Human Cancer Markers

442 Pages·1982·19.92 MB·English

by  William C. Raschke (auth.)

Human Cancer Markers
Contemporary Biomedicine
Human Cancer Markers, edited by Stewort
Sell and Britto Wahren, 79 82
Cancer Markers: Diagnostic and Developmental
Significance, edited by Stewart Sell, 1980
HUMAN
CANCER
MARKERS
Edited bV
STEWART SEll
Universitv of California, San Diego
and
BRITTA WAHREN
Harolinska Hospital, Stockholm, Sweden
Humana Press . Clifton, New Jersey
Library of Congress Cataloging in Publication Data
Main entry under title:
Human cancer markers.
(Contemporary biomedicine)
Includes bibliographies and index.
1. Tumor antigens. 2. Cancer-Diagnosis. I. Sell,
Stewart. II. Wahren, Britta. III. Title: Cancer
markers. IV. Series. [DNLM: 1. Neoplasms-Diagnosis.
2. Neoplasms-Classification. 3. Antigens, Neoplasms.
QZ 241 H918]
RC268.3.H85 616.99'40756 81-80902
ISBN-13: 978-1-4612-5810-0 e-ISBN-1J: 97R-1-46\2-5808-7
DOl: 10.1007/978-\-46\2-5808-7 AACR2
©1982 the HUMANA Press Inc.
Softcover reprint of the hardcover 1s t edition 1982
Crescent Manor
P.O. Box 2148
Clifton, NJ 07015
All rights reserved
No part of this book may be reproduced, stored in a retrieval system,
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photocopying, microfilming, recording, or otherwise without
written permission from the Publisher.
PREFACE
The ability to diagnose cancer by simple measurement of a serum or
tissue' 'marker" has been a goal of medical science for many years. There
is ample evidence that tumor cells are different from normal cells and pro
duce substances that can be detected by currently available immuno
chemical or biochemical methods. These "cancer markers" may be se
creted proteins, enzymes, hormones, fetal serum components,
monoclonal immunoglobulins, cell surface components, or cytoplasmic
constituents. The purpose of this book is to present the current status of our
knowledge of such cancer markers.
The first tumor marker identified by laboratory means was Bence
Jones protein. In a series of lectures delivered to the Royal College of Phy
sicians in London in 1846, Dr. H. Bence Jones described studies on a urine
sample sent to him with the following note: "Dear Dr. Jones-The tube
contains urine of very high specific gravity. When boiled it becomes
slightly opaque .... etc." Dr. Jones found that heating of the urine after
addition of nitric acid resulted in formation of a heavy precipitate; acid ad
dition may have been required to bring the urine to pH 4-6 at which Bence
Jones proteins are more likely to precipitate when heated. This urinary pre
cipitate was associated with a bone disease termed "mollities ossium. "
[H. Bence Jones, Papers on Chemical Pathology, Lecture III. Lancet 2,
269-274 (1847)]. It is now known that this precipitate represents
immunoglobulin light chains passed into the urine of many patients with
multiple myeloma [Edelman and Galley, J. Exp. Med. 116,207 (1962)J.
A definitive chapter on monoclonal immunoglobulins as biomarkers of
cancer was written for the first volume of this series (Sell, S., Cancer
Markers, Humana Press, Clifton, NJ, 1980) by Alan Solomon and this
subject is therefore not treated in the present volume.
The second era of cancer markers started in 1963 with the discovery
of alphafetoprotein (AFP) by the noted Soviet scientist Garri I. Abelev.
Abelev identified this protein in the sera of fetal mice and in the sera of
adult mice with hepatocellular cancer, but not in normal adult mice. With
the development of more sensitive assays, AFP has now also been found in
normal adult sera, but in very small amounts. Thus AFP, like other "can
cer markers," is not uniquely produced by cancer, but is normally pro
duced during development and in small amounts by mature adult tissue. It
v
vi PREFACE
is rapidly secreted into the blood so that measurement in serum accurately
reflects the synthesis rate.
A second relatively well-studied cancer marker is carcinoembryonic
antigen (CEA), discovered by Gold and Freedman in 1965. CEA is a nor
mal cell surface glycoprotein found in the cells lining the gastrointestinal
tract, particularly in the large intestine. Normally very small amounts of
this cell surface glycoprotein appear in the circulation. The cells that make
CEA usually secrete most of the CEA produced into the gastrointestinal
tract. With the development of tumors of the gastrointestinal lining cells,
the secretory polarity of the cells is changed so that CEA is secreted into
the blood, where it may be detected by immunochemical techniques.
Unfortunately, elevations of the serum concentrations of both AFP
and CEA are not limited to cancer, but are also found in non-neoplastic
inflammatory conditions such as hepatitis and cirrhosis (AFP) or ulcera
tive colitis (CEA), as well as other diseases. Thus these markers do not
fulfill the ultimate goal of being diagnostic markers unique for cancer.
However, determination of the serum concentrations of these markers is an
important part of the diagnostic and prognostic evaluation of patients with
suspected cancer. Elevations of serum AFP above 1000 ng/mL (normal
5-10 ng/mL) are essentially diagnostic of hepatocellular or yolk sac tu
mors (see Chapter 6). Although elevation of CEA above normal cannot by
itself be considered diagnostic of cancer, the serum concentrations of CEA
after treatment of a CEA-producing tumor may be extremely useful in fol
lowing the effects of therapy. If the CEA level falls to normal and stays
there, it is almost certain that the patient has been successfully treated; if
the CEA remains elevated or becomes re-elevated after falling to normal,
recurrence or metastasis is likely.
Other "cancer markers" include hormones or enzymes whose abnor
mal production may aid in the diagnosis of cancer, particularly that of en
docrine organs. These markers may be extremely useful for a small num
ber of individuals, but have had little impact on the diagnosis of cancer in
general. Although active investigation continues on many other serum
cancer markers that might be used diagnostically, none has been convin
cingly shown to be useful to the point of general application at this time.
However, surveys now underway may well provide the clinical oncologist
with important new diagnostic and prognostic serologic markers for
cancer.
Markers that are not found in the blood may be useful for the identifi
cation of tumor tissue. Pathologists are often faced with the problem of
determining the origin of a metastatic lesion. Using immunohistologic
techniques, CEA and AFP localization in metastatic lesions has already
been widely used to identify the tissue origin of the primary lesion. Other
markers for breast, pancreatic, and prostatic cancer are now being evalu
ated with promising preliminary results.
PREFACE vii
Cancer markers have also been used to detect sites of tumor growth in
vivo. Antibody to the marker is radiolabeled, injected into the patient and
localization determined by radioscintigraphy. This technique, "radio
immunoscintigraphy, " is considered by some to have great promise for
detecting occult tumors, but as yet has been successful in only a few se
lected patients screened for CEA-producing tumors. Application of other
markers for this purpose is expected in the future.
Immune reactants may also be used to direct chemotherapeutic agents
or suitable isotopes to cancer cells in vivo. Therapy with anti-AFP alone
has produced marginal results in experimental models, but conjugation of
chemotherapeutic agents, such as daunomycin, to antibodies to a cancer
marker might provide more effective therapy.
The application of hybridoma technology and enzyme immunoassay
to the identification and quantitation of tumor markers signals a third era in
cancer markers. These techniques have the promise of providing a new
generation of cancer markers. In Chapter 1, Dr. William Raschke summa
rizes hybridoma techniques, while in Chapter 2, Dr. Robert Fox and his
colleagues provide a more detailed description of the application of
hybridoma reagents to markers of lymphoproliferative diseases. In Chap
ter 3, Dr. Reisfeld and his colleagues describe the molecular approach to
identification and charactization of a tumor antigen. These three chapters
set the tone for the remainder of the volume, articles that not only review
the present status of tumor markers for various organ sites, but that also, in
most instances, point out prospects for the future.
Thus, this volume on cancer markers appears at an exciting and po
tentially critical time. Although the clinical applications of CEA and AFP
have not fulfilled the optimistic expectations that many predicted, these
markers do have a place in cancer diagnosis and management. Will new
cancer markers be as good or better? Many of the new markers will almost
certainly not be as useful as their uncritical proponents argue. Claims of a
universal cancer marker have been made repeatedly in the past and have
gone unsubstantiated. New cancer markers usually generate high enthusi
asm from those that find them [see, for instance, Maugh, T. H., Science
24, 909 (1981)], but unfortunately most have not performed as advertised
when subjected to critical evaluation. However, the availability of new
technology may justify some of the current enthusiam! A continued search
for new tumor markers is more than justified by the tremendous potential
for clinical application. It is hoped that this book will help stimulate and
focus the quest for cancer markers.
CONTRIBUTORS
STEPHEN BAIRD . University of California, San Diego, California
STEPHEN B. BAYLIN . Oncology Center and the Department of
Medicine, The Johns Hopkins University School of Medicine and
Hospital, Baltimore, Maryland
DARRELL D. BIGNER . Department of Pathology, Duke University
Medical Center, Durham, North Carolina
JEAN-CLAUDE BYSTRYN . Department of Dermatology, New
York University School of Medicine, New York, New York
T. MING CHU . Department ofD iagnostic Immunology Research and
Biochemistry, Roswell Park Memorial Institute, Buffalo, New York
THOMAS S. EDGINGTON . Department of Molecular Immunology,
Research Institute of Scripps Clinic, La Jolla, California
EVA ENG VALL . La Jolla Cancer Research Foundation, La Jolia,
California
ROBERT FOX . Department o/Clinical Research, Scripps Clinic and
Research Foundation, La Jolla, California
D. R. GALLOWAY' Department of Molecular Immunology, Scripps
Clinic and Research Foundation, La Jolla, California
JOHN R. HOBBS . Department of Chemical Pathology, Westminster
Medical School, London, Great Britain
TREVOR R. JONES . Department of Pathology, Duke University
Medical Center, Durham, North Carolina
CARL S. KILLIAN . Department of Diagnostic Immunology
Research and Biochemistry, Roswell Park Memorial Institute, Buf
falo, New York
PATRICK KUNG . Ortho Pharmaceutical Corporation, Raritan,
New Jersey
MANABU KURIY AMA . Department of Diagnostic Immunology
Research and Biochemistry, Roswell Park Memorial Institute, Buf
falo, New York
PAUL H. LANGE . Department of Urologic Surgery, University of
Minnesota College of Health Sciences, Minneapolis, Minnesota
ix
x CONTRIBUTORS
CHING-LI LEE Department of Diagnostic Immunology Research
and Biochemistry, Roswell Park Memorial Institute, Buffalo, New
York
RON LEVY . Stanford University Medical Center, Stanford,
California
K. ROBERT McINTIRE . Diagnosis Branch, Division of Cancer
Biology and Diagnosis, National Cancer Institute, Bethesda,
Maryland
GEOFFREY MENDELSOHN . Oncology Center and the Department
of Pathology, The Johns Hopkins University School of Medicine and
Hospital, Baltimore, Maryland
GERALD P. MURPHY . Department of Diagnostic Immunology
Research and Biochemistry, Roswell Park Memorial Institute, Buf
falo, New York
ROBERT M. NAKAMURA . Department of Molecular Immunology,
Research Institute of Scripps Clinic, La Jolla, California
LAWRENCE D. PAPSIDERO . Department of Diagnostic Immunol
ogy Research and Biochemistry, Roswell Park Memorial Institute,
Buffalo, New York
PETER PERLMANN . Department of Immunology, University of
Stockholm, Stockholm, Sweden
WILLIAM C. RASCHKE . Developmental Biology Laboratory, The
Salk Institute, San Diego, California
R. A. REISFELD . Department of Molecular Immunology, Scripps
Clinic and Research Foundation, La Jolla, California
IVOR ROYSTON . University of California, San Diego, California
STEWART SELL . Department of Pathology, University of Cali
fornia Medical School, San Diego, La Jolla, California
MARKKU SEPpALA . Department of Obstetrics and Gynecology,
University Central Hospital, Helsinki, Finland
HANS O. SJOGREN . The Wallenberg Laboratory, University of
Lund, Lund, Sweden
TORGNY STIGBRAND . Department of Physiological Chemistry,
University of Umea, Umea, Sweden
LUIS A. VALENZUELA . Department of Diagnostic Immunology
Research and Biochemistry, Roswell Park Memorial Institute,
Buffalo, New York
BRITTA W AHREN . Radiumhemmet, Karolinska Hospital, Stock
holm, Sweden
MING C. WANG . Department of Diagnostic Immunology Research
and Biochemistry, Roswell Park Memorial Institute, Buffalo, New
York
CONTENTS
Preface .••...•.•.•.••••.•......•••..•....•...•.•••••••••••••..... v
CHAPTER 1
Monoclonal Antibodies to Human Tumor Antigens
William C. Raschke
1. Introduction........................................... 1
2. Monoclonal Antibodies to Preselected Antigens-Technology. .. 3
2.1. Hybridomas....................................... 3
2.2. Epstein-Barr Virus Transformation of Human
Lymphocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 9
3. Monoclonal Antibodies to Human Tumors ................. 11
3.1. Leukemia Antigens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.2. Melanoma Antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.3. Colorectal Carcinoma Antigens . . . . . . . . . . . . . . . . . . . . .. 20
3.4. Alphafetoprotein.................................. 22
3.5. Neuroblastoma Antigens. . . . . . . . . . . . . . . . . . . . . . . . . . .. 23
4. Potential Diagnostic and Therapeutic Uses of Monoclonal
Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 23
5. Potential Problems with Monoclonal Antibody Usage. . . . . . . .. 25
6. Final Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 28
CHAPTER 2
Cell Surface Antigens on Normal and Neoplastic
Human Lymphoid Cells
Robert Fox, Stephen Baird, Patrick Kung, Ron Levy,
and Ivor Royston
1. Three Major Classes of Immunocompetent Lymphocytes. . . . .. 34
1.1. Subsets of Lymphocytes Defined by Rosetting with Sheep
Red Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35
xi