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www.crcpress.com
Growth Regulation
and
Carcinogenesis
Volume I
Editor
Walter R. Paukovits
Department of Growth Regulation
Institute of Tumor Biology and Cancer Research
University of Vienna
Austria
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
First published 1991 by CRC Press
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Reissued 2018 by CRC Press
© 1991 by CRC Press, Inc.
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Library of Congress Cataloging in Publication Data
Growth regulation and carcinogenesis/editor, Walter R. Paukovits.
p. cm.
Includes bibliographical references.
Includes index.
ISBN 0-8493-5960-0 (v. 1). — ISBN 0-8493-5961-9 (v. 2)
1. Cells—Growth—Regulation. 2. Cancer cells—Growth-
-Regulation. 3. Growth factors. 4. Carcinogenesis. I. Paukovits,
Walter R., 1939-
[DNLM: 1. Cell Differentiation. 2. Cell Division. 3. Cell
Transformation, Neoplastic. 4. Growth Substances. 5. Neoplasms-
-etiology. QZ 202 G8848]
QH604.G77 1990.
S16.99’4071—dc20
DNLM/DLC
for Library of Congress 90-2227
A Library of Congress record exists under LC control number: 90002227
Publisher’s Note
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may be apparent.
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contact.
ISBN 13: 978-1-315-89322-8 (hbk)
ISBN 13: 978-1-351-07232-8 (ebk)
Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the
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PREFACE
Theexploitationofmoleculargenetictechniques, especiallyinthefieldofgrowthfactors
and oncogenes, the improvements made in cell culture systems and their correlation with
thein vivo situation, as well as the improvedtechniques forpurificationandcharacterization
ofmicroamountsofregulatoryfactors, havecontributedtothe increasedknowledge we have
now about regulatory mechanisms of cellular growth and their relationships to the control
of differentiation and maturation. This multidisciplinary approach has also resulted in an
improved understanding of what goes wrong when a cell becomes malignant.
The work on proliferation regulators has, however, also demonstrated how little we
actually know, even in those systems which are most intensively investigated. Many ofthe
identified growth regulatory factors, whether stimulatory or inhibitory, have other nonpro-
liferative functions as well, and only in some situations do the combined set of properties
ofsuch factors allow reasonable speculation about the integrated regulation system ofpro-
liferation, differentiation, maturation, and function. This integral viewpoint on regulation
processes makes it clear how various types of controls must cooperate in a well-balanced
way to constituteaproperlyfunctioning system, andhow malfunctions (mutationalchanges,
gene amplification, overexpression) may contribute to the emergence ofpathological (e.g.,
transformed) states.
This bookintends to layastrongemphasisonsuchan integratedviewofthephenomena
involved in growth regulation. The recent upsurge of progress in the interconnected fields
ofgrowth regulation-oncogenes-cell transformation has been amply documented in various
kinds of publications. The intention of this book is not to add yet another example to this
growing list of highly similar reviews; instead, it attempts to bring together some distin-
guished workersfromthefields ofgrowthfactors/inhibitors, oncogenes, celltransformation,
carcinogenesis, etc. Several of them, to whom I am particularly indebted, have taken the
trouble torespondto thesomewhatdifficultrequestofprovidingtwoarticlesforthis volume
- onedescribingorsummarizingintheusual wayrelevantpartsoftheirexperimentalwork,
and anotherdescribing how they thinktheirwork and results fit into alargercontext. Ihope
thereaderwillfindthisdualconfigurationparticularlyinteresting, becauseoften(instandard
papers) the author's strategies and opinions, the "philosophy" behind the actual work, has
to be guessed from reading between the lines in the introduction or discussion.
The readerwill notice anotherdifference from otherpublications onthis topic: there are
(almost) no contributions dealing directly with one or other of the already overreviewed
growth factors themselves. The reason for this policy was to find a way back from "factor
X has now been cloned and is, therefore, highly important" to actual biology. I hope that
this book is a step in this direction.
I wish to express my gratitude to all those who helped to complete this work without
major difficulties. Most of all I am indebted to the contributors of the chapters for their
excellent work and also for their cooperation in keeping the deadline set by the publisher.
Iappreciateverymuchthepatienceofmyco-workersattheLaboratoryofGrowthRegulation
at the Institute for TumorBiology-CancerResearch ofthe University ofVienna when Iwas
frequently not available for dealing with the daily problems ofour ongoing research work,
and I also wish to thank the director of this Institute, Professor R. Schulte-Hermann, for
his continuing interest and support of the project. The cooperation with R. Larrondo and
others from CRC Press was pleasant and efficient at all times, and I thank them all for their
efforts and assistance to bring this work to a successful end.
THE EDITOR
Walter R. Paukovitsreceived his education in chemistry and physics atthe University
ofVienna. In 1966, hejoined the former osterreichisches Krebsforschungsinstitut, which is
now incorporated in the Medical Faculty of the University of Vienna as the Institute for
Tumor Biology and Cancer Research. After some years oftheoretical work with computer
simulations ofcellular regulation processes, he established the Laboratory ofGrowth Reg-
ulation which he still heads. The main field ofhis work is concerned with inhibitors ofcell
proliferation, with a special emphasis on small peptides acting on hematopoiesis. Recent
developments include the identification of a hemoregulatory pentapeptide which was later
synthesized and biologically characterized. Dr. Paukovits' investigations on this and related
peptides have played a major role in defining their functions in normal and leukemic he-
matopoiesis. The workofhis group is presently focused on the applicationofsuch peptides
as hemoprotectors against the damaging side effects ofcytostatic drugs on the stemcells of
the hematopoietic system, especially theirprotective role during cancertreatmentand inthe
prevention of secondary leukemia. Dr. Paukovits has established worldwide intensive col-
laborative contacts in his field. His work is documented in almost 100 publications in
scientific journals and books. He is a member ofnumerous international scientific organi-
zations including the International Society of Experimental Hematology, the International
Association for Comparative Research on Leukemia and Related Diseases, the European
Stem Cell Club, the European Study Group of Cell Proliferation, the European Peptide
Society, and others.
CONTRIBUTORS
Hinrich Abken, M.D. Marila Cordeiro-Stone, Ph.D.
Division ofMolecular Genetics Associate Professor
Institute ofGenetics Department ofPathology
University ofBonn University ofNorth Carolina
Bonn, Federal Republic ofGermany Chapel Hill, North Carolina
Kathy Alexandre Michele Delronche
Research Associate Research Associate
Laboratory ofCytology and Experimental Laboratory ofCytology and Experimental
Cancerology Cancerology
School ofMedicine School ofMedicine
Free University ofBrussels Free University ofBrussels
Brussels, Belgium Brussels, Belgium
Kari Alitalo, M.D., Ph.D. Ronald A. DePinho, M.D.
Professor Assistant Professor
Department ofUrology and Pathology Department ofMicrobiology and
University ofHelsinki Immunology
Helsinki, Finland Albert Einstein College ofMedicine
Bronx, New York
H. Scott Boswell, M.D.
Associate Professor ofMedicine, Hans Guenter Derigs, M.D.
Hematology/Oncology Fellow in Hematology/Oncology
Department ofMedicine Department ofMedicine, Hematology/
Indiana University School ofMedicine Oncology
Indianapolis, Indiana Indiana University School ofMedicine
Indianapolis, Indiana
Gem S. Burgess, M.S.
Research Associate Norman A. Doggett, Ph.D.
Division ofHematology/Oncology StaffScientist
Department ofMedicine Genetics Group
Indiana University School ofMedicine Life Sciences Division
Indianapolis, Indiana Los Alamos National Laboratories
Los Alamos, New Mexico
Christa Cerni, M.D.
Assistant Professor Denis English, Ph.D.
Department ofTumor Virology Assistant Professor
Institute for Tumor Biology and Cancer Department ofMedicine and Pathology
Research Indiana University School ofMedicine
University of Vienna Indianapolis, Indiana
Vienna, Austria
Susan J. Friedman, Ph.D.
John L. Cleveland Senior Investigator
Assistant Professor Laboratory ofBiological Chemistry
Department ofBiochemistry National Cancer Institute/National
St. Jude Children's Research Hospital Institute ofHealth
Memphis, Tennessee Bethesda, Maryland
Theodore G. Gabig, M.D. Jim Horner, B.S.
Professor ofMedicine, Hematology/ Laboratory Technician
Oncology Department ofMicrobiology and
Division ofHematology/Oncology Immunology
Department ofMedicine Albert Einstein College ofMedicine
Indiana University School ofMedicine Bronx, New York
Indianapolis, Indiana
Lowell Inhorn, M.D.
Paul Galand, Ph.D. Oncologist
Director Oncology and Hematology Associates of
Laboratory ofCytology and Experimental Southwest Virginia, Inc.
Cancerology Roanoke Memorial Hospital
School ofMedicine Roanoke, Virginia
Free University ofBrussels
Brussels, Belgium Daniele Jacobovitz, M.D.
Consultant
Ingeborg Ganglberger Department ofAnatomical Pathology
Master ofScience Erasme University Hospital
Department ofGrowth Regulation Free University ofBrussels
Institute for Tumor Biology and Cancer Brussels, Belgium
Research
University ofVienna Herbert Jungfer, M.D.
Vienna, Austria Boehringer Mannheim GmbH
Penzberg, Federal Republic ofGermany
Mark Hannink, Ph.D.
Postdoctoral Fellow David G. Kaufman, M.D., Ph.D.
Department ofOncology Professor
University ofWisconsin Department ofPathology
Madison, Wisconsin University of North Carolina
Chapel Hill, North Carolina
Maureen A. Harrington, Ph.D.
Assistant Professor Debra K. Klingberg, B.S.
Department ofMedicine and Research Associate
Biochemistry Department ofMedicine and
Indiana University School ofMedicine Pharmacology
Indianapolis, Indiana Indiana University School ofMedicine
Indianapolis, Indiana
Kimi S. Hatton, Ph.D.
Postdoctoral Fellow Walter Kolch, M.D.
Department ofMicrobiology and Visiting Fellow
Immunology Division ofCancer Etiology
Albert Einstein College ofMedicine National Cancer Institute
Bronx, New York Frederick, Maryland
Meenhard Herlyn, D.V.M. Paivi Koskinen
Associate Professor Master of Science
The Wistar Institute of Anatomy and Department ofGenetics
Biology University ofHelsinki
Philadelphia, Pennsylvania Helsinki, Finland
Ole Didrik Laerum, M.D., Ph.D. Theresa Stines Nahreini, B.S.
Professor Graduate Student
Department ofPathology Department ofChemistry
The Gade Institute, Haukeland Hospital Indiana-Purdue University at Indianapolis
University ofBergen Indianapolis, Indiana
Bergen, Norway
Vinyas Patel
Caroline H. Laundon, Ph.D. Student-Trainee
Associate Director Department ofMicrobiology and
Genetics Associates Immunology
Chapel Hill, North Carolina City College ofthe City University
ofNew York
Heikki Lehvaslaiho, M.Sci. Bronx, New York
Researcher
Cancer Biology Laboratory UlfR. Rapp, M.D.
Department ofPathology and Virology Chief, Viral Pathology Section
University ofHelsinki Division ofCancer Etiology
Helsinki, Finland National Cancer Institute
Frederick, Maryland
Kathy Mahon, Ph.D.
Senior StaffFellow Ulrich Rodeck, M.D.
Laboratory ofMammalian Genes and Assistant Professor
Development The Wistar Institute of Anatomy and
NICHD Biology
National Institute ofHealth Philadelphia, Pennsylvania
Bethesda, Maryland
Kalle Saksela
Tomi P. Makela, M.D. Department ofVirology and Pathology
Department of Virology and Pathology University ofHelsinki
University ofHelsinki Helsinki, Finland
Helsinki, Finland
Patricia Servais
Friedrich R. R. Marks, Dr.rer.nat. Research Associate
Professor Laboratory ofCytology and Experimental
Department ofBiochemistry Cancerology
German Cancer Research Center School ofMedicine
Heidelberg, Federal Republic ofGermany Free University ofBrussels
Brussels, Belgium
Wolfgang Martin, Dr.rer.nat.
Division ofMolecular Genetics Philip Skehan, Ph.D.
Institute ofGenetics Developmental Therapeutics Program
University ofBonn National Cancer Institute
Bonn, Federal Republic ofGermany Frederick, Maryland
Sharon Dianne Morgenbesser, M.S. Gerard Taton, M.D.
Research Associate Resident
Department ofMicrobiology and Department ofSurgery
Immunology Erasme University Hospital
Albert Einstein College ofMedicine Free University ofBrussels
Bronx, New York Brussels, Belgium
Howard M. Temin, Ph.D. Klaus Willecke, Dr.rer.nat.
Professor Professor
Department ofOncology Division ofMolecular Genetics
University ofWisconsin-Madison Institute ofGenetics
Madison, Wisconsin University ofBonn
Bonn, Federal Republic ofGermany
Richard Torres, B.S.
Graduate Student
Department ofMicrobiology and
Immunology
Albert Einstein College ofMedicine Erhard Wintersberger, Ph.D.
Bronx, New York Professor
Institute ofMolecular Biology
Everardus J. J. Van Zoelen, Ph.D. University ofVienna
Professor Vienna, Austria
Department ofCell Biology
University of Nijmegen
Nijmegen, The Netherlands
Robert V. Wallen, B.S. Lin Xu, M.S.
Research Technician Research Associate
Department ofMicrobiology and Department ofMicrobiology and
Immunology Immunology
Albert Einstein College ofMedicine Albert Einstein College ofMedicine
Bronx, New York Bronx, New York
TABLE OF CONTENTS
Volume I
SECTION 1: GENERAL CONCEPTS
Chapter 1
The Classical Concepts ofthe Origin and Development ofMalignant Tumors 3
Ole Didrik Laerum
Chapter 2
Control ofGene Expression during Cell Cycle and Growth ofMammalian Cells 13
Erhard Wintersberger
Chapter 3
Transit, Exit, and Arrest Models for Control ofthe Mammalian Cell Cycle 31
Philip Skehan
Chapter 4
Cancer-A Disease ofTissue Neogenesis? 45
Philip Skehan and Susan J. Friedman
Chapter 5
Neoplasia and the Wound Response: The Lesson Learned from the Multistage
Approach of Skin Carcinogenesis 53
Friedrich Marks
SECTION 2: CELL TRANSFORMATION
Chapter 1
The Role ofPolypeptide Growth Factors in Phenotypic Transformation of
Normal Cells 83
Everardus J. J. van Zoelen
Chapter 2
Density-Development Control ofCell Proliferation: Molecular Mechanisms
Involved in Contact-Inhibition 91
Everardus J. J. van Zoelen
Chapter 3
Cancer as a Mutation-Driven Evolutionary Process 95
Mark Hannink and Howard M. Temin
Chapter4
Mutation-Driven Evolution ofRev-T 99
Mark Hannink and Howard M. Temin
