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Environmental Factors in Skin Diseases
Current Problems in
Dermatology
Vol. 35

Series Editor

P. Itin, Basel
Environmental
Factors in Skin
Diseases

Volume Editor

E. Tur, Tel Aviv

25 figures, 10 in color, and 25 tables, 2007

Basel · Freiburg · Paris · London · New York ·

Bangalore · Bangkok · Singapore · Tokyo · Sydney
 Current Problems in Dermatology

Ethel Tur
Department of Dermatology, Ichilov Medical Center
6 Weizman Street
IL-64239 Tel Aviv (Israel)
E-Mail [email protected]

Library of Congress Cataloging-in-Publication Data

Environmental factors in skin diseases / volume editor, E. Tur.

p. ; cm. – (Current problems in dermatology ; v. 35)
Includes bibliographical references and indexes.
ISBN-13: 978-3-8055-8313-8 (hard cover : alk. paper)
1. Skin–Diseases–Environmental aspects. I. Tur, E. II. Series.
[DNLM: 1. Skin Diseases–etiology. 2. Environmental Exposure–adverse
effects. 3. Environmental Pollutants–adverse effects. 4. Skin–radiation
effects. W1 CU804L v.35 2007 / WR 140 E6 2007]
RL72.E55 2007
616.5⬘07–dc22
2007018837

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and
Index Medicus.

Disclaimer. The statements, options and data contained in this publication are solely those of the individ-
ual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the
book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness,
quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property
resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and
dosage set forth in this text are in accord with current recommendations and practice at the time of publication.
However, in view of ongoing research, changes in government regulations, and the constant flow of information
relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for
any change in indications and dosage and for added warnings and precautions. This is particularly important when
the recommended agent is a new and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or
utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying,
or by any information storage and retrieval system, without permission in writing from the publisher.

© Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)

www.karger.com
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISSN 1421–5721
ISBN 978–3–8055–8313–8
 Contents

VII Foreword
Tur, E. (Tel Aviv)

Genetic Predisposition, Genetic Modifiers and Extrinsic Factors

in Aging of the Skin and in UV Carcinogenesis

1 Exogenous Factors in Skin Aging

Landau, M. (Holon)

14 Ultraviolet Radiation and Cutaneous Carcinogenesis

Molho-Pessach, V.; Lotem, M. (Jerusalem)

28 Genetic Factors in the Pathogenesis of UV-Induced Skin Cancer

Sprecher, E. (Haifa)

External Factors, Other than UV, in Skin Carcinogenesis

39 Viral Carcinogenesis in Skin Cancer

Molho-Pessach, V.; Lotem, M. (Jerusalem)

52 Environmental Risk Factors for Mycosis Fungoides

Wohl, Y.; Tur, E. (Tel Aviv)

External Factors in Skin Diseases with Genetic and Intrinsic Predisposition

65 Exogenous Factors in Connective Tissue Diseases

Trattner, A. (Tel Aviv)

V
78 Vitiligo
Matz, H.; Tur, E. (Tel Aviv)

103 Environmental and Cosmetic Factors in Hair Loss and Destruction

Horev, L. (Jerusalem)

118 Environmental Factors and Psoriasis

Dika, E.; Bardazzi, F.; Balestri, R. (Bologna); Maibach, H.I. (San Francisco, Calif.)

Skin and the Nervous System: Stress, Itch and More

136 Pathogenesis of Stress-Associated Skin Disorders:

Exploring the Brain-Skin Axis
Pavlovsky, L.; Friedman, A. (Beersheva)

146 Exogenous Factors in Itch Response

Yelverton, C.B.; Yosipovitch, G. (Winston-Salem, N.C.)

154 Atopic Dermatitis

Guttman-Yassky, E. (New York, N.Y./Haifa/Ramat Gan)

Work-Related Skin Diseases

173 Occupational Factors in Skin Diseases

Slodownik, D. (Jerusalem/Carlton); Nixon, R. (Carlton)

190 Author Index

191 Subject Index

Contents VI
 Foreword

Ever since its appearance on mother Earth, the human race has had to protect
itself from the adverse effects of the surrounding environment. Unfortunately,
starting with the industrial revolution, if not before, mankind has begun to consis-
tently mistreat the environment, which has reciprocated in exposing the offenders
to new dangers. Being in permanent interaction with the environment, our skin,
more than any other organ, is affected by the environment. Increased exposure to
UV radiation, industrial pollution, and climatic determinants are but a few exam-
ples of modern environmental insults that mercilessly attack the skin. But the
term ‘environment’ is not limited to our physical surrounding. The modern emo-
tionally stressful lifestyle, the excessive use of drugs, together with other exoge-
nous factors also affect our skin. It is not surprising, therefore, that the need for a
thorough investigation of environmental factors is exponentially growing, since in
parallel with the mounting danger, there has been impressive scientific progress
in understanding and combating these harmful effects.
The interaction between the skin and the environment presents a fascinat-
ing and challenging research subject. Such research is needed in order to better
understand the pathogenesis and the disease process and to develop new thera-
peutic strategies and preventive measures. Interactions between genetic risk
factors and environmental triggers are involved in skin aging and skin carcino-
genesis, as well as in psoriasis, atopic dermatitis and autoimmune diseases.
In the last years, a substantial body of work has been created by the use of
novel technologies to investigate skin responses to environmental stimuli. Such
techniques allow researchers to investigate the interplay among environmental
and genomic elements in skin cell biology, to decipher the biochemical steps

VII
undertaken in the process, and also to study the genetic factors underlying vari-
ations in skin response to environmental factors. Just a few months ago, an
innovative study identified a gene implicated in the pathogenesis of vitiligo and
other autoimmune diseases associated with it.
Recent research, covered in the following chapters, is roughly divided into
five overlapping subjects, each involving both clinical and investigational data:
(1) aging of the skin and UV carcinogenesis; (2) external factors, other than UV,
in skin carcinogenesis; (3) external factors in skin diseases with genetic and
other predisposing factors; (4) skin and the nervous system, including stress,
itch and more, and finally (5) work-related skin diseases. Due to space limita-
tion we chose to cover subjects that were less discussed in the past and thus cer-
tain diseases, including bullous diseases, were left out. Hopefully these will be
covered in a further publication.
I hope that this book will not only provide good coverage of the state-of-
the-art of research, ranging from epidemiology to molecular biology, but also
prompt further research in this challenging subject.
I would like to extend my appreciation to all contributors for their meticu-
lous contributions. I would also like to thank the people at Karger, especially
Susanna Ludwig and Elizabeth Anyawike for putting their effort and expertise
into the present publication.
Ethel Tur, Tel Aviv

Foreword VIII
 Genetic Predisposition, Genetic Modifiers and Extrinsic
Factors in Aging of the Skin and in UV Carcinogenesis

Tur E (ed): Environmental Factors in Skin Diseases.

Curr Probl Dermatol. Basel, Karger, 2007, vol 35, pp 1–13

Exogenous Factors in Skin Aging

Marina Landau
Dermatology, Wolfson Medical Center, Holon, Israel

Abstract
The dramatic alteration in the appearance of the skin with aging is related to both
intrinsic (genetic) and exogenous factors. While intrinsic aging is an insidious degenerative
process predictable in outcome, the superposition of environmental factors is neither univer-
sal nor inevitable. There are distinct morphologic and histological features differentiating
intrinsic and extrinsic aging of the skin. The most well appreciated environmental factors
affecting skin aging are sun exposure and smoking. Recent advances in molecular biology
have increased our understanding of the mechanisms by which exogenous factors contribute
to the cutaneous aging. The skin is equipped with numerous inherent mechanisms that pro-
tect and defend against accelerating aging. But the efficacy of these mechanisms decreases
significantly over a lifetime. In this review, we summarize the features of extrinsic aging and
biochemical steps involved in this process.
Copyright © 2007 S. Karger AG, Basel

What is Aging?

Aging is a progressive process involving reduction in maximal function

and reserve capacity of the whole organism [1]. It is a consequence of both
genetic program and cumulative environmental effects. Central theories of
aging attempt to elucidate both the genetically determined and the environmen-
tal processes responsible for senescence. According to telomere shortening the-
ory, aging is part of the inherent process [2]. Telomeres, the terminal portions of
chromosomes, shorten at every cell cycle. Once the telomere reaches a critical
length, cell cycle arrests and apoptosis occurs [3]. Free radical theory, high-
lights the role and function of the external factors [4]. According to this theory,
aging results from accumulation of cellular damage produced by excess reac-
tive oxygen species (ROS) that are generated as a consequence of oxidative
metabolism [5, 6]. Age-associated cellular damage includes oxidation of DNA
resulting in mutations, oxidation of proteins causing their reduced function, and
oxidation of membrane lipids affecting transport efficiency and possibly trans-
membrane signaling. The main source of excess ROS implicated in aging is
mitochondrial oxidative energy generation.

Intrinsic Cutaneous Aging

In the skin both genetic (intrinsic) and exogenous factors contribute to the
phenotypic and functional changes occurring with age. Chronologically aged skin
is dry, lax and atrophic with fine wrinkles and a variety of benign neoplasms (fig. 1).
The most consistent histological changes of intrinsic cutaneous aging include
flattening of the dermal-epidermal junction. This results in a considerably smaller
contact surface between the epidermis and dermis and presumably less communi-
cation and nutrient transfer. Generally, epidermal thickness remains constant with
advancing age, but variability in epidermal thickness and individual keratinocyte
size increases. At the electron microscope level, sun-protected old skin is charac-
terized by some widening of interkeratinocyte spaces and by reduplication of
lamina densa and anchoring fibril complex in the basement membrane zone [7].
In addition, in the aging epidermis progressive decrease in melanocyte and
Langerhans cell density is observed [8]. Dermal thickness decreases especially
after the eighth decade. Old skin is relatively acellular and avascular and is char-
acterized by loss of capillary loops and decrease in dermal fibroblasts and extra-
cellular matrix.
Functional changes in skin during intrinsic aging include slow wound heal-
ing due to decreased keratinocyte and fibroblast proliferating ability, reduced
cytokine production, and delayed recovery of barrier function after damage
[9–11]. The barrier to water loss is more easily disturbed, in part because of
decreased lipid synthesis capacity [12]. Relative unresponsiveness of cutaneous
immunity is related to decreased production of immune cytokines and
decreased density of Langerhans cells [13]. The decreased number of melanocytes
may contribute to reduced protection against UV [14]. Decrease in DNA repair
rate correlates inversely with mutation risk and cancer susceptibility [15].
Changes in vessel wall architecture contribute to vascular fragility and compro-
mised thermoregulation [16]. With age, skin ability to create active forms
of vitamin D decreases together with perception of light touch and vibratory
sensation [17, 18].
The activity of enzymes involved in synthesis and degradation of extra-
cellular matrix proteins is affected by aging. While expression of collagenases
and metalloproteinases increases, the level of the tissue inhibitor of meta-
lloproteinases 1 is decreased [19–21]. Therefore, a shift in balance between

Landau 2
synthesis and degradation of collagen occurs that causes a reduction in dermal
thickness.

Exogenous Cutaneous Aging

Since skin is in direct contact with environment, it undergoes changes as a

consequence of external factors. Among harmful environmental factors that
contribute to the extrinsic aging of the skin, exposure to UV light (photoaging)
is considered to be the most significant and well recognized. The term photoag-
ing has been coined by Kligman in 1989 [22]. Photoaging refers to the effects
of long-term UV exposure superimposed on intrinsically aged skin. Photoaging
is a cumulative process which depends primarily on the degree of sun exposure
and skin pigment. Individuals who have outdoor lifestyles, live in sunny places,
and are lightly pigmented experience greater degree of photoaging.
Photodamaged skin appears sallow, irregularly pigmented, wrinkled, atrophic,
with multiple telangiectases, and variety of premalignant lesions (fig. 2a).
Histological changes in photodamaged skin include thickening of the epidermis,
disorganization and cytologic atypia of the keratinocytes, uneven distribution of
melanocytes in basal layer with significant decrease of Langerhans cells and
masses of amorphous elastic material in the papillary dermis.
The instant effect of sun exposure includes immediate pigment dark-
ening and delayed formation of new melanin. Those reactions are reversible.
Prolonged and recurrent sun exposure creates constant changes in melanin
amount and distribution in the skin. In genetically predisposed individuals,
freckling begins in the first years of life and consists histologically of large and
overactive melanocytes [23]. Depending on the individual’s complexion, within
few decades sun-exposed skin becomes indefinitely hyperpigmented remaining
darker than the sun-protected skin even in the absence of further sun exposure.
This is due to increased melanocyte density, increased epidermal melanin and
increased number of dermal melanophages [24]. The density of melanocytes in
habitually sun-exposed skin is approximately twice that in protected skin [25].
Solar lentigines and guttate hypomelanosis are typical consequences of recur-
rent sun exposure. The exact mechanism of their production is not clear. While
histologically, solar lentigines consist of an increase in both number and
activity of melanocytes, guttate hypomelanosis is epidermal foci devoid of
melanocytes.
Deposition of amorphous elastic material in the papillary dermis instead of
a normal connective tissue is considered to be the principal element differenti-
ating chronological aging from photoaging (fig. 2b). Damage to the collage-
nous matrix is thought to underlie the course, rough, wrinkled appearance of

Exogenous Factors in Skin Aging 3

1

2a

2b

Landau 4
 Table 1. Changes in intrinsic and photodamaged skin

Skin components and cells Intrinsic aging Photoaging

Epidermis decrease [26] or increase [23]

constant [27]
Dermis decrease decrease
Dermal-epidermal junction normal to flat flat
Keratinocytes decrease in proliferative loss of polarity, atypia
capacity
Melanocytes decrease [28] increase
Langerhans cells decrease decrease
Collagen disorganized severely disorganized
Elastic fibers decrease [29] increase, abnormal [24]
Blood vessels loss of vascular loops ectatic vessels with
atrophic walls
Fibroblasts decrease decrease
Inflammatory infiltrate absent present
Matrix metalloproteinase activity increase increase
Inhibitors of matrix decrease decrease
metalloproteinase activity

photodamaged skin. The main changes in skin components of intrinsically aged

and photoaged skin are summarized in table 1.

Mechanism of Photodamage

UVB irradiation is absorbed maximally by DNA and creates photoprod-

ucts, such as cyclobutane pyrimidine dimers and pirymidine pyrimidone photo-
products [30]. These mutations are clinically relevant to premalignant cutaneous
tumors and skin malignancies. However, their relevance to other clinical mani-
festations of photoaging, such as wrinkles, is not completely elucidated.
The role of UVA in skin aging is carried out through the generation of ROS.
These unstable molecules damage the DNA, cellular membranes, lipids and pro-
teins [31]. The marker of the UVA damage is considered to be a ‘common

Fig. 1. Intrinsic versus extrinsic aging. This 86-year-old woman presents typical features
of intrinsic aging on the sun-protected skin and extrinsic aging on her face and upper chest.
Fig. 2. a Histological picture of chronologically aged skin. b Histological picture of
photoaged skin. Deposition of amorphous elastic material in the papillary dermis is the
major feature differentiating chronological aging from photoaging.

Exogenous Factors in Skin Aging 5

deletion’ in the mitochondrial DNA [32]. Since mitochondria have the highest
ROS turnover in the cell, mutations in the mitochondrial genome may be associ-
ated with the changes seen with UVA-induced photoaging [33].

Photoaging and Connective Tissue

Ultraviolet irradiation invokes a complex sequence of specific molecular

responses that damage skin connective tissue (fig. 3). UV irradiation disrupts
the skin collagen matrix by two interdependent pathways: stimulation of colla-
gen degradation and inhibition of collagen production. The cellular machinery
that mediates this UV damage includes cell surface receptors, signal transduc-
tion pathways, transcription factors, and enzymes that synthesize and degrade
structural proteins in the dermis.
The primary mechanism by which UV irradiation initiates molecular res-
ponses in the skin is by photoproduction of ROS, which induce signaling path-
ways such as intracellular kinases [34]. Activated kinases upregulate expression
and activation of transcription factors, such as activated protein 1 (AP-1) and
nuclear transcription factor-
B (NF-
B). Nuclear transcription factor AP-1
stimulates transcription of genes for matrix-degrading enzymes such as metal-
loproteinase (MMP) 1 (collagenase), MMP3 (stromelysin 1), and MMP9 (92-
kDa gelatinase) [35, 36]. Ultraviolet-induced MMP1 initiates cleavage of type I
and III collagens in skin [37]. Once cleaved by MMP1, collagen can be further
degraded by elevated levels of MMP3 and MMP9 [38]. Thereby, UV irradiation
degrades skin collagen and impairs the structural integrity of the dermis [39].
Collagen VII reduction was also found in photodamaged skin. Collagen VII com-
poses anchoring fibrils and, thus, is important in maintaining dermal-epidermal
junction integrity [40].
NF-
B is also activated by UV light. This transcription factor stimulates
the transcription of inflammatory cytokines, such as interleukin I, VI, and
tumor necrosis factor- and therefore is involved in attraction of neutrophils
containing preformed neutrophil collagenases [41, 42].
In addition to degrading mature dermal collagen, UV irradiation impairs
ongoing collagen synthesis. It has been found that collagen I formation is sig-
nificantly decreased in the papillary dermis of photodamaged skin primarily
through downregulation of type I and type III procollagen gene expression [43, 44].
The two mechanisms contributing to reduction in procollagen gene expression
are induction of transcription factor AP-1 [45] and downregulation of type II
transforming growth factor- (TGF-) receptor [46]. Finally, damaged collagen
itself downregulates new collagen synthesis [47, 48]. Poor adhesion of fibrob-
lasts to damaged collagen causes a decreased neocollagenesis [49].

Landau 6
 Production of ROS

Activation of intracellular kinases

AP-1 ↑ NF-
B Type II TGF- receptor ↓

Transcription of Type I and type III

MMP1, 3, 9 ↑
inflammatory cytokines ↑ procollagen gene
expression ↓

Attraction of neutrophils ↑

Neutrophil collagenase (MMP1,

MMP8 and MMP9) ↑ Damaged collagen

Collagen degradation ↑ Collagen synthesis ↓

Fig. 3. The effect of UV light on collagen metabolism. UV-generated ROS which

induce signaling pathways, such as intracellular kinases. Activated kinases upregulate
expression and activation of transcription factors AP-1 and NF-
B. (1) AP-1 stimulates tran-
scription of genes for matrix-degrading enzymes (MMP). (2) NF-
B stimulates the tran-
scription of inflammatory cytokines that are involved in attraction of neutrophils containing
preformed neutrophil collagenases. (3) Expression of procollagen gene type I and type III is
decreased due to induction of AP-1 and downregulation of type II TGF- receptor.
(4) Damaged collagen downregulates new collagen synthesis.

Smoking

It is well documented that cigarette smoking is associated with significant

cardiovascular and pulmonary morbidity. As early as in 1856, a relation
between smoking and wrinkling was noted [50]. Since then, various studies

Exogenous Factors in Skin Aging 7

 b

a
Fig. 4. Smoker’s skin. a Wrinkles radiating from the corner of the eyes with slightly
grayish pigmentation of the skin. b Perioral wrinkling.

indicated that cigarette smoking affects facial skin [51, 52]. The complex of
facial wrinkles radiating from the corner of the eyes with slightly grayish pig-
mentation of the skin or alternatively a reddish hue has been described as the
‘smoker’s face’ [53]. This complex wrinkling pattern is not an exclusive feature
of smokers. Premature appearance of wrinkled facial skin especially in perioral
area is a characteristic feature of smoking men and women (fig. 4).
Smoking was found to be an independent risk factor for premature facial
wrinkling even after controlling for sun exposure, age, sex, and skin pigmenta-
tion. The relative risk of moderate to severe wrinkling for current smokers was
found to be 2.3 for men and 3.1 for women [48]. Wrinkling increases with
increased pack years of smoking, and heavy smokers are more likely to be wrin-
kled than nonsmokers [47]. When smoking and excessive sun exposure coex-
ists, the effect on wrinkling is multiplied. With excessive sun exposure and
heavy smoking, the risk of developing wrinkles was found to be 11.4 times
higher than in normal age-controlled population [54].

Molecular Basis of Smoking-Induced Skin Aging

The exact mechanism of smoking-associated cutaneous aging is poorly

understood (fig. 5). Studies have shown that skin microvasculature is influenced

Landau 8
 ROS TGF-1 receptor ↓
Toxic products

MMP1 and -3 mRNA ↑

Increase in plasma Type I and type III

neutrophil elastase Effect on cutaneous procollagen gene
activity microvasculature Damage to collagen expression ↓

Damage to elastic fibers Collagen degradation ↑ Collagen synthesis ↓

Fig. 5. The effects of smoking on skin. (1) Cigarette smoke increases plasma neu-
trophil elastase activity, which together with ischemic effect contributes to abnormal elastin
formation. (2) Increase in MMP1 and -3 mRNA is induced by water-soluble extract of
tobacco smoke. (3) Tobacco smoke downregulates TGF-1 receptor, thus contributing to
reduction in procollagen type I and III gene expression and decrease in collagen production.

by acute and chronic effects of cigarette smoking [55, 56]. Chronic ischemia of
the dermis likely plays a role in damage to elastic fibers and decreased collagen
synthesis [57]. Increased elastosis was found in sun-exposed skin of smokers
[58]. Elastic fibers from nonsun-exposed skin have been shown to be thicker and
fragmented when compared with those in nonsmoking age-matched control sub-
jects [59]. Cigarette smoke has been shown to increase plasma neutrophil elas-
tase activity, which may also contribute to abnormal elastin [60]. It has been
found that cigarette smoke condensate is phototoxic to skin and therefore sug-
gested that as the facial skin of smokers is exposed to both smoke and UV, the
premature aging is due to photosensitization [61].
On the molecular level, smokers have less collagen in their nonsun-exposed
skin and their ability to intensify collagen production after skin wounding is
reduced [62, 63]. It has been suggested that cutaneous effects of nicotine are
mediated through -3 nicotinic acetylcholine receptor on fibroblasts [64].
Significant increase in MMP1 and MMP3 mRNA and decrease in type I and III
procollagens were detected when human fibroblasts were exposed to water-sol-
uble extract of tobacco smoke. Pretreatment of the cells with antioxidants, such
as vitamins C and E, prevented the tobacco-induced alteration of MMP1. These
findings suggest that ROS might also contribute to the premature skin aging in

Exogenous Factors in Skin Aging 9

smokers [65]. Tobacco smoke was shown to downregulate TGF-1 receptor and
to induce nonfunctional forms of TGF-1 [66]. These changes may contribute
to reduction in procollagen gene expression. The increase in MMP1 mRNA
level was found in nonsun-exposed skin of smokers also in vivo [67].
Conflicting results have been reported regarding the effect of cigarette smoke
on tissue inhibitor of metalloproteinases 1 [56, 60].

Prevention and Treatment

Numerous endogenous mechanisms protect the skin from exogenous dam-

age. These include increased epidermal thickness, melanin, DNA repair mecha-
nisms, apoptosis, tissue inhibitors of metalloproteinase, and antioxidants. Over
a lifetime, the efficacy of these defense mechanisms declines leading to accel-
erated skin damage. While prevention of the exposure to the known exogenous
factors remains the most important strategy in delaying skin aging process, new
and emerging therapies, such as antioxidants, anti-inflammatory drugs, hor-
monal and growth factors, cytokines, etc., give rise to new horizons aiming to
reverse environment-induced skin aging.

References

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64 Arredondo J, Hall LL, Ndoye A, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A,
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Marina Landau, MD
Dermatology, Wolfson Medical Center
IL–64239 Holon (Israel)
Tel. 972 9 9505151, Fax 972 3 5752622, E-Mail [email protected]

Exogenous Factors in Skin Aging 13

 Tur E (ed): Environmental Factors in Skin Diseases.
Curr Probl Dermatol. Basel, Karger, 2007, vol 35, pp 14–27

Ultraviolet Radiation and Cutaneous

Carcinogenesis
Vered Molho-Pessacha, Michal Lotemb
Departments of aDermatology and bOncology, Hadassah Medical Center and the
Hebrew University, Jerusalem, Israel

Abstract
Nonmelanoma skin cancer (NMSC) is the most common type of human cancer. Solar
ultraviolet radiation (UVR) is the main causative factor in the development of NMSC. UVR
plays a variety of roles in the induction of skin cancers. It can serve as a complete carcinogen
or as a promoter of carcinogenesis. The typical UV-induced DNA damage is the generation
of dimeric photoproducts between adjacent pyrimidine bases. Tumor suppressor gene p53 is
a common target of UVR-induced mutations. There is a proliferative advantage of p53
mutant keratinocytes over normal keratinocytes that eventuates in neoplastic transformation.
While UVB causes considerable DNA damage in the skin, UVA has only recently been
shown to induce pyrimidine dimers and oxygen and nitrogen reactive species which damage
DNA, proteins and lipids. The immunosuppressive effect of UVR contributes to its carcino-
genic activity. Finally, any one of these effects of UVR may contribute to the induction of
skin cancers by other agents such as X-rays, viruses, or chemical carcinogens. The mecha-
nism by which UVR leads to cutaneous malignant melanoma is less clear and it may be a
cofactor rather than an initiator of this tumor. Primary prevention of UVR exposure is the
most effective means of reducing UVR carcinogenesis. Systemic retinoids may influence the
appearance of new tumors in patient populations at increased risk of developing NMSC such
as xeroderma pigmentosum and organ transplant recipients, but their efficacy is hindered by
their side effects.
Copyright © 2007 S. Karger AG, Basel

Nonmelanoma skin cancer (NMSC) is the most common type of human

cancer, and its incidence is continually increasing. Over the past two decades,
a worldwide increase in the incidence of skin cancer to near epidemic propor-
tions has led to increased morbidity and appreciating cost. The exact incidence
of NMSC is unknown because these cancers are not reported to cancer reg-
istries in most countries. However, the average increase of NMSC in white
populations in Europe, the United States, Canada, and Australia was 3–8% per
year since the 1960s [1] and it is estimated that more than 1 million cases of
NMSC occur in the United States every year [2]. The absolute numbers and
proportions worldwide vary due to differences in sun exposure and skin type
of resident population. The two major causes of the increased rate of NMSC
are both related to solar ultraviolet radiation (UVR) exposure. One is related to
tanning habits and lifestyle that promote intentional and excessive UVR expo-
sure [3]. The second is the decreased filtering effect of the stratospheric ozone
layer that is constantly depleted by release of chlorofluorocarbon compounds
into the atmosphere. While the estimated decrease in the ozone concentration
is still small and has occurred too recently to have had an impact on skin
cancer incidence [4], it is expected that ozone concentration will remain lower
for another half-century, and that further doubling in NMSC will occur in
the next 10 years [5]. Though solar UVR is the main causative factor for the
development of NMSC, other implicated factors include x or ␥ ionizing
irradiation, chemical carcinogens, viral infections, genetic aberrations, and
immunosuppression.
This chapter reviews and analyzes the role of UVR in the induction and
development of skin cancer.

Physical Aspects of Ultraviolet Radiation

Approximately 5% of the solar radiation on Earth is composed of UVR

which is defined as wavelengths between 100 and 400 nm. UVR is subdivided
into UVA (315–400 nm), UVB (280–315 nm), and UVC (100–280 nm). Solar
UVR on Earth’s surface is approximately 95–98% UVA and 2–5% UVB, while
UVC is completely absorbed by stratospheric ozone. The amount and composi-
tion of solar UVR depends on a number of factors, particularly the solar zenith
angle, which varies with the time of day, season and latitude, the stratospheric
ozone concentration, pollution, cloud cover and altitude [6].

Evidence Supporting the Carcinogenic Effects of

Ultraviolet Radiation

The wavelengths of solar radiation involved in tumor induction appear to

be within the UV region of the spectrum (wavelengths between 200 and
400 nm), especially in the UVB (290–315 nm) range. Epidemiologic studies
and experimental models indicate that repeated exposure to solar UVR is the
primary cause of most NMSCs [7].

Ultraviolet Radiation and Cutaneous Carcinogenesis 15

 Epidemiological Data
The incidence of NMSC is correlated to epidemiological factors that are all
impacting on solar UVR exposure. NMSC, especially squamous cell carcinoma
(SCC), frequently occurs on parts of the body that receive maximum exposure to
sunlight: face, head, neck, backs of the hands, and arms. The incidence of these skin
cancers increases with increasing age as well, implying that cumulative lifetime
exposure to sunlight is responsible for skin cancer induction [8]. Pigmentation and
skin type are tightly related to the risk of skin cancer. People who sunburn easily and
never tan are at constitutive risk to develop NMSC. Residents of higher latitudes are
exposed to lower amounts of UVR and have a decreased frequency of NMSCs as
opposed to residents of lower latitudes. Migration from temperate climates (higher
latitudes) to areas of high ambient solar radiation is associated with increased risk
for the development of NMSC [9].
The pattern of sun exposure affects the histological type of skin cancer.
Cumulative exposure and childhood sunburn enhance SCCs, whereas intermit-
tent exposure and sunburn at any age lead to the development of basal cell car-
cinoma (BCC) [10]. The latitude gradient is steeper for SCC than for BCC.
Altogether, SCC is more dependent on sunlight exposure than BCC. Other fac-
tors may be involved in the induction of BCC [11].
Taken together, these findings present compelling evidence that exposure
to sunlight is a major cause in the appearance of NMSC.

Experimental Data
The traditional basic proof of a carcinogenic effect of an insulting agent
was obtained using an animal model. With the advent of modern techniques of
molecular genome analysis, it is now easier to discern early molecular events on
the cascade leading to tumor development.
Skin cancers have been induced experimentally with UVR in a variety of
laboratory animals. Mice have been widely used as an animal model, in partic-
ular, hairless mice have been valuable for investigating the formation of SCC.
These animals develop SCC after several UV exposures. The action spectrum
for carcinogenesis in the albino hairless mouse closely approximates the action
spectra for UV-induced erythema in human skin [12]. The most effective wave-
lengths for cancer induction are between 295 and 305 nm, and the activity
decreases sharply with increasing wavelengths above this range [3]. UVB radi-
ation is around 1,000 times more efficient than UVA radiation in producing
murine skin cancers. However, when UVA radiation is given in sufficient doses,
it also produces skin cancers in mice [13].
BCC may substantially differ from SCC in terms of wavelengths and doses.
The originating cells probably arise from a deeper zone than SCC – interfollicular
basal cells, hair follicles or sebaceous glands [14]. In the past, there were no

Molho-Pessach/Lotem 16
 Table 1. Biologic effects of UVR

Acute effects Chronic effects

Erythema Photoaging (dermatoheliosis)

Tanning Carcinogenesis
DNA photodamage
Release of pharmacologic mediators
Immunosuppression
Hyperplasia of epidermis
Activation of antioxidant pathways
Photosynthesis of vitamin D

animal models to study the development of BCC. However, recently the genera-
tion of a mouse with one allele of the ptch gene knocked out (ptch⫹/⫺) has allowed
the study of BCC induction by UVR [15]. The UV dose used was three times the
minimum erythema dose. With longer exposure, mice developed SCC as well.

Mechanisms of Ultraviolet Radiation-Induced Carcinogenesis

UVR has a wide range of acute and chronic effects on normal skin (table 1).
DNA photodamage and immunosuppression are the most important for
carcinogenesis [6].
Microarray analyses show that following UVR exposure of human skin
there is a wide range of activation and silencing of genes. Numerous genes were
demonstrated to be modulated by UVR. Categorization of affected genes
into clusters with a common denominator revealed association with cellular
processes including DNA damage and repair, cell cycle regulation, intercellular
signaling, and apoptosis [16]. Step-by-step analysis of specific genes, gene
families and signal transduction pathways sheds light on major mechanisms of
UV-induced biological effect.
Both UVA and UVB induce DNA damage, which is inherently repaired by
cellular mechanisms, many times only partially. The typical UV DNA damage
is the generation of dimeric photoproducts between adjacent pyrimidine bases.
Two types of these bulky modifications are produced, namely cyclobutane
pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts [17]. UV-
induced DNA linkage between two adjacent pyrimidines (e.g. CC or TT, where
C ⫽ cytosine and T ⫽ thymine) on the same DNA strand is by itself not muta-
genic and is usually repaired by nucleotide excision repair enzymes before
replication. However, if this repair is incomplete or delayed, DNA polymerase

Ultraviolet Radiation and Cutaneous Carcinogenesis 17

inserts adenine dinucleotide (AA) opposite unrepaired pyrimidine dimers [18].
The pairing of AA with TT is normal, and thus no mutations occur, but if AA
erroneously pairs with CC or CT-linked photoproducts, mutations are observed
as CC→TT and C→T, respectively. Such mutations are characteristically UV
induced (‘UV signature’ mutations), since they are produced only by UV and
not by any other mutagen. While UVB is long known to cause DNA damage in
the skin, the role of UVA has only recently been elucidated. The debate per-
sisted because UVA is not directly absorbed by DNA. Nevertheless, as with
UVB, it was found that the majority of UVA-induced mutations are C–T transi-
tions and CC–TT tandem mutations. For both UVA and UVB, these transitions
were found within runs of pyrimidines, at identical hotspots, and with the same
predilection for the nontranscribed strand [19]. The rate of removal of UVA-
generated cyclobutane pyrimidine dimers is lower than the rate of removal of
those produced by UVB irradiation of skin [20].
Recently, it has been pointed out that in addition to the typical pyrimidine
photoproduct mutations, DNA damage can also be the direct result of reactive
oxygen species. Apparently, UVA has a greater impact than UVB on oxidative
stress in the skin [21]. UVA induces reactive oxygen and nitrogen species which
damage DNA, proteins and lipids and lead to energy loss from cells. The dam-
age may eventuate in tumor initiation, promotion and progression [22, 23].
UVR induces local immunosuppression in the skin that interferes with host
defense against skin tumors. The mechanisms involve a number of components:
depletion of Langerhans cells and other antigen-presenting cells in the skin,
recruitment of macrophages into the dermis and epidermis which have different
antigen-presenting capabilities than normal resident antigen-presenting cells,
the release of immune inhibitory inflammatory mediators such as TNF-␣, IL-10
and enhance regulatory T cells, which inhibit cell-mediated immune responses
to newly encountered antigens [24–27].
There are conflicting data concerning the role of tanning in affording pho-
toprotection [3]. Epidermal hyperplasia and thickening of the dermis may play
a part. Antioxidants, internal and external, take part in the defense against
the oxidative stress produced by UVR exposure. These include antioxidant
enzymes and nonenzymic antioxidants, notably glutathione and ascorbic acid
(vitamin C), tocopherols (vitamin E) and ubiquinol. Eumelanin is also capable
of scavenging free radicals including superoxide [28].

Genotoxic Effect of Ultraviolet Radiation

The process of carcinogenesis begins when the DNA is damaged, which

then initiates a cascade of events leading to the development of a tumor. On the

Molho-Pessach/Lotem 18
 Activation of p53 gene

Cell cycle arrest Excision repair Apoptosis

Repair of UVR-induced
damage

Fig. 1. Molecular mechanisms activated by acute UVR exposure.

basis of mutations found in human premalignant actinic keratosis lesions and

data from UV-induced carcinogenesis models in mice, acquisition of mutations
in the p53 tumor suppressor gene by epidermal keratinocytes appears to be the
initiating event in skin tumor development [29]. The p53 gene encodes for a
53-kDa phosphoprotein that modulates cell cycle via transcriptional control of
regulatory genes. Numerous studies in cell culture, mouse epidermis and
human tissue have shown that UVR activates the p53 protein. It was shown that
p53 activation was induced by UV signature lesions in the DNA (pyrimidine
dimers) and that these were accompanied by excision repair-associated DNA
strand breaks [30–34].
The accumulation of activated p53 protein induces a cell cycle arrest at the
G1 phase, which allows the repair of DNA damage before its replication in the
S phase. Activated p53 facilitates DNA damage repair by regulation of the cell
cycle and by directly inducing pathways of excision repair [30, 34]. Moreover,
p53 directly upregulates expression of proapoptotic genes, promoting apoptosis
of UVR-damaged cells [33, 34]. At the same time that UVR activates cell cycle
checkpoints and apoptosis via p53, it also stimulates cell surviving mechanisms
and induces cell proliferation, which is evident from epidermal hyperplasia.
UVR triggers these processes by activating receptors to various growth factors
and cytokines (fig. 1) [35, 36].
When UV-induced mutations occur in the p53 gene itself, an early genetic
event in the development of skin cancer begins (fig. 2). Thousands of p53
mutant cell clones are found in normal-appearing sun-exposed skin, in prema-
lignant actinic keratoses and in Bowen’s disease lesions. A high proportion of
these mutations were found to be C→T transitions [37, 38]. Long-term exposure to

Ultraviolet Radiation and Cutaneous Carcinogenesis 19

 UVR signature mutations in p53
Inhibition of Mutations/
gene
Fas-Fas ligand amplification
pathway of ras genes

Proliferation of p53 mutant Effects on

keratinocytes other genes
Inhibition of
apoptosis

Clonal expansion

Tumor development

Fig. 2. Molecular mechanisms involved in UVR-induced cutaneous carcinogenesis.

UVR also affects expression of the Fas receptor and its ligand in the epidermis.
The Fas-Fas ligand interaction is involved in UVR-induced apoptosis.
Following an initial phase of upregulated Fas and Fas ligand expression, tran-
scriptional inhibition of Fas ligand expression occurs after 1 week of continu-
ous UVR exposure in mice. This is accompanied by a dramatic decrease in
apoptotic cells [39]. The resistance to UVR-induced apoptosis and a prolifera-
tive advantage of p53 mutant keratinocytes over normal keratinocytes con-
tributes to clonal expansion of p53 mutant cells under repeated UVR exposure
[40]. Nevertheless, it has been shown that discontinuation of UVR exposure
results in the regression of the precancerous p53-mutated clones, but does not
eliminate the susceptibility of developing skin tumors [41].
The ras family of oncogenes participates in the transduction of signals
from the cell surface growth factor receptors to the nucleus, controlling cell
growth. Mutations and amplifications in ras genes have been found in UVR-
induced skin tumors in mice and in human skin cancers [42, 43]. Mutations in
the patched gene (PTCH) are seen in patients with Gorlin’s syndrome, xero-
derma pigmentosum and also in sporadic BCCs but with a relatively low fre-
quency of UVR signature compared with p53 mutations, implicating some
differences in the mechanisms of induction of BCCs versus SCCs [15, 30].
A subset of SCCs and BCCs also carries mutations in the INK4␣-ARF tumor

Molho-Pessach/Lotem 20
suppressor gene which encodes two independent growth inhibitors and effec-
tors of cellular senescence (p16INK4␣, p19ARF). These may also be involved in
the process of UVR-induced carcinogenesis [30, 44].
From the experimental studies of UV carcinogenesis, it is clear that UVR
can play a variety of roles in the development of skin cancers. It can serve as a
complete carcinogen, as an initiating agent in multistage carcinogenesis and as
a promoter of carcinogenesis. The immunosuppressive effect of UVR also con-
tributes to its carcinogenic activity. Finally, any one of these effects of UVR
may contribute to the induction of skin cancers by other agents such as X-rays,
viruses, or chemical carcinogens [3].

Factors Affecting UV-Induced Carcinogenesis

Human Papilloma Virus

Persons with erythrodysplasia verruciformis tend to develop SCC. Tumors
generally appear on sun-exposed body sites, suggesting that there may be an
interaction between human papilloma virus (HPV) and sunlight exposure that
promotes the development of skin cancer [3, 45].

Chronic Immunosuppression
Organ transplant patients have a markedly increased skin cancer incidence –
being 65–250 times more frequent than in the general population. Often these
patients suffer from multiple lesions, mostly SCCs. SCCs in transplant recipi-
ents appear to be more aggressive, tend to grow rapidly, show a higher rate of
local recurrences and metastasize in 5–8% of the patients. This largely differs
from BCCs which are less frequent in transplant recipients and are only
increased by a factor of 10 in this population, implying that BCCs may be less
dependent on immune surveillance [46]. Studies in renal transplant patients
demonstrated that the risk of developing skin cancer was increased four- to
sevenfold in areas of low sun exposure and more than twentyfold in areas of
high sun exposure [47, 48]. The tumors appear predominantly on sun-exposed
body sites and generally occur within a few years of transplantation. Careful
examination of the skin of such patients revealed a high incidence of warts as
well as carcinoma in situ and SCC. HPV has been associated with the skin can-
cers, suggesting that immune suppression, HPV and UVR all interact to pro-
duce skin cancer in immunosuppressed patients [49].

Chemicals
Psoralens, photosensitizing compounds, were shown to enhance develop-
ment of skin cancer. The long-term use of 8-methoxypsoralen plus UVA

Ultraviolet Radiation and Cutaneous Carcinogenesis 21

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