice. Interestingly, the antibody did not accumulate in various normal tissues and organs (particularly kidney) which also express LeX (Ballou et al., 1984, 1986, 1987).These results suggest that either the Lex antigen expressed in normal tissues was cryptic, or the anti-SSEA-1 antibody was unable to recognize low density LeX but could recognize this antigen organized in high density at the tumor cell surface (Hakomori et al., 1981).
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A Acetylcholine, B cell-associated surface molecules and, 98 Activation B cell-associated surface molecules and. 127-132 Bgp95, 116 biochemically defined molecules, 119 CDZO, 91-99 CD21, 103 CDw40, 114, 115 expression, 127-132 pathway, 83-85 receptors, 125-127 T cells, 132 glutathione transferase and, 233 glycosylation in tumors and, 258, 312 Acute lymphoblastic leukemia chromosome abnormalities and, 18-22, 25 gene rearrangements and hematological neoplasias. 65, 66 simultaneous occurrence, 71 T cell antigen receptor, 55, 57 T cell receptor, 75 Acute myeloblastic leukemia, gene rearrangements and. 68, 70 Acute myeloid leukemia. chromosome abnormalities and, 9 Acute nonlymphocytic leukemia, chromosome abnormalities and. 9-14, 18 Acute promyelocytic leukemia, chromosome abnormalities and, 12 Adenovirus proteins, 151-154, 160, 161 MHC expression El9 protein, 155-157 early region l A , 154, 155 viral pathogenicity, 157-159 viral tumorigenicity, 159, 160 Adriamycin glutathione transferase and, 241 multidrug resistance and, 167 coamplified genes, 194 P-glycoprotein, 172, 173, 180, 189
Adult T cell leukemia chromosome abnormalities and, 24 gene rearrangements and. 59, 61 Agnogenic myeloid metaplasia, chromosome abnormalities and, 18 Alveolar rhabdomyasarcoma. chromosome abnormalities and, 30 Amino acids adenovirus proteins and, 154-157 B cell-associated surface molecules and CDZO, 93, 97-99 CD22, 107 CDZ3, 109. 110 CDw40. 113 chromosome abnormalities and, 37 gene rearrangements and, 46, 50-53 glutathione transferase and molecular forms, 216, 221, 222 preneoplasia, 208, 232, 233 multidrug resistance and, 180, 181, 187, 188 Anemia, chromosome abnormalities and, 13 Angioimmunoblastic lymphadenopathy, gene rearrangements and, 66, 67, 71 Anthracyclins, multidrug resistance and, 170, 193 Antibodies B cell-associated surface molecules and, 84, 85 Bgp95, 115 biochemically defined molecules, 118, 120 CD19, 99 CD20. 93 CD21, 103, 104 CD23, 109. 111 expression on activated cells, 128, 129 history, 86, 87 receptors, 126 gene rearrangements and, 46 B cell antigen receptor, 46-48 hematological neoplasias, 58, 67 simultaneous occurrence, 69 T cell antigen receptor, 49-51
3 34
INDEX
Antibodies (cont.) glutathione transferase and, 209, 224, 225, 227, 238. 239 glycosylation in tumors and, 259, 260, 317, 318 carbohydrate antigens, 264, 286, 289-291 diagnostic applications, 302-309 glycolipid antigens, 261, 262, 269, 270, 274, 275, 277, 280, 283 Hanganutziu-Deicher antigens, 296, 297 histo-blood group ABH antigens, 294 histo-blood p u p P antigens, 295 preneoplastic tissues, 297 requirements, 298-302 therapeutic applications, 310-316 multidrug resistance and, 195-197 amplified genes, 176 clinic, 194 P-glycoprotein, 175, 189-191 Antigens adenovirus proteins and, 151, 152, 160, 161 MHC expression, 153, 155, 158, 159 B cell-associated surface molecules and, 83, 84, 89-91, 134 Bgp95, 115, 116 biochemically defined molecules, 116-119, 121-123 CD19, 99-102 CD20, 91-99 CD21, 102-104 CD22. 105-108 CD23, 108-112 CDw40, 112-115 expression on activated cells, 128-130, 133 history, 86, 87 receptors, 127 T cells, 132 gene rearrangements and, 46 B cell antigen receptor, 46-49 hematological neoplasias, 58, 62, 63, 68 simultaneous occurrence, 69 T cell antigen receptor, 49-57 glutathione transferase and, 205, 210 glycosylation in tumoxs and, see Glycosylation in tumors multidrug resistance and, 183 Antioncogenes. chromosome abnormalities and, 31-34, 38
myelodysplastic syndromes, 15 solid tumors, 29 Ataxia-telangiectasia, gene rearrangements and. 75
B cell antigen receptor, gene rearrangements and, 46-49 B cell-associated surface molecules, 82, 83, 134, 135 activation. 83-85 biologically defined molecules BLA, 121, 122 CDlO, 116-118 CD24, 118, 119 CD37, 119, 120 CD39, 120, 121 expression, 122-124 differentiation antigens Bgp95, 115, 116 CD19, 99-102 CD20, 91-99 CD21. 102-104 CD22. 105-108 CD23, 108-112 CDw40, 112-115 expression, 89-91 expression on activated cells, 127-129 early, 129, 130 late, 130-132 history heteroantisera, 85-87 monoclonal antibodies, 87-89 receptors, 125-127 T cells, 132-134 B cell growth factors, 84, 85 biochemically defined molecules, 120 CD19. 102 CD20, 92, 96 CD21, 104 CD23, 110-112 CDw40, 114. 116 expression on activated cells, 129 receptors, 126, 127 B cell-stimulating factor 1, see Interleukin-4 B cell-stimulating factor 2, see Interleukin-6
INDEX
B cells chromosome abnormalities and acute lymphoblastic leukemia, 18, 20-22 chronic lymphoproliferative disorders, 22, 23 malignant lymphoma, 26 gene rearrangements and, 46 B cell antigen receptor, 46-49 hematological neoplasias, 58, 59, 64. 65. 68 simultaneous occurrence, 70, 72 T cell antigen receptor, 55, 56 glutathione transferase and, 240 B lymphocyte carcinoma cross-reacting antigen, 115, 120, 124, 131, 133 Bgp95, B cell-associated surface molecules and, 115, 116, 124 Bladder carcinoma, chromosome abnormalities and, 29 Bleomycin, multidrug resistance and, 167 Bone marrow chromosome abnormalities and acute lymphoblastic leukemia, 18 acute nonlymphocytic leukemia, 10, 11 cytogenic data, 7, 8 myelodysplastic syndromes. 13, 16 gene rearrangements and, 58 Burkitt's lymphoma B cell-associated surface molecules and biochemically defined molecules, 120-122, 124 differentiation antipens, 92, 108, 116 expression on activated cells. 129, 131 history, 87 receptors. 126 T cells. 133 chromosome abnormalities and acute lymphoblastic leukemia. 21 chronic myeloproliferative disorders, 23 malignant lymphoma, 25 oncogenes, 34, 35, 37 gene rearrangements and, 49, 64, 73 glycosylation in tumors and, 283, 298
C Calcium B cell-associated surface molecules and, 89 Bgp95, 116
335
biochemically defined molecules, 120. 121, 124 CD19, 101. 102 CDZO, 93, 97 CD21, 104 CD22, 107 expression on activated cells, 133 gene rearrangements and, 50 glutathione transferase and. 209 multidrug resistance and, 171, 193 Carbohydrate adenovirus proteins and, 156 B cell-associated surface molecules and biochemically defined molecules. 118 differentiation antigens, 100. 105, 106, 115. 116 multidrug resistance and, 172, 174. 183 Carbohydrate antigens, glycosylation in tumors and, 258, 260, 262-266. 316-318 background, 283, 284 glycoprotein, 287-291 lacto-series antigens, 284. 285 peptide, 291. 292 requirements, 298-302 T antigens, 285-287 therapeutic applications, 309-316 Carcinoembryonic antigen, glycosylation in tumors and, 285, 308 CDl molecules, B cell-associated surface molecules and, 133 CDZ molecules, B cell-associated surface molecules and, 85, 133, 134 CD3 molecules B cell-associated surface molecules and, 88, 133 gene rearrangements and hematological neoplasias, 60-63, 67 T cell antigen receptor, 50, 52 CD4 molecules B cell-associated surface molecules and, 85, 88, 108 gene rearrangements and hematological neoplasias, 60, 61, 63 T cell antigen receptor, 49, 51 CD5 molecules, B cell-associated surface molecules and, 88, 132, 133 CD8 molecules B cell-associated surface molecules and, 85 gene rearrangements and
336
INDEX
CD8 molecules, gene arrangements and (cont.) hematological neoplasias, 60. 63 T cell antigen receptor, 49, 51 CDlO molecules, B cell-associated surface molecules and, 100. 116-118 CD18 molecules, B cell-associated surface molecules and, 85 CD19 molecules, B cell-associated surface molecules and, 135 biochemically defined molecules, 124 differentiation antigens, 91, 97, 99-102, 116 CDZO molecules, B cell-associated surface molecules and. 135 activation, 91-99 biochemically defined molecules, 124 differentiation antigens, 102, 103, 110, 114 CDZl molecules, B cell-associated surface molecules and, 85, 102-104, 131 CDZZ molecules, B cell-associated surface molecules and, 91, 97. 105-108 CD23 molecules, B cell-associated surface molecules and, 85 biochemically defined molecules, 121 differentiation antigens, 114 expression on activated cells, 128, 131 CD24 molecules, B cell-associated surface molecules and, 118, 119 CD37 molecules, B cell-associated surface molecules and, 97, 119, 120, 123 CD39 molecules, B cell-associated surface molecules and, 97, 116, 120, 121 cDNA B cell-associated surface molecules and. 134, 135 biochemically defined molecules, 120, 121 CDZO, 96, 97 CD21, 104 CD22, 105, 106 CDZ3, 109 CDw40, 113, 115 T cells, 133 gene rearrangements and, 50-52 glutathione transferase and molecular forms, 216, 218, 222 multidrug resistance, 242 preneoplaia, 209, 223, 224, 231-233 glycosylation in tumors and, 290
multidrug resistance and, 197 clinic, 193 P-glycoprotein, 175, 176, 180, 184. 185, 188, 191 CDw40, B cell-associated surface molecules and, 134, 135 biochemically defined molecules. 123 differentiation antigens, 97, 112-116 expression on activated cells, 128 Centromeres chromosome abnormalities and, 6 gene rearrangements and, 55, 75 Ceramide, glycosylation in tumos and, 301, 302 Chloramphenicol acetyltransferase. glutathione transferase and, 232 Chromatin, gene rearrangements and, 72 Chromosome abnormalities, 2-4, 37, 38 acute lymphoblastic leukemia, 18-22 acute nonlymphocytic leukemia, 9-13 antioncogenes. 30-34 chronic myeloproliferative disorders, 16-18 cytogenic data, 7-9 cytogenic nomenclature, 4-7 malignant lymphoma, 24-27 myelodysplastic syndromes, 13-16 oncogenes, 30, 31, 34-37 solid tumors, 27-30 Chromosomes B cell-associated surface molecules and. 130, 131 gene rearrangements and B cell antigen receptor, 49 hematological neoplasias, 58, 64 T cell antigen receptor, 52, 53. 55 T cell receptor, 72-75 glutathione transferase and, 233 multidrug resistance and, 176, 178 Chronic lymphocytic leukemia B cell-associated surface molecules and differentiation antigens, 100. 103, 105 expression, 130, 131 history, 87 T cells, 132, 133 chromosome abnormalities and, 22, 23, 26 gene rearrangements and, 60, 64, 65 Chronic lymphoproliferative disorders, chromosome abnormalities and. 22-24
INDEX
Chronic myeloid leukemia chromosome abnormalities and, 2, 3, 16, 17 acute lymphoblastic leukemia, 21 acute nonlymphocytic leukemia, 10 oncogenes, 36, 37 gene rearrangements and, 73 Chronic myelomonocytic leukemia, chromosome abnormalities and, 13. 15. 16 Chronic myeloproliferative disorders, chromosome abnormalities and, 16-18, 22-24 Chronic myelosis, chromosome abnormalities and, 13 Clones adenovirus proteins and, 158 B cell-associated surface molecules and, 96, 97, 102, 104, 120 chromosome abnormalities and, 38 acute lymphoblastic leukemia, 18 acute nonlymphocytic leukemia, 9 cytogenic nomenclature. 7 myelodysplastic syndromes, 16 solid tumom 29 gene rearrangements and, 46 B cell antigen receptor, 48 hematological neoplasias, 57-59, 63, 64, 66, 68 simultaneous occurrence, 69, 70, 72 T cell antigen receptor, 49-52 glutathione transferase and, 216, 232, 233 glycosylation in tumom and, 290, 312 multidrug resistance and, 185 Cutaneous T cell lymphomas. gene rearrangements and, 59-61 Cyclosporin A, multidrug resistance and, 171, 195 Cysteine, B cell-associated surface molecules and, 97, 99, 110, 113 Cytokines. B cell-associated surface molecules and, 125-127 Cytoplasm adenovirus proteins and, 156, 157 B cell-associated surface molecules and, 83 biochemically defined molecules, 124 CD19, 100-102 CD20, 91, 98, 99 CD21, 104
337
CD22, 105-107 CD23, 110 CDw40, 113 expression on activated cells, 133 gene rearrangements and, 59 multidrug resistance and, 182, 183 Cytosol, glutathione transferase and molecular forms, 212, 214, 215, 220, 222 preneoplasia, 225, 229, 236 Cytotoxic T lymphocytes, adenovirus proteins and, 151, 158, 159
Daunorubicin, multidrug resistance and, 167, 171, 195 Delayed type hypersensitivity, glycosylation in tumors and, 315 Deletion chromosome abnormalities and acute lymphoblastic leukemia, 20 acute nonlymphocytic leukemia, 12 Togenic nomendature, 6 malignant lymphoma, 26 myelodysplastic syndromes, 15 gene rearrangements and, 63-65 Dendrites, B cell-associated surface molecules and, 92, 103 Diethylenetriaminepentaaceticacid, glycosylation in tumors and, 308, 309 Differentiation, B cell-associated surface molecules and, 82, 134 antigens, see Antigens biochemicallydefined molecules, 118. 119. E2 expression on activated cells, 128 history, 86, 87 pathway, 83-85 receptors, 125 T cells, 132 Disulfide bonds, B cell-associated surface molecules and, 98, 105 DNA adenovirus proteins and, 152-154 B cell-associated surface molecules and, 89, 96 chromosome abnormalities and, 3. 38 antioncogenes, 31, 32
338
INDEX
DNA, chromosome abnormalities and (cont.) chronic myeloproliferative disorders, 17 malignant lymphoma, 26 oncogenes, 35 gene rearrangements and, 45 B cell antigen receptor, 47 hematological neopiasias, 57-59, 64, 65 T cell antigen receptor. 52, 53 glutathione transferase and molecular forms, 218, 222 multidrug resistance. 242 preneoplasia, 223, 224, 231, 232, 237 multidrug resistance and, 166, 167 amplified genes, 176, 178 P-glycoprotein, 179, 180, 183, 186
CD19, 100 CDZO. 93, 99 CD21, 102-104 CD23, 108, 112 expression on activated cells, 131, 133 history, 88 receptors, 126 glycosylation in tumors and, 283 Escherichiu coli, multidrug resistance and, 184 Essential thrombocytopenia, chromosome abnormalities and, 18 Eukaryotes adenovirus proteins and, 156 mukidrug resistance and, 185 Ewing’s sarcoma, chromosome abnormalities and, 30
E F Electron microscopy, multidrug resistance and, 189 Endoplasmic reticulum adenovirus proteins and, 156, 157, 160, 161 multidrug resistance and, 189 Eosinophils, chromosume abnormalities and, l2 Epidermal growth factor, multidrug resistance and, 172 Epitopes B cell-associated surface molecules and, 134 biochemically defined molecules, 118-120 CD19, 100 CDZl, 103, 104 CDPP, 105, 107 CD23, 109, 111 CDw40, 113, 115 gene rearrangements and, 47 glycosylation in tumors and, 317 carbohydrate antigens, 262, 286-292, 302 diagnostic applications, 303, 305, 308 glycolipid antigens. 283-285 histo-blood group ABH antigens, 294 therapeutic applications, 311, 314, 316 multidrug resistance and, 183, 189 Epoxide hydrolase, glutathione transferase and. 210 Epstein-Barr virus B cell-associated surface molecules and biochemically defined molecules, 121
Fibroblasts, gene rearrangements and, 52, 59 Fibronectin, glycosylation in tumors and. 291. 317 Fonsman antigens, glycosylation in tumors and, 294-296 French-American-Britishclassification, chromosome abnormalities and, 9, 12, 13, 18 Fucosylation, glycosylation in tumors and, 316, 317 diagnostic applications, 303 glycolipid antigens, 268-270, 273-275, 277
Ganglio-series antigens, glycosylation in tumors and. 277-281, 316 Gangliosides. glycosylation in tumors and, 259, 317 carbohydrate antigens, 298, 300. 302 diagnostic applications, 306. 307, 309 glycolipid antigens, 262, 277-281 histo-blood group ABH antigens, 296, 297 therapeutic applications, 311, 312, 315. 316 Gangliotriaosylceramide,glycosylation in tumors and carbohydrate antigens, 299, 301. 311 glycolipid antigens, 261, 280 oncogenes, 267
339
INDEX
Gene rearrangements, lymphoproliferative disorders and, see Lymphoproliferative disorders Globo-series antigens, glycosylation in tumors and, 281-283, 316 Glucose 6-phosphate dehydrogenase, gene rearrangements and, 58 Glutathione transferase. 205-207, 242, 243 human GT-q. 239, 240 molecular forms, 221, 222 human, 218-220 mouse, 280, 221 properties, 212-215 rat, 215-218 multidrug resistance, 241, 242 preneoplastic markers, 223, 226, 238, 239 hepatic enzymes, 207-211 nonhepatic enzymes, 211, 212 rat GT-P application, 237 extrahepatic preneoplasia, 237, 238 function. 233, 234, 236, 237 gene expression, 231-233 hepatocarcinogenesis, 225, 227-229 identification, 222, 224 specificity, 229-231, 235 tissue distribution, 224. 225 Glycolipid antigens, glycosylation in tumors and, 259, 260, 317 carbohydrate, 264 diagnostic applications, 302, 303, 308 ganglio-series, 277-281 globo-series, 281-283 histo-blood group P antigens, 295 lacto-series, 268-277 oncogenes, 267 preneoplastic tissues, 297 requirements, 298, 300-302 therapeutic applications, 313, 314 Glycoprotein. see also Permeability glycoprotein adenovirus proteins and. 152, 156 B cell-associated surface molecules and biochemically defined molecules, 117, 119, 121, 123, 124
diagnostic applications, 305-308 glycolipid antigens, 267 histo-blood group P antigens, 295 therapeutic applications, 313-315 multidrug resistance and, 172 Glycosphingolipids. glycosylation in tumors and, 262, 267, 307, 316 Glycosylation B cell-associated surface molecules and biochemically defined molecules, 118, 121, 123
differentiation antigens, 100, 106, 107, 110, 113
expression on activated cells, 131 multidrug resistance and, 173, 175. 183 Glycosylation in tumors, 258-260, 316-318 carbohydrate antigens, 262-266 background, 283, 284 glycoprotein, 287-291 lacto-series, 284, 285 peptide, 291, 292 requirements, 298-302 T antigens, 285-287 therapeutic applications, 309-316 diagnostic applications earlier studies, 302. 303 serum antigen-antibody complex, 307, 308 serum antigen levels, 303-307 tumor imaging, 308, 309 Forssman antigens, 296 glycolipid antigens, 260-262 background, 267 ganglio-series, 277-281 globo-series, 281-283 lacto-series type 1 chain, 268-271 lacto-series type 2 chain, 270, 272-277 Hanganutziu-Deicher antigens, 296, 297 histo-blood group ABH antigens, 292-294 histo-blood p u p P antigens, 294-296 oncogenes, 264. 267 preneoplastic tissues, 297 Gramkidin, multidrug resistance and, 167
H
differentiation antigens, 100, 103, 108, 113, 115, 116
gene rearrangements and. 50 glycosylation in tumors and. 260, 316, 317 carbohydrate antigens, 262, 283-291
Hairy cell leukemia, chromosome abnormalities and, 24 Hanganutziu-Deicher antigens, glycosylation in tumors and, 296, 297
340
INDEX
Heat shock, adenovirus proteins and, 154 Hematological neoplasias, gene rearrangements and, 57-68 Hematopoietic cells, gene rearrangements and, 72 Hematopoietic dpplasia, chromosome abnormalities and, 13 Hemolysin, multidrug resistance and, 181-184 Hemopoietic stem cells, gene rearrangements and, 49 Hepatic marker enzymes, glutathione transferase and, 207-211 Hepatitis B virus, adenovirus proteins and, 158 Hepatocarcinogenesis, glutathione transferase and, 206, 242 molecular forms. 216, 221 preneoplasia, 209, 211. 222, 225, 227-234, 237 Herpes simplex virus, adenovirus proteins and, 159 Heteroantisera, B cell-associated surface molecules and, 85-87, 97. 115, 122 Histo-blood group ABH antigens, glycosylation in tumors and, 292-294 Histo-blood group P antigens, glycosylation in tumors and, 294-296 Hodgkin’s disease chromosome abnormalities and, 24, 26, 27 gene rearrangements and, 66-68 Homology, gene rearrangements and, 47, 50, 53. 55 Hormones B cell-associated surface molecules and, 113, 125 glutathione transferase and, 214, 231, 236 HTLV-I retrovirus chromosome abnormalities and, 24 gene rearrangements and. 61 Hybridomas B cell-associated surface molecules and, 109 glycosylation in tumors and, 264, 280, 296. 304 Hybrids adenovirus proteins and, 157 chromosome abnormalities and, 31 gene rearrangements and. 50, 55, 58, 72, 75
glutathione transferase and, 209 multidrug resistance and amplified genes. 175-177 P-glycoprotein, 179, 187, 189
I Idiopathic myelofibrosis. chromosome abnormalities and, 18 Immunoglobulins adenovirus proteins and, 152, 157 B cell-associated surface molecules and, 83, 118, 120, 122, 124, 129 biochemically defined molecules, 118, 120, 122, 124 CD19, 99, 101, 102 CD20, 91, 93, 96 CDZI, 102, 103 CD22, 105-108 CD23, 108-112 CDw40, 114, 115 expression on activated cells, 129 history, 86, 87 T cells, 132 chromosome abnormalities and acute lymphoblastic leukemia, 20-22 chronic lymphoproliferative disorders, 23 malignant lymphoma, 25, 26 oncogenes, 35 gene rearrangements and, 46 B cell antigen receptor, 46-49 hematological neoplasias, 57-68 simultaneous occurrence, 69-72 T cell antigen receptor, 50-56 T cell receptor, 73 glycosylation in tumors and carbohydrate antigens, 299, 311. 314-316 diagnostic applications, 302, 304 glycolipid antigens, 261, 270 Immunoprecipitation. gene rearrangements and, 51 Insulin, chromosome abnormalities and, 18 Interferon adenovirus proteins and, 155, 160 B cell-associated surface molecules and, 126, 127 chromosome abnormalities and, 12 glutathione transferase and, 221 Interleukin, gene rearrangements and, 50
INDEX
Interleukin-1, B cell-associated surface molecules and, 126, 127 Interleukin-2 B cell-associated surface molecules and, 84, 85 expression on activated cells, 127, 130, 132 receptors, 125 T cells, 133 glutathione transferase and, 233, 240 glycosylation in tumors and, 312 Interleukin-4, B cell-associated surface molecules and, 134 differentiation antigens, 108, 111, 114, 116 expression on activated cells. 127 receptors, 125-127 Interleukin-5, B cell-associated surface molecules and, 84 Interleukin-6, B cell-associated surface molecules and, 85, 126, 127, 134 Internalization B cell-associated surface molecules and biochemically defined molecules, 118 CD20. 92, 93, 96 CD21, 104 CD23, 110, 111 glycosylation in tumors and, 313, 314 Inversion, chromosome abnormalities and, 6
K Ki 1' lymphomas, gene rearrangements and, 67. 71
L Lacto-series antigens, glycosylation in tumors and, 283-285 type 1, 316 carbohydrate antigens, 262 glycolipid antigens, 268-271 type 2. 316 carbohydrate antigens, 262 glycolipid antigens, 270, 272-277 Latent membrane protein, B cell-associated surface molecules and, 99 Lectin, glycosylation in tumors and, 285, 289, 293, 301, 314
341
Lennert's lymphoma, gene rearrangements and, 66, 69, 70 Leukemia, see also specific leukemia B cell-associated surface molecules and biochemically defined molecules, 116-118, 120 differentiation antigens, 91, 92, 96. 100, 114 expression on activated cells, 130-132 history, 87 receptors, 125 chromosome abnormalities and, 3, 38 gene rearrangements and hematological neoplasias, 59, 62, 63 simultaneous occurrence, 70-72 T cell antigen receptor, 50, 52, 56 T cell receptor, 74 glutathione transferase and, 215 glycosylation in tumom and, 264, 275, 280 multidrug resistance and, 195 Ligands B cell-associated surface molecules and, 85, 110, 127, 134 chromosome abnormalities and, 37 glycosylation in tumors and, 301, 313 Light microscopy, chromosome abnormalities and, 20 Lipids glutathione transferase and, 213, 234 glycosylation in tumors and, 258, 259, 262, 302 multidrug resistance and. 170, 173 Lipogenic tumors, chromosome abnormalities and. 29, 30 Lung cancer, chromosome abnormalities and, 27 Lymphoblasts, chromosome abnormalities and, 20 Lymphocytes, gene rearrangements and hematological neoplasias, 57, 58, 63, 64, 66, 67 T cell antigen receptor, 54 Lymphoid cells, gene rearrangements and B cell antigen receptor, 47 hematological neoplasias, 57, 58, 66, 68 simultaneous occurrence, 69-72 Lymphokines. gene rearrangements and, 49 Lymphomas, see also specific lymphoma chromosome abnormalities and acute lymphoblastic leukemia, 21, 22
342
INDEX
Lymphomas, chromosome abnormalities and (cont.) cytogenic data, 8 malignant. 24-27 gene rearrangements and hematological neoplasias, 59-62, 64,66-68 simultaneous occurrence, 70, 71 T cell receptor, 74 Lymphomatoid papulosis, gene rearrangements and, 64 Lymphoproliferativedisorders. 45, 46 B cell antigen receptor, 46-49 hematological neoplasias, 57-59 acute myeloblastic leukemia, 68 B cell malignancies, 64, 65 chronic T cell malignancies, 59-61 lymphomas, 66-68 lymphomatoid papulosis, 64 pre-B cell malignancies, 65, 66 T cell acute lymphoblastic leukemia, 62, 63 T cell lymphomas, 61. 62 T lymphoproliferative disorder, 63 immunoglobulin genes, 69-72 T cell antigen receptor genomic organization, 52-56 role, 49 somatic rearrangement, 56, 57 structure, 49-52 T cell receptor chromosomal translocation, 72-75 simultaneous occurrence. 69-72 Lymphotoxin, B cell-associated surface molecules and, 84, 112, 127 Lysosomes, multidrug resistance and, 169
M Major histocompatibility complex adenoviw proteins and, 151, 152. 160, 161 expression, 154-160 B cell-associated surface molecules and, 83 antigens. 91-93, 112-114. 116 expression, 128, 131 gene rearrangements and, 49-51 Meningioma, chromosome abnormalities and, 30 Metallothionein, chromosome abnormalities and, 12 Methotrexate, multidrug resistance and, 168
&-Microglobulin, adenoviw proteins and, 152, 155 Mitogens, chromosome abnormalities and, 22 Monoclonal antibodies B cell-associated surface molecules and. 85, 116, 118-124, 134 Bgp95, 116 CD19. 100-102 CD20, 92, 93, 96 CD21, 102-104 CD22, 105, 107 CD23, 108, 109, 111, 112 CDw40, 113-115 expression. 127, 129, 130 history, 87-89 T cells, 133 glutathione transferase and, 211 glycosylation in tumors and, 260, 316-318 carbohydrate antigens, 262, 264, 284-289, 291, 300 diagnostic applications, 303-308 Forssman antigens. 296 glycolipid antigens, 261, 267, 269. 273-277, 280, 283 Hanganutziu-Deicher antigens, 293, 294 oncogenes, 267 therapeutic applications, 310-313 multidrug resistance and, 174, 175, 183. 189 Monosomy, chromosome abnormalities and, 13, 15, 16, 29, 30 mRNA B cell-associated surface molecules and, 96, 97, 112. 135 chromosome abnormalities and, 20, 36, 37 gene rearrangements and, 62, 63, 72, 75 glutathione transferase and, 209, 224, 231-233, 240 multidrug resistance and, 176, 179, 187, 189 Multidrug resistance, 165, 166 alterations, 172-174 amplified genes, 175-178 clinic, 194, 195 coamplified genes. 192-194 drugs affected. 166-168 events, 169-171 glutathione transferase and, 241-243 outlook, 195-197 P-glycoprotein diversity, 185-188 expression, 189-192 genes. 178-180
343
INDEX
mutation, 188, 189 overproduction, 174, 175 structure, 180-185 pharmacological reversal, 171, 172 Mutation adenovirus proteins and, 154, 158 B cell-associated surface molecules and, 134 chromosome abnormalities and, 2, 4, 34 gene rearrangements and, 47, 50 glutathione transferase and, 237 multidrug resistance and, 167. 196 amplified genes, 175 coamplified genes, 194 P-glycoprotein, 175, 185, 188, 189 Mycosis fungoides, gene rearrangements and, 59-61
Myelodysplastic syndromes, chromosome abnormalities and, 10, 13-17
acute nonlymphocytic leukemia, 12 malignant lymphoma, 25. 26 myelodysplastic syndromes. 15 gene rearrangements and, 49, 57, 73, 75 glycosylation in tumors and, 264, 267, 316 Open reading frames, adenovirus proteins and, 154 Osteosarcoma, chromosome abnormalities and, 33
P Parasites, B cell-associated surface molecules and, 111 Peptides adenovirus proteins and, 152, 155, 161 B cell-associated surface molecules and, 97. 106, 115
N
gene rearrangements and. 50, 51 glycosylation in tumors and, 284, 287. 291, 292
Natural killer cells, gene rearrangements and, 63 Neoplasia chromosome abnormalities and, see Chromosome abnormalities glutathione transferase and, 205, 206, 238 hematological, gene rearrangements and, 57-68
Neoplasms, gene rearrangements and, 70, 72 Nerve growth factor, B cell-associated surface molecules and, 113, 114 NIL cells, glycosylation in tumors and, 260, 261
Non-Hodgkin’s lymphomas, chromosome abnormalities and, 24-27 Nucleotides adenovirus proteins and, 155 chromosome abnormalities and, 36 gene rearrangements and, 47. 53 glutathione transferase and, 232 mulridrug resistance and, 181, 196
Oncogenes chromosome abnormalities and, 31, 33-38 acute lymphoblastic leukemia, 19, 20
multidrug resistance and, 167, 184 Permeability gtycoproteins glutathione transferase and, 241 multidrug resistance and, 166. 195-197 alterations, 172-174 clinic, 195 coamplified genes, 192-194 diversity, 185-188 expression, 189-192 genes, 178-180 mutation, 188. 189 overproduction, 174, 175 structure, 180-185 pH, B cell-associated surface molecules and, 109, 113
Phenobarbitol. glutathione transferase and, 208. 209. 228
Phenotype adenovirus proteins and, 154 B cell-associated surface molecules and, 102, 122
chromosome abnormalities and. 19, 31, 32 gene rearrangements and hematological neoplasias, 59, 62-64 simultaneous occurrence, 69-71 glutathione transferase and, 205, 206. 210, 211
glycosylation in tumors and. 258. 264
344
INDEX
Phenotype (cont.) multidrug resistance and, 185, 188, 196 alterations, 173, 174 coamplified genes, 192-194 Philadelphia chromosome, chromosome abnormalities and. 2. 3, 16, 17, 21 Phorbol myristate acetate, B cell-associated surface molecules and Bgp95, 116 CD20, 92, 93 CD22, 105, 106 CDw40, 115 expression, 129 Phosphatidylinositol. B cell-associated surface molecules and, 131 Plasma cells, B cell-associated surface molecules and, 82 biochemically defined molecules, 119. , 120, 122 differentiation antigens, 91, 99 expression on activated cells, 128 history, 86, 88 T cells, 133, 134 Pokeweed mitogen. B cell-associated surface molecules and, 91, 119. 125 Polycythemia Vera, chromosome abnormalities and, 17, 18 Polypeptides adenovirus proteins and. 156 B cell-associated surface molecules and, 82, 134 biochemically defined molecules, 120, 122-124 differentiation antigens, 109, 110, 112, 113 expression on activated cells, 129-131 chromosome abnormalities and, 35, 37 gene rearrangements and B cell antigen receptor, 46-48 T cell antigen receptor, 49-52, 54 glutathione transferase and, 225 glycosylation in tumors and, 262, 291. 292, 317 multidrug resistance and, 175, 184 Preneoplasia glutathione transferase and, see Glutathione transferase glycosylation in tumors and, 293, 297 Prolymphocytic leukemia B cell-associated surface molecules and, 92
chromosome abnormalities and, 23, 24 Proteases B cell-associated surface molecules and, 106, 110, 126 glycosylation in tumors and, 260, 287. 300, 301 multidrug resistance and, 193 Protein adenovirus, see Adenovirus proteins B cell-associated surface molecules and, 89, 135 biochemically defined molecules, 122, 124 CD19. 99, 101 CD20, 96-99 CD21, 103 CD22, 105. 106 CD23, 108, 110, 112 CDw40, 113 expression on activated cells, 129 chromosome abnormalities and, 21, 32, 35-37 gene rearrangements and, 50, 51, 55 glutathione transferase and, 242 molecular forms, 212-214, 216 P-glycoprotein, 211, 231, 236 glycosylation in tumors and carbohydrate antigens, 262, 290, 291. 300, 301 diagnostic applications. 307, 308 multidrug resistance and, 166 alterations, 172. 174 amplified genes, 176 coamplified genes, 192, 193 P-glycoprotein. 175, 180, 181, 183-185, 187-190 Protein kinase, gene rearrangements and, 50 Protein kinase C B cell-associated surface molecules and. 92, 93, 103 glutathione transferase and, 242 multidrug resistance and, 192 Protooncogenes, chromosome abnormalities and, 21, 22, 34, 35
R Receptors adenovirus proteins and, 151
345
INDEX
B cell-associatedsurface molecules and, 134 biochemically defined molecules, 118 cytokines, 125-127 differentiation antigens, 107, 112-115 expression on activated cells, 127. 130 Reed-Stemberg cells. gene rearrangements and, 66-68 Refractory anemia with excess of blasts, chromosome abnormalities and, 13, 14, 16 Refractory anemia with excess of blasts in transformation, chromosome abnormalities and, 13, 14, 16 Refractory anemia with ringed sideroblasts, chromosome abnormalities and, 13, 15 Refractory anemia without excess of blasts, chromosome abnormalities and, 15-15 Renal cell carcinoma, chromosome abnormalities and, 27, 29 Replication, adenovirus proteins and, 153, 154 Restriction fragment length polymorphism chromosome abnormalities and, 31, 32 gene rearrangements and, 52 Retinoblastoma, chromosome abnormalities and, 31-33 Retrovirus chromosome abnormalities and, 24, 34 gene rearrangements and, 61 glycosylation in tumors and, 264, 267 multidrug resistance and, 197 RNA B cell-associated surface molecules and, 96, 98, 107 chromosome abnormalities and. 36 gene rearrangements and, 70 glutathione transferase and, 218, 231, 232 glycosylation in tumors and, 259 multidrug resistance and, 166, 176, 177. 190
S Salivary gland tumors, chromosome abnormalities and, 27, 29 Sezary syndrome, gene rearrangements and, 60, 61 Sialic acid, glycosylation in tumors and, 280, 291
Signal transduction, B cell-associated surface molecules and, 99, 114, 134 Small cell lung cancer, chromosome abnormalities and, 27 Solid tumors, chromosome abnormalities and, 8, 27-30, 38 Somatic hypermutation, gene rearrangements and, 47, 53 Steroids glutathione transferase and, 213, 214 multidrug resistance and, 168 Synovial sarcoma, chromosome abnormalities and. 30
T T cell acute lymphoblastic leukemia, gene rearrangements and, 62, 63, 66, 73 T cell antigen receptor, gene rearrangements and, 46 genomic organization, 52-56 role, 49 somatic rearrangement, 56, 57 structure, 49-52 T cell chronic lymphocytic leukemia, gene rearrangements and, 59-61 T cell prolymphocytic leukemia, gene rearrangements and, 59, 60 T cell receptor genes, gene rearrangements and, 46 chromosomal translocations, 72-75 hematological neoplasias, 57-68 simultaneous occurrence, 69-72 T cells adenovirus proteins and, 152 B cell-associated surface molecules and, 82, 132-134 biochemically defined molecules, 118, 119, 124 CD20, 91 CD21, 103 CD22, 105, 107, 108 CDZ3, 109 expression on activated cells, 127, 130-132 history, 86-88 receptors. 125, 127 chromosome abnormalities and, 22-24, 26 glutathione transferase and, 240 glycosylation in tumors and, 310, 312. 315
346
INDEX
Terminal deoxynucleotidyltransferase,gene rearrangements and, 47, 54, 68, 73 12-0-Tetradecanoylphorbol-13acetate B cell-associated surface molecules and, 93. 99, 102, 111. 114, 119
glutathione transferase and, 233, 242 Thymocytes B cell-associated surface molecules and, 86 gene rearrangements and, 51, 56, 71, 72 Topoisomerase 11, multidrug resistance and, 167. 193
Transcription adenovirus proteins and, 152-155 B cell-associated surface molecules and, 83, 98
chromosome abnormalities and, 21, 25. 26, 35
glutathione transferase and, 232 multidrug resistance and, 195 amplified genes, 176 P-glycoprotein, 179, 185, 186, 188, 192 Transfemn B cell-associated surface molecules and, 110
chromosome abnormalities and, 10 Transforming growth factor, B cell-associated surface molecules and, 85 Translation, B cell-associated surface molecules and, 96, 98 Translocation chromosome abnormalities and acute lymphoblastic leukemia, 19-22 acute nonlymphocytic leukemia, 10-12 chronic lymphoproliferative disorders, 23. 24
chronic myeloproliferative disorders, 16, 17
cytogenic nomenclature, 6 malignant lymphoma, 25, 26 oncogenes, 34-36 solid tumors, 27. 29, 30 gene rearrangements and, 46 B cell antigen receptor, 49 hematological neoplasias, 57 T cell receptor, 72-75 multidrug resistance and, 183 Tiisomy 3, chromosome abnormalities and, 25 TrisOmv 7, chromosome abnormalities and, 29
Trisomy 8, chromosome abnormalities and, 13, 15, 16
Tubulin, multidrug resistance and, 166, 194 Tumor necrosis factor adenovirus proteins and, 158 B cell-associated surface molecules and, 84. 127
Tumors adenovirus proteins and, 159, 160 B cell-associated surface molecules and biochemically defined molecules, 117, 118, 122
differentiation antigens, 92, 108, 114 history, 86 receptors, 125 chromosome abnormalities and, 2-4, 37. 38 acute lymphoblastic leukemia, 22 antioncogenes. 31-33 malignant lymphoma, 25 oncogenes, 30. 31, 34 solid tumors, 27-30 gene rearrangements and hematological neoplasias, 58, 59, 61, 64, 67
simultaneous occurrence, 71 T cell antigen receptor, 57 T cell receptor, 72 glutathione transferase and, 205. 243 multidrug resistance, 241 preneoplasia, 229, 232, 239, 240 glycosylation in, see Glycosylation in tumors multidrug resistance and, 166. 167 amplified genes, 174 clinic, 194, 195 P-glycoprotein, 178, 189 Tyrosine kinase, chromosome abnormalities and, 21, 37
U Uterine leiomyomas, chromosome abnormalities and, 29
v Verapamil, multidrug resistance and. 171, 172, 180
347
INDEX
Vesicular stomatitis virus. glycosylation in tumoni and, 261 Vinblastine, multidrug resistance and, 171, 175, 189 Vincristine. multidrug resistance and, 167
Y Yeast, multidrug resistance and, 185
Z Zinc, chromosome abnormalities and, 12 Wild-type virus, adenovirus proteins and, 158 Wilms’ tumor chromosome abnormalities and, 31-33 gene rearrangements and, 73
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