Tumor Suppressor Genes in Human Cancer

385 Pages·2001·10.646 MB·English

by  Jordan A. Kreidberg MD, PhD, Thomas A. Natoli PhD (auth.), David E. Fisher MD, PhD (eds.)

TuMoR SuPPRESSOR GENES IN HuMAN CANCER
CANCER DRUG DISCOVERY AND DEVELOPMENT
Beverly A. Teicher, Series Editor
Thmor Suppressor Genes in Human Cancer, edited by David E. Fisher,
2001
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J. Clendeninn and KrzysztofA ppelt, 2001
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and Caroline Dive, 1999
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TUMOR SUPPRESSOR
GENES IN
HUMAN CANCER
Edited by
E.
DAVID FISHER,
MD, PhD
Dana Farber Cancer Institute,
Harvard Medical School,
Boston, .MA
*
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© 2001 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 2001.
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Cover illustration: The cover shows the histologic appearance of a Wilm's tumor stained with hematoxylin and eosin
(purple) or immunostained for the Wilm's tumor suppressor protein (black and white inset). Cover photos were generously
provided by Scott Granter, MD, Department of Pathology, Brigham and Women's Hospital, Boston, MA.
Cover design by Patricia F. Cleary.
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Library of Congress Cataloging-in-Publication Data
Tumor suppressor genes in human cancer I edited by David E. Fisher.
p.; cm.--(Cancer drug discovery and development)
Includes bibliographical references and index.
ISBN 978-1-61737-198-1 ISBN 978-1-59259-230-2 (eBook)
DOI 10.1007/978-1-59259-230-2
I. Antioncogenes. I. Fisher, David E. (David Erich) II. Series.
[DNLM: I. Genes, Suppressor, Tumor. 2. neoplasms--genetics. QZ 202 T9248 2000]
RC268.43 .T8634 2000 00-027593
61699'4042--dc21 CIP
PREFACE
The war against cancer has seen enormous successes, but also painful frustra
tion. While rnaj or conceptual breakthroughs have been made in our understanding
of how cell proliferation is regulated, the translation of this information into
effective treatment discoveries has lagged terribly behind. Modern molecular
oncology has begun to inch closer to treatment-related questions because the
pathways under study are now known to regulate events such as cell death, the
precise goal of cancer treatment. Because tumor suppressor biology has not yet
translated into a therapy-oriented discipline, the purpose of Tumor Suppressor
Genes in Human Cancer is to present a view of the current field which simulta
neously highlights the clinically relevant directions which have already emerged
while stimulating the discovery of new ones.
Through the detailed presentation of tumor suppressor genes with a molecular
biological and genetic perspective, two paradigms emerge: 1) a finite number of
discrete pathways exist into which tumor suppressors and dominant oncogenes
reside and 2) cancer biology rests heavily on both regulators of cell proliferation
and cell death. In the current climate of informatics, genomics, and molecularly
driven drug discovery, cancer research holds greater promise than ever. Tumor
Suppressor Genes in Human Cancer first sets the stage by presenting the back
ground of systems for the study of tumor suppressor genes as well as the fields of
apoptotic cell death and cancer drug discovery. The second section of Tumor
Suppressor Genes in Human Cancer proceeds to present detailed analyses of
major tumor suppressors and, most important, the pathways into which they fit.
The intended audience is the student of cancer biology, from those engaged in
graduate or medical education to clinicians or drug development professionals
seeking to understand the context of cancer cell biology and its promise for thera
peutic gains in the coming years.
The concept that individual genes underlie the biology of malignant transfor
mation hearkens back to the early 1900s with the discovery by Peyton Rous of
avian sarcomas that were caused by infectious viruses. Many decades later, the
identification of the Src oncogene placed into focus the notion of the dominant
oncogene, a factor whose inappropriate activation confers cellular changes asso
ciated with malignant transformation. Alfred Knudsen predicted the existence of
a second class of oncogenes whose contribution to cancer is recessively inherited.
His hypothesis was based upon clinical observations of cancer risk in familial
cancer inheritance patterns and the notion that disease predisposition may repre
sent a multi-hit phenomenon with loss-of-function mutations contributing to the
malignant phenotype. Thus the concept of tumor suppressor gene was born and
has been abundantly validated by observations that span bench to bedside.
The most striking validation of the tumor suppressor concept comes from the
discovery of inactivating mutations or deletions of candidate genes in cancer
v
vi Preface
prone families. Originally discovered for retinoblastoma, the list has been dra
matically extended to include p53, pl6/Ink4a/ARF, the NF family, DNA mis
match repair genes, Wilms, von Hippel Lindau, Fanconi Anemia, and other genes.
In these cases heterozygous germline disruption of a single allele is associated
with cancer predisposition in affected family members. Loss of heterozygosity is
frequently observed at the genetic locus within tumors that develop in affected
individuals. Mechanisms for tumor suppressor inactivation are diverse and are
still being discovered today. For example, in addition to traditional loss of func
tion mutations or deletions, the more recently appreciated inactivating mecha
nisms include transcriptional silencing (e.g., p16/lnk4a), targeted protein
degradation (e.g., p53), and functional disruption oft umor suppressing gene activi
ties (e.g., bcl-2 or Mdm2). These diverse mechanisms of tumor suppressor inac
tivation highlight one of the most striking breakthroughs in cancer biology, the
discovery of discrete pathways in which dominantly acting and tumor suppress
ing genes converge.
The functional convergence ofd ominant oncogenes and tumor suppressor genes
in cellular growth or survival pathways represents such a powerful clue in the
puzzle of carcinogenesis that the ability to fit into a known growth regulatory
pathway has become a virtual requirement for a gene's acceptance as a true cancer
modifier. Moreover much of the data defining these interactions stemmed from
the convergence of clinically derived questions with more basic laboratory sci
ence. For example, the retinoblastoma tumor suppressor was found to be targeted
by multiple dominant oncogenes discovered through the analysis of animal DNA
tumor viruses. The e~istence of additional interactions between tumor suppres
sors and dominant oncogenes has cemented the notion that key cellular pathways
produce the phenotypes associated with cancer, and the homeostatic regulators of
these pathways are potent and common targets of carcinogenic disruption.
The pathways that tumor suppressor genes modulate in cancer have been found
to cluster around regulation of the cell cycle, cell death, growth factor signaling,
DNA damage responses, and other stress responses. Nearly all tumor suppressors
are thought to act through modulation of one (or several) of these pathways. Cell
cycle regulation has been the traditional pathway thought to be targeted in the
etiology of cancer. More recent observations have added a dramatic new dimen
sion to this view in suggesting that cell survival pathways exist as distinct, geneti
cally selected entities and may profoundly influence behaviors we associate with
malignancy. Either dysregulated growth or inefficient death (or both) are strongly
associated with tumorigenesis. The current revolution in molecular oncology
has been fueled largely by the ability to place individual cancer genes within such
functional pathways ofknown importance. Perhaps more important, these func
tional classifications have in some cases led to investigations that relate more than
ever before to cancer treatment.
The study of cancer cell death carries with it the hope of intervening in the very
same process for therapeutic benefit. Rarely has a field of fundamental basic
Preface vii
science become so mainstream in biologic inquiry while simultaneously focusing
on questions of direct therapeutic importance. The interface between research on
cell death and clinical ramifications of that work is well illustrated by the actions
of tumor suppressor genes, many of which are now recognized to regulate cell
survival.
Tumor Suppressor Genes in Human Cancer is not an attempt to fully synthe
size cancer biology and treatment, since the field has not arrived at a stage where
such a synthesis is yet possible. However the convergence of new technologies
suggests that the coming years will begin to see treatment discoveries more directly
interface with basic research. Genomics and systematic gene expression tech
nologies will provide thorough catalogs of information whose discovery cur
rently occupies substantial research effort. Linkage of these catalogs to clinical
data including treatment responses (pharmacogenomics) promises to dramati
cally alter drug discovery and treatment design. The pillar of this revolution is the
basic biology of disease, and tumor suppressor genes lie at the core of that pillar.
David E. Fisher
CONTENTS
Preface ............................................................................................................................ v
Contributors ................................................................................................................... xi
PART I. ANALYSIS AND CLINICAL IMPLICATIONS OF TUMOR
SuPPRESSOR GENES
1 Animal Models for Tumor Suppressor Genes ................................. 3
Jordan A. Kreidberg and Thomas A. Natoli
2 Viral Oncoproteins as Probes for Tumor Suppressor Function ..... 29
Srikumar P. Chellappan
3 Tumor Suppressors in Metastasis ................................................... 49
Taoujik Ouatas, Melanie T. Hartsough, and Patricia S. Steeg
4 Apoptosis: Machinery ofC ell Death in Development and Cancer .... 79
Jinyan Du and David E. Fisher
5 Drug Discovery in Oncology ........................................................ 10 3
Alex Matter
PART II. TUMOR SUPPRESSOR pATHWAYS
6 Retinoblastoma Protein in Growth Control
and Differentiation ................................................................ , ... 131
Lilia Stepanova and J. Wade Harper
7 p53 Tumor Suppressor Protein ..................................................... 159
Margaret Ashcroft and Karen H. Vousden
8 p16 Tumor Suppressor .................................................................. 183
Alexander Kamb and Ken McCormack
9 DNA Mismatch Repair in Tumor Suppression ............................ 197
Guo-Min Li, Scott McCulloch, and Liya Gu
10 PTEN: Regulator ofP hosphoinositide 3-Kinase
Signal Transduction .................................................................. 231
Jen Jen Yeh and William R. Sellers
11 Neurofibromatoses ........................................................................ 253
Andre Bernards and Andrea I. McClatchey
12 Von Hippel-Lindau Disease: Clinical and Molecular Aspects ... 281
Othon lliopoulos and William G. Kaelin, Jr.
13 Wilms' Tumor: A Developmental Anomaly ................................. 307
Aswin L. Menke and Nick D. Hastie
14 Fanconi Anemia Pathway and Cancer Susceptibility .................. 351
Yanan Kuang, Irene Garcia-Higuera, Eric Nisbet-Brown,
Anna Savoia, and Alan D. D'Andrea
Index ........................................................................................................................... 371
ix
CONTRIBUTORS
MARGARET AsHCROFT, PHD • ABL Basic Research Program, NCI-FCRDC, Frederick, MD
ANDRE BERNARDS, PHD • Massachusetts General Hospital Cancer Center and Harvard
Medical School, Charlestown, MA
SRIKUMAR P. CHELLAPPAN, PHD • Department of Pathology, College of Physicians
and Surgeons, Columbia University, New York, NY
ALAN D. D'ANDREA, MD • Division of Pediatric Oncology, Dana Farber Cancer
Institute, and Department ofP ediatrics, Harvard Medical School, Boston, MA
JINY AN Du • Division ofP ediatric Hematology and Oncology and Graduate Program
in Biological and Biomedical Sciences, Harvard Medical School, Children's Hospital,
and Dana Farber Cancer Institute, Boston, MA
DAVID E. FISHER, MD, PHD • Division of Pediatric Hematology and Oncology
and Graduate Program in Biological and Biomedical Sciences, Harvard Medical School,
Children's Hospital, and Dana Farber Cancer Institute, Boston, MA
IRENE GARCIA-HIGUERA, PHD • Division of Pediatric Oncology, Dana Farber Cancer
Institute, and Department ofP ediatrics, Harvard Medical School, Boston, MA
LIY A Gu, PHD • Department of Pathology and Laboratory Medicine, University
ofK entucky, Lexington, KY
J. WADE HARPER, PHD • Verna and Marrs McLean Department ofB iochemistry, Baylor
College ofM edicine, Houston, TX
MELANIE T. HARTSOUGH, PHD • Women's Cancers Section, Laboratory of Pathology,
Division of Clinical Sciences, National Cancer Institute, Bethesda, MD
NICK D. HASTIE, PHD • MRC Human Genetics Unit, Western General Hospital,
Edinburgh, UK
0THON ILIOPOULOS, MD • Dana Farber Cancer Institute and Harvard Medical School,
Boston, MA
WILLIAM G. KAELIN, JR., MD • Howard Hughes Medical Institute, Boston, MA
ALEXANDER KAMB, PHD • Arcaris, Salt Lake City, UT
JoRDAN A. KREIDBERG, MD, PHD • Department of Medicine, Children's Hospital,
and Department ofP ediatrics, Harvard Medical School, Boston , MA
Y ANAN KuANG, PHD • Division ofP ediatric Oncology, Dana Farber Cancer Institute,
and Department ofP ediatrics, Harvard Medical School, Boston, MA
Guo-MIN LI, PHD • Department ofP athology and Laboratory Medicine, Markey Cancer
Center, and the Graduate Center for Toxicology, and Multidisciplinary Ph.D. Program
in Nutritional Sciences, University ofK entucky, Lexington, KY
ALEX MATTER, MD • Oncology Research, Novartis Pharma AG, Basel, Switzerland
ANDREA I. McCLATCHEY, PHD • Massachusetts General Hospital Cancer Center
and Harvard Medical School, Charlestown, MA
KEN McCoRMACK, PHD • Arcaris, Salt Lake City, UT
ScoTT McCuLLOCH, PHD • Graduate Center for Toxicology, University of Kentucky,
Lexington, KY
AswiN L. MENKE, PHD • MRC Human Genetics Unit, Western General Hospital,
Edinburgh, UK
xi
xii Contributors
THOMAS A. NATOLI, PHD • Department ofMedicine, Children's Hospital, and Department
ofP ediatrics, Harvard Medical School, Boston, MA
ERIC NISBET-BROWN, MD, PHD • Division ofP ediatric Oncology, Dana Farber Cancer
Institute, and Department ofP ediatrics, Harvard Medical School, Boston, MA
TAOUFIK OuATAS, PHD • Women's Cancers Section, Laboratory ofP athology, Division
of Clinical Sciences, National Cancer Institute, Bethesda, MD
ANNA SAVOIA, MD • Division of Pediatric Oncology, Dana Farber Cancer Institute,
and Department ofP ediatrics, Harvard Medical School, Boston, MA
WILLIAM R. SELLERS, MD • The Departments ofA dult Oncology and Internal Medicine,
Dana Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical
School, Boston, MA
PATRICIA S. STEEG, PHD • Women 's Cancers Section, Laboratory ofP athology, Division
of Clinical Sciences, National Cancer Institute, Bethesda, MD
LILIA STEPANOVA, PHD • Verna and Marrs McLean Department of Biochemistry,
Baylor College ofM edicine, Houston, TX
KAREN H. VousDEN, PHD • ABL Basic Research Program, NCI-FCRDC, Frederick, MD
JEN JEN YEH, MD • The Departments of Adult Oncology and Internal Medicine,
Dana Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical
School, and the Department ofS urgery, Boston University Medical Center, Boston, MA