Carcinogenesis. Proceedings of a Symposium on the Biology of Skin Held at the University of Oregon Medical School, 1965

357 Pages·1966·10.75 MB·English

by  William Montagna and Richard L. Dobson (Eds.)

ADVANCES IN BIOLOGY OF SKIN
Already published:
Vol. 1 Cutaneous Innervation, Edited by W. MONTAGNA (1960).
Vol. 2 Blood Vessels and Circulation, Edited by W. MONTAGNA and
R. A. ELLIS (1962).
Vol. 3 Eccrine Sweat Glands and Eccrine Sweating, Edited by W. MON-
TAGNA, R. A. ELLIS and A. F. SILVER (1962).
Vol. 4 The Sebaceous Glands, Edited by W. MONTAGNA and R. A. ELLIS
(1963).
Vol. 5 Wound Healing, Edited by W. MONTAGNA and R. E. BILLINGHAM
(1964).
Vol. 6 Aging, Edited by W. MONTAGNA (1964).
ADVANCES IN
BIOLOGY OF SKIN
Vol. VII
CARCINOGENESIS
Proceedings of a Symposium on the Biology of Skin
held at the University of Oregon Medical School
1965
Edited by
WILLIAM MONTAGNA
and
RICHARD L. DOBSON
University of Oregon Medical School
Portland, Oregon
Oregon Regional Primate Research Center
Beaverton, Oregon
Publication No. 87 from the Oregon Regional
Primate Research Center
SYMPOSIUM PUBLICATIONS DIVISION
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First edition 1966
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PREFACE
THE focus of interest of most biologists has been and is still upon growth and
differentiation. When we clearly understand the factors that control growth
and differentiation in skin, we shall have knowledge of its function under
normal and under abnormal conditions. It is with this in mind that we have
included carcinogenesis in a series of symposia principally dedicated to the
biology of skin. That cancer is a problem of growth and differentiation is
made clear in nearly every chapter of this book. Cutaneous cancer, then, to
be understood will require a thorough knowledge of the biologic properties
of skin.
We have not attempted to treat here all of the aspects of cutaneous car-
cinogenesis; we have, however, put together the thoughts of some of the
leading authorities in this field. It is always a good beginning to attempt to
define problems in meaningful terms. In Chapter I, a brilliant synthesis of the
problems of mitosis, Bullough and Laurence give perspective to nearly all
that follows.
We have attempted to cover in this book as much ground as possible, from
problems of molecular interactions to problems of clinical importance. We
have considered etiology, pathogenesis, pathology and clinical features. Most
of the authors are concerned with broad definitions, attempting to establish a
framework upon which to fasten the many details which up to now have
seemed to be isolated.
Withal, this should not be considered to be a book about cancer; it is still a
book about the biology of skin. Many important fundamental things are
discussed here which are related to the problem of cancer only because cancer
is a biological problem. Finally, it seems to us that by studying carcinogenesis
we learn about the normal biologic properties of skin and vice versa.
With the exception of the first, the chapters of this book were presented to
the fifteenth Symposium on the Biology of Skin, held at the Oregon Regional
Primate Research Center on April 9, 10 and 11, 1965, under the auspices of
the University of Oregon Medical School. The symposium was supported in
part by a grant from the United States Public Health Service (AM 09431-01).
Additional contributions were made by Chesebrough-Pond's, Inc., Colgate-
Palmolive Company, Lever Brothers Company, Pergamon Press Ltd.,
Procter & Gamble Company and Warner-Lambert Research Institute. To
all of these we are deeply grateful.
W. MONTAGNA
R. DOBSON
xi
LIST OF CONTRIBUTORS
THOMAS S. ARGYRIS, Department of Zoology, Syracuse University, New York
EULA L. BINGHAM, Department of Environmental Health, University of Cincinnati College
of Medicine, Cincinnati, Ohio
WILLIAM S. BULLOUGH, Birkbeck College, University of London, London, England
RONALD E. DAVIES, The Skin and Cancer Hospital, Department of Dermatology, Temple
University Health Sciences Center, Philadelphia, Pennsylvania
RICHARD L. DOBSON, Division of Dermatology, University of Oregon Medical School,
Portland, Oregon
JOHN H. EPSTEIN, Division of Dermatology, Department of Medicine, University of
California School of Medicine, San Francisco, California
P. DONALD FORBES, The Skin and Cancer Hospital, Department of Dermatology, Temple
University Health Sciences Center, Philadelphia, Pennsylvania
LAWRENCE GARFINKEL, Statistical Research Section, American Cancer Society, New York,
New York
GERALD A. GELUN, Department of Dermatology, New York University School of Medicine
and the Skin and Cancer Unit, University Hospital, New York, New York
BEPPINO C. GIOVANELLA, McArdle Laboratory for Cancer Research, University of
Wisconsin Medical School, Madison, Wisconsin
JAMES H. GRAHAM, The Skin and Cancer Hospital of Philadelphia, Departments of
Dermatology and Pathology, Temple University School of Medicine, Philadelphia,
Pennsylvania
CHARLES HEIDELBERGER, McArdle Laboratory for Cancer Research, University of
Wisconsin Medical School, Madison, Wisconsin
ELSON B. HELWIG, The Division of Pathology and Branch of Dermal Pathology, The
Armed Forces Institute of Pathology, Washington, D.C.
A. WESLEY HORTON, Division of Environmental Medicine and Department of Biochemistry,
University of Oregon Medical School, Portland, Oregon
OLAV HILMAR IVERSEN, Institutt for Generell og Eksperimentell Patologi, Universitetet i
Oslo, Rikshospitalet, Oslo, Norway
HADLEY KIRKMAN, Department of Anatomy, Stanford University School of Medicine,
Stanford, California
ALFRED W. KOPF, Department of Dermatology, New York University School of Medicine
and the Skin and Cancer Unit, University Hospital, New York, New York
EDNA B. LAURENCE, Birkbeck College, University of London, London, England
J. A. MCCARTER, Department of Biochemistry, Dalhousie University, Halifax, Canada
WILBUR P. MCNULTY, JR., Oregon Regional Primate Research Center, Beaverton, Oregon
JOHN W. ORR, Department of Pathology, Medical School, Birmingham, England
HERMANN PINKUS, Department of Dermatology, Wayne State University School of
Medicine, Detroit, Michigan
JEFFREY S. PINTO, Division of Dermatology, University of Oregon Medical School, Portland,
Oregon
PHILIPPE SHUBIK, Division of Oncology, The Chicago Medical School, Institute for Medical
Research, Chicago, Illinois
PAUL A. VAN DREAL, Division of Environmental Medicine and Department of
Biochemistry, University of Oregon Medical School, Portland, Oregon
EUGENE J. VAN SCOTT, Dermatology Branch, National Cancer Institute, National Institutes
of Health, Bethesda, Maryland
FREDERICK URBACH, The Skin and Cancer Hospital, Department of Dermatology, Temple
University Health Sciences Center, Philadelphia, Pennsylvania
xiii
CHAPTER I
TISSUE HOMEOSTASIS IN ADULT
MAMMALS
WILLIAM S. BULLOUGH AND EDNA B. LAURENCE
Birkbeck College, University of London, London, England
I. INTRODUCTION
It should surely be obvious that while the nature of tissue homeostasis
remains obscure, no satisfactory explanation of the phenomenon of carcino-
genesis is likely to be obtained. In view of the self-evidence of this statement it
is surprising how little effort has been devoted within the vast field of cancer
research to the study of normal control mechanisms, and indeed, only within
the last few years have any significant attempts been made. These have
included studies on gene control (see Monod and Jacob, 1961), on histone
function (see Bonner and Ts'o, 1964), and on mitotic homeostasis (see Bullough,
1962, 1965). Much of this work has recently been reviewed by Bullough (1965)
but the present statement takes account of still more recent results.
From a wide range of studies of mammalian and other vertebrate tissues
the broad outlines of the processes of tissue formation and tissue homeostasis
are now beginning to appear. Regarding tissue formation, it is evident that
during embryonic differentiation (a phenomenon that is not considered here)
the originally totipotent cell genome is severely restricted (see Beam and Färber,
1964) so that in a differentiated tissue the few alternative activities in which a
cell can indulge are directed by a mere remnant of the original genome.
Regarding tissue homeostasis, evidence is reviewed below to reveal at least
the outline of the mechanism that directs and controls the expression of these
alternative activities in adult mammalian tissues, and some consideration is
also given to the possible relation of this mechanism to certain aspects of
carcinogenesis.
II. THE BASIC SITUATION IN NORMAL TISSUES
The majority of adult mammalian tissues show mitotic activity either
spontaneously or when they are appropriately stimulated, and it is these
I
2 WILLIAM S. BULLOUGH AND EDNA B. LAURENCE
tissues which are mainly considered below. The special case of tissues which
are incapable of mitosis is considered on p. 17.
A most obvious characteristic of any ordinary adult tissue is its constant
mass, which is ensured by the precise balance that exists between the rates of
cell gain and of cell loss. At first sight the precision of this balance may seem
remarkable but it is in fact something which must develop in any situation
where both the mitotic rate and the life expectancy of the functional tissue
cells remain constant. In each tissue this constancy would appear to be
genetically determined, and throughout the various tissues of the body there
is the widest range both of the mitotic rate and of the life expectancy of the
cells. From a survey of this range there emerge the generalizations, first, that
within wide limits the mitotic rate of any tissue is inversely proportional to
the life expectancy of the tissue cells, and second, that also within wide limits
the mitotic rate is directly proportional to the speed with which the cells
pass from one mitosis to the next.
The most obvious questions that arise are related to the manner of control,
first, of the mitotic rate and, second, of the life expectancy of the tissue cells.
It appears that the mitotic rate is basically determined by the chance that the
products of any mitosis will again prepare for mitosis or that they will instead
prepare for tissue function. If the chances favor mitosis then a larger propor-
tion of the tissue cells will be involved in the mitotic cycle, but if the chances
favor tissue function then a smaller proportion of the tissue cells will be
involved in the mitotic cycle. The essence of the question thus turns on the
nature of the choice made by any cell when it emerges from mitosis, a choice
which is essentially between alternative programs of genetic activity and thus
of protein synthesis. This is discussed in the next section.
Less is known of the factors controlling the life expectancy of the tissue
cells, but it is already clear that a cell does not usually die because it is worn
out. The evidence in fact suggests that a cell commits suicide while it is still
capable of functioning properly. This is discussed on p. 15.
III. THE CHOICE IN THE DICHOPHASE
The critical period in the life of a cell when the choice is made between
preparation for yet another mitosis or preparation for tissue function has
been called the dichophase (Bullough, 1963,1965). It has often been suggested
that in any adult tissue the two cells produced by each mitosis are not
equivalent but "are unequal in size, form and function, and have a different
subsequent development" (Setälä, 1965). There is in fact no evidence to
support this view and indeed in epidermis the plane of each division is usually
such as to ensure that both daughter cells remain in the mitotically active
basal layer (Bullough and Laurence, 1964a). In this way, pressure is evidently
TISSUE HOMEOSTASIS IN ADULT MAMMALS 3
built up so that from time to time, in what is perhaps a random manner,
epidermal cells are forced into the more superficial layers, where keratin
synthesis begins (see Mercer, 1962). Thus, at least in the stratified epidermis
the dichophase choice seems to be made primarily in terms of the position of
the cell within the tissue, which may mean that the decision is made in terms
of the cell environment. It seems probable that the same may also be true
in non-stratified tissues, although in them the situation is less simple.
It thus appears possible that the nature of the cell environment may in
some way dictate gene expression in differentiated mammalian cells. The
most probable hypothesis is that the instructions pass in chemical form, and
that, for instance, in epidermis as a cell moves outwards, it is the increasing or
decreasing concentration of some specific chemical that inactivates the
mitosis genes and activates those genes that direct synthesis for tissue func-
tion. Such a conclusion is immediately reminiscent of gene control by effector
substances in micro-organisms (see Monod and Jacob, 1961 ; Monod, Jacob
and Gros, 1961 ; Monod, Changeux and Jacob, 1963). Briefly, in such organisms
the production of a particular enzyme or of a related sequence of enzymes is
controlled by a structural gene or by a group of adjacent structural genes,
which are collectively called an operon. Whether an operon is active or
inactive depends on the concentration of a repressor substance which is
synthesized at a constant rate in response to the activity of a regulator gene.
The ability of a repressor to inhibit the activity of the relevant structural
genes is either promoted or inhibited by an effector substance, which is some
critically important metabolite. In this way the rate at which a particular
enzyme (or a related sequence of enzymes) is synthesized at any one moment
depends on the needs of that moment as expressed by the concentrations
of particular metabolites within the cell. Thus, in the presence of a particular
food material the enzymes necessary for its digestion are produced, and in the
absence of some essential metabolite the enzymes necessary for its synthesis
are produced. It is by exploiting the potentialities of the genome in this way
that micro-organisms are able to show a remarkable versatility in their
reactions to changing circumstances.
Although the work done on micro-organisms is extensive and the con-
clusions drawn from it are well documented, the converse is the case with
mammalian cells. Nevertheless, Monod and Jacob (1961) have tentatively
extended their conclusions to include the differentiated cells of higher
organisms, and indeed the basic similarities of all cells are such that both the
structure and the function of the genes are likely to be essentially similar.
In the cells of a differentiated adult mammalian tissue the situation seems
to be that, with the greater part of the original gene potentialities blocked
during embryonic life, the only unblocked genes remaining are those directing
the synthesis of enzymes essential to the basic metabolic pathways, and those
B
4 WILLIAM S. BULLOUGH AND EDNA B. LAURENCE
directing either mitosis or tissue function. Since it is well established that
synthesis for mitosis and synthesis for tissue function tend to be mutually
exclusive, it is clear that the full activation of the "mitosis operon" involves
the inactivation of the "tissue operon", and vice versa.
It is the choice between these opérons that is decided in the dichophase,
and if this choice is made in terms of the intracellular concentration of some
effector, then it is of the greatest importance to attempt to define its nature.
In the differentiated tissues of a highly organized mammal it is most unlikely
that such critically important effectors will prove to be merely simple meta-
bolites of the kind that are known to operate in micro-organisms. It is more
probable that each tissue will prove to be controlled by one or more specific
Cytoplasm:
+ chalone
Tissue enzymes Mitosis enzymes
FIG. 1
Diagram of the partially blocked genome of a differentiated tissue cell. It is sug-
gested that the choice between the alternative syntheses for mitosis or for tissue
function is made in terms of the concentration of a tissue-specific chalone which
is also synthesized within the cell.
substances which have evolved with the tissue in which they are also pro-
duced. Such a system of tissue autoregulation, considered mainly in terms of a
negative feedback mechanism controlling mitotic activity, has often been postu-
lated (see Osgood, 1957, 1959; Glinos, 1960;Iversen, 1961; Bullough, 1962;
Mercer, 1962), and recent work has led to the extraction of at least one of the
substances responsible. A summary of the way in which this substance,
which is now called a chalone, may perhaps work is shown in Fig. 1.
IV. TISSUE AUTOREGULATION
In the past, many attempts have been made to extract from tissues sub-
stances which can influence, whether positively or negatively, the growth and
proper functioning of these same tissues. Indeed, that such substances do
TISSUE HOMEOSTASIS IN ADULT MAMMALS 5
exist was an idea that lay at the very root of ancient medical practice and that
led to the dictum of Paracelsus that "similia similibus curantur". In modern
times the actions of tissue extracts have been most extensively studied in
relation to liver and kidney regeneration (see p. 7).
However, the present account of mitotic control by tissue chalones began
with the attempt by Bullough and Laurence (1960a) to discover why the
infliction of a skin wound causes a reversion to active mitosis in those
adjacent epidermal cells that are beginning to synthesize keratin. It has been
commonly believed that this reversion is a reaction to the production by the
damaged tissue of a mitosis stimulating wound hormone. From a series of
studies (Bullough and Laurence, 1960a, b, 1961; Bullough, Hewett and
Laurence, 1964) the following main points have emerged:
i. The increased mitotic activity adjacent to a wound is due to the disappearance of a
previously present mitotic inhibitor, or chalone, the actions of which are tissue-
specific.
ii. In the epidermis and in many other tissues the antimitotic power of the chalone is
augmented by adrenalin, which perhaps acts as a cofactor. As the chalone disappears
from the neighborhood of a wound and the mitotic activity rises, the ability of
adrenalin to suppress mitosis is lost.
iii. In many normal tissues one consequence of the adrenalin action is the diurnal
mitotic cycle, which is the inverse of the diurnal cycle of adrenalin output. No
diurnal mitotic cycle is found in any tissue, normal or damaged, in which there is
reason to believe the chalone is absent.
iv. Aqueous extracts of macerated epidermis contain the epidermal chalone and it can
be shown in vitro that this substance only exercises its full power in the presence of
adrenalin. Epidermal chalone extracts have also been prepared by Iversen, Aandahl
and Elgjo (1965).
v. Although the epidermal chalone is tissue-specific it is not species-specific and so far
the largest quantities tested on mice have been prepared from pig epidermis (Homan
and Hondius-Boldingh, 1965).
Recently, considerable progress has been made in the isolation and
characterization of the epidermal chalone. Bullough, Hewett and Laurence
(1964) were able to recover most of the chalone originally present in water
solution in the precipitate obtained as the 70-80 per cent ethanol fraction, and
from its physical properties they suggested that it might be a protein. Since
then, Homan and Hondius-Boldingh (1965) have obtained an apparently pure
sample from which it appears that the epidermal chalone may be a basic
glycoprotein with some optical activity and a molecular weight of perhaps
40,000. The details of its chemical structure are now being investigated.
In being water soluble, non-dialyzable, and heat labile the epidermal
chalone resembles the organ-specific antimitotic substances extracted by
Saetren (1956, 1963) from liver and kidney and also the tissue-specific anti-
mitotic substance extracted by Rytömaa and Kiviniemi from granulocytes
(see Bullough and Rytömaa, 1965). Evidence for the existence of tissue-specific