Table Of ContentRecent Results 128
in Cancer Research
Managing Editors
Ch. Herfarth, Heidelberg· H. -J. Senn, St. Gallen
Associate Editors
M. Baum, London· V. Diehl, K6ln
F. Gutzwiller, Zurich· M.F. Rajewsky, Essen
M. Wannenmacher, Heidelberg
Founding Editor
P. Rentchnick, Geneva
E. Hecker E.G. Jung F. Marks
W. Tilgen (Eds.)
Skin Carcinogenesis
in Man and
in Experimental Models
With a Foreword by Harald zur Hausen
With 67 Figures and 44 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Prof. Dr. E. Hecker
Deutsches Krebsforschungszentrum
Division: Mechanisms of Tumorigenesis
Research Program 3: Risk Factors of Cancer
and Cancer Prevention, 1m Neuenheimer Feld 280
W-6900 Heidelberg, Germany
Prof. Dr. E.G. Jung
Director, Department of Dermatology
Mannheim Medical School, University of Heidelberg
Postfach 10 80 23, Theodor-Kutzer-Ufer
W-6800 Mannheim, Germany
Prof. Dr. F. Marks
Deutsches Krebsforschungszentrum
Division: Biochemistry of Tissue Specific Regulation
Research Program 2: Tumor Cell Regulation
1m Neuenheimer Feld 280
W-6900 Heidelberg, Germany
Privatdozent Dr. W. Tilgen
Department of Dermatology
University of Heidelberg, Voss-Str. 2
W-6900 Heidelberg, Germany
ISBN-13 :978-3-642-84883-4 e-ISBN-13:978-3-642-84881-0
DOl: 10.1007/978-3-642-84881-0
Library of Congress Cataloging-in-Publication Data. Skin carcinogenesis in man
and in experimental models 1 E. Hecker ... let al.] (ed.). p. cm. - (Recent
resuls in cancer research : 128) Includes bibliographical references and index.
ISBN-I3:978-3-642-84883-4 1. Skin - Cancer -
Congresses. 2. Skin - Cancer - Animal models - Congresses. 3. Carcinogenesis
Congresses. 4. Carcinogenesis - Animal models - Congresses. I. Hecker, Erich.
n. Series. [DNLM: 1. Disease Models, Animal - congresses. 2. Melanoma -
congresses. 3. Neoplasms, Experimental - congresses. 4. Skin Neoplasms -
congresses. WI REI06P v.l28 19931 WR 500 S62828 1993] RC261.R35
no. 128 [RC280.S5] 616.99'4 s - dc20 [616.99'4.77'071] DNLMIDLC
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Secretary General of the Symposium
E. Hecker, Honorary Chairman, Heidelberg
Scientific Program Committee
F. Marks, Chairman experimental aspects, Heidelberg
E. G. Jung/W. Tilgen, Chairmen clinical aspects, Heidelperg
A. Balmain, Glasgow
R. K. Boutwell, Madison
G. Fiirstenberger, Heidelberg
N. E. Fusenig, Heidelberg
R. J. M. Fry, Oak Ridge
L. Gissmann, Heidelberg
V. Kinzel, Heidelberg
R. M. Kripke, Houston
J. C. van der Leun, Utrecht
R. M. MacKie, Glasgow
R. Schmidt, Heidelberg
H. W. Thielmann, Heidelberg
Local Organizing Committee
N. E. Fusenig, Chairman, Heidelberg
E. Egenlauf, Heidelberg
J. Hietzker, Heidelberg
E. Mang, Heidelberg
F. Marks, Heidelberg
Foreword
The detection of cancer risk factors and their possible avoid
ance would most effectively contribute to the fight against
cancer. Research in these areas depends to a substantial
degree on in vivo experimental animal models and on epide
miologic studies, including data from cancer registries.
When the Deutsches Krebsforschungszentrum was
founded in 1964, its division "Mechanisms of Tumorigenesis"
and a number of other divisions became engaged in research
on chemical carcinogenesis of the skin, mainly using the
mouse skin as an experimental model. Their interest orig
inated in part from investigations of the new and at that
time controversial pathogenic principle of conditional car
cinogens as represented by certain tumor promoters which
are per se noncarcinogenic. During the past 25 years,
conditional carcinogens in terms of tumor promoters were
established as anew, nonclassical category of cancer risk
factors besides the classical solitary carcinogens.
In the course of this exciting period, scientists of our
center started cooperative programs with clinical dermato
logists of the University of Heidelberg at the Clinics of
Dermatology in Heidelberg and Mannheim, to extend the
scope of their investigations into clinical oncology and to
contribute by experimental approaches to solving problems
in clinical oncology. This led to a gradual shift from mere
animal studies to the more direct analyses of human tumors
and opened up for us a new phase of research. At this stage
it appeared to be most appropriate that the scientists of the
Deutsches Krebsforschungszentrum and the clinicians of the
University of Heidelberg jointly organize an international
symposium on Skin Carcinogenesis in Man and in Experi-
VIII Foreword
mental Models. It was held on October 29-31, 1991, at the
Deutsches Krebsforschungszentrum in Heidelberg.
The inviting institutions were pleased to welcome
clinicians and experimentalists active in skin cancer research
from allover the world. Intensive discussions during the
meeting documented the interest of the scientific com
munity. I am, therefore, pleased that the present volume
of Recent Results in Cancer Research documents as the
proceedings of the symposium the most important areas
of current research which were, unanimously, recognized
to mark problems deserving particular scientific efforts.
It should provide an overview of the current state of the
art in experimental and clinical investigations of skin
carcinogenesis, a particularly important topic in cancer
research and cancer prevention.
I trust these Proceedings will be welcomed by the
scientific community.
Heidelberg, Harald zur Hausen
January 1993 Chairman of the Management Board
Deutsches Krebsforschungszentrum
Preface
The slow, but steady increase in the incidence of skin can
cers in human beings urged scientists of the Deutsches
Krebsforschungszentrum (DKFZ) and clinicians of the Uni
versity of Heidelberg to call and invite experts in science
and medicine for an international symposium on which this
book is based. The increase of skin cancer over the last
decades is well documented by epidemiologic evidence. It
may have a number of different causes, of which the gen
eration and existence of so-called "holes" in the ozone layer
resulting from a depletion of stratospheric ozone-now to
be found above both of the earth's poles-causes many
headlines in the media and deep general concern as ex
pressed, e.g., by the United Nations Environment Program
(UNEP)l. Investigations on risk factors for cancer of the skin
and on prevention of skin cancer are therefore considered
"hot spots" in present-day cancer research. Scientists of the
DKFZ have been dealing with etiologies and mechanisms of
skin carcinogenesis in experimental models for about 25
years, and continue to do so. As a result, many contacts
were developed with the Departments of Dermatology of
the University of Heidelberg, one located traditionally in
Heidelberg city and the other in the neighboring city of
Mannheim. Such a background of traditional, experimental,
and clinical engagement in skin cancers made it seem par
ticularly appropriate and timely to invite scientists to an
international symposium on Skin. Carcinogenesis in Man
and in Experimental Models. It was held October 29-31,
1991, at the DKFZ and intended to update, analyze,
1 See especially the contribution by van der Leun et al. on p. 263.
X Preface
and discuss the latest facts in the etiology of, and in the
mechanisms involved in, the generation of cancer of the
skin.
For the first time, a report was presented on the German
Melanoma Register which collects in Germany scientific
data on the incidence and possible causes of this most ag
gressive skin cancer. Besides the many other practical
aspects, numerous theoretical considerations on the gen
eration of skin cancer were discussed, nourished essentially
by experimental models. Thus, a large body of experimental
facts on the impact of exogenous (environmental) risk fac
tors on genetic and epigenetic elements of target cells in the
skin were presented. Also, the role of genetic predisposition
and elimination of crucial genomic damage were themes of
the symposium. In this context the role of oncogenes and
suppressor genes as sources of endogenous risk factors was
accounted for specifically.
The organizers of the symposium-the Secretary General,
the international scientific program committee and the local
organizing committee-were pleased to welcome in the
DKFZ about 250 registered participants, clinicians from
many departments of dermatology as well as experimental
ists working on skin cancer from Western and Eastern
Europe, from the USA, and from the Far East. To take
part, some of the visitors had travelled long distances, from
as far as Japan, or had come from areas such as Slovenia
and Russia. Many of them contributed actively to the
symposium-by holding one of the 27 invited lectures, as
chairpersons of the scientific sessions, or as presenters
of more than 70 posters. The organizers believe that this
symposium has generated an overview of the current state
of the art in scientific experimental and clinical investiga
tions on the generation and the prevention of cancer of the
skin. From the results presented, marked refinements in the
assessment of the risk of cancer associated with environ
mental and endogenous factors, including tumor viruses,
will hopefully be stimulated. Moreover, new ideas should
emerge for developing specific approaches to explore the
mechanistic, i.e., ultimately the molecular-bielogical, causes
of skin cancers and others. In addition, the experimental
utilization of oncogenes and of other techniques from
molecular biology at all levels of the biology of tissues and
cells may open up entirely new facets in research on skin
cancer. Detailed knowledge of the mechanistic aspects of
skin carcinogenesis may give important hints on how to
Preface XI
"tailor-make" and utilize new antitumor agents in the
therapy of skin cancer for the benefit of the cancer patient.
This book, as the proceedings of the symposium, covers
all 27 invited lectures, arranged according to the three sec
tions of the symposium's scientific program; for the cor
responding posters the book of abstracts for the symposium
may be consulted (J Cancer Res Clin Oncol 116 (Suppl)
S61-S88 (1991)). Many thanks are due from the organizers
to Mrs. E. Mang and Dr. B. Sorg for compiling the indices
of the book and to the publishers, Springer-Verlag, for their
efficient cooperation in the technical editing and production
of the proceedings.
Heidelberg, Erich Hecker
January 1993 Director at the
Deutsches Krebsforschungszentrum,
Head, Division Mechanisms of
Tumorigenesis Research Program 3,
Risk Factors of Cancer and
Cancer Prevention
Contents
I. General Aspects 1
I. C. Barrett
Genetic Determinants in Carcinogenesis. . . . . . . . . . . . 1
L. Dagnino, I.A. Pietenpol, E. Y. Yang, and
H.L. Moses
Transforming Growth Factor Regulation of
Keratinocyte Growth ............................ 15
R.M. Lavker, S.J. Miller and T. T. Sun
Epithelial Stem Cells, Hair Follicles, and
Tumor Formation.. . . . . ... . .. . . . . . .. . . ... . . . .. . . 31
G. Stingl
The Skin: Initiation and Target Site of
Immune Responses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
II. Melanocyte Carcinogenesis 59
W. Tilgen
Melanocyte Carcinogenesis: Facts and Fancies. . . . . . . 59
C. Garbe, I. Weiss, S. Kruger, E. Garbe, P. Buttner,
I. Bertz, H. Hoffmeister, 1. Guggenmoos-Holzmann,
E.G. lung, and c.E. Orfanos
The German Melanoma Registry and
Environmental Risk Factors Implied . . . . . . . . . . . . . . . 69
A. {j)sterlind
Fair Complexion and Risk of Malignant Melanoma of
the Skin Based on Experience from
the Danish Cancer Registry. . . . . . . . . . . . . . . . . . . . . . . 91
