Rev Environ Health 2014; 29(3): 265–273
Silvia E. Mancebo and Steven Q. Wang*
Skin cancer: role of ultraviolet radiation in carcinogenesis Abstract: UV radiation is a carcinogen known to play a role in the development of non-melanoma and melanoma skin cancers. Acute and chronic exposure to UV radiation causes clinical and biological effects that promote the unregulated proliferation of skin cells. In recent decades, changes in climate and increased air pollution have led to environmental changes that increase UV light transmission. In this chapter, we discuss sources of UV radiation that are relevant to human health, as well as the acute and chronic effects that result from UV radiation exposure.
DOI 10.1515/reveh-2014-0041 Received May 15, 2014; accepted August 21, 2014; previously published online September 24, 2014
of DNA mutations, which promote the uncontrolled replication of skin cells (4). Although there are other risk factors for carcinogenesis, UV light has been attributed to the development of nearly 90% of non-melanoma skin cancers (NMSC) and about 65% of melanoma skin cancers (5, 6). Therefore, changes in the environment leading to increased UV light transmission have direct implications on human health. In this chapter, we will focus on the role of UV light in the development of skin cancer. We describe the sources of UV radiation, which are relevant to human health, and also review the impact of geographic and environmental variations on the transmission of solar UV light. Furthermore, we aim to describe the biological events resulting from acute and long-term UV light exposure and explain how these processes promote carcinogenesis.
Introduction
Sources of UV radiation
The environment plays an important role in regulating the amount of ultraviolet (UV) radiation that reaches the surface of the Earth. Changes in stratospheric ozone as well as climate and air pollution impact UV light transmission. In recent decades, increased air pollution with ozone-depleting chemicals has led to the deterioration of the ozone layer, particularly in areas of high latitude (1). Although regulations have been implemented to restore the ozone layer and prevent further depletion, these largescale environmental changes have led to increased solar UV light transmission (2). UV radiation is a known carcinogen involved in the development of non-melanoma and melanoma skin cancers (3). Acute exposure to UV light can lead to transient biological events that can be repaired. However, longterm or recurrent exposure to UV radiation causes chronic inflammation, immune suppression and ineffective repair
Solar UV radiation
Keywords: carcinogenesis; skin cancer; UV light.
*Corresponding author: Steven Q. Wang, MD, Dermatology Service, Memorial Sloan Kettering Cancer Center, 136 Mountainview Blvd, Basking Ridge, NJ 07920, USA, Phone: +(908) 542-3400, Fax: +(908) 542-3216, E-mail: [email protected] Silvia E. Mancebo: Memorial Sloan Kettering Cancer Center, Dermatology Service, New York, NY, USA
Sunlight is a continuous spectra of electromagnetic radiation composed of UV radiation (200–400 nm), visible light (400–700 nm), and infrared radiation ( > 700 nm) (3). Within the spectrum of UV radiation, biological effects vary with wavelength, resulting in the classification of three distinct regions. Among environmental and dermatological photobiologists, these regions are defined as UVA (400–320 nm), UVB (320–290 nm), and UVC (290–200 nm) (Figure 1) (7). With regards skin health, UVC radiation is a non-factor because it does not reach the surface of the earth. UVA and UVB radiation are divided at 320 nm due to inherent differences in their photobiological activities. UVA radiation has been further divided into UVA-I (340–400 nm) and UVA-II (320–340 nm) due to similarities that have been identified in the properties of short-wavelength UVA light and UVB light.
Artificial UV radiation Artificial sources of UV radiation have become increasingly relevant to human health. Indoor tanning with
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266 Mancebo and Wang: Role of UV radiation in skin cancer
Figure 1 Spectrum of ultraviolet radiation. UV radiation is divided into three wavebands: UVC (200–290 nm), UVB (290–320 nm), and UVA (320–400 nm). UVA radiation is further classified into UVAII (320–340 nm) and UVAI (340–400 nm). Note that electromagnetic wavelength increases and frequency decreases as the UV spectrum progresses from UVC to UVA radiation.
devices that produce radiation similar or stronger than sunlight has been identified as a risk factor for the development of non-melanoma and melanoma skin cancer (8–12). Currently, it is estimated that over 28 million Americans undergo indoor tanning annually, including 2.3 million teenagers (13, 14). Over the years, there have been shifts in the types of devices used for indoor tanning. Prior to the 1980s, devices available were known to emit higher levels of UVB radiation compared with natural sunlight (15). However, these devices were quickly replaced by UVA-emitting lamps due to growing concerns that UVB radiation was implicated in the development of skin cancer and induction of sunburn (16, 17). In the 1990s, UVB lamps were reintroduced with high-intensity or high-speed devices, which were marketed for their ability to produce deeper tans. UVA lamps were also upgraded with high-pressure fluorescent lamps that could emit up to ten times more UVA light than natural sunlight (18). In general, the devices that are available today vary from predominantly emitting UVA light to producing a mixture of UVA and UVB radiation (15). As of June 2014, the U.S. Food and Drug Administration (FDA) has reclassified tanning beds as moderate-risk (i.e., class II) medical devices due to the increased association with the development of skin cancers. This new classification allows the FDA to review the design and safety before the manufacturers can sell the devices (19). Artificial UV radiation is also employed in medical settings for therapeutic purposes. Phototherapy is a form of light treatment, which can be particularly useful for skin conditions such as eczema, psoriasis, and vitiligo (20–22). The instruments used to administer phototherapy have also changed over the years. In 1925, William Goeckerman reported the successful use of broadband UV radiation combined with topical crude coal tar for the treatment of psoriasis (23). In the 1960s and early 1970s, there was a shift towards administering phototherapy with low-output UVA-emitting lamps (24). In 1974, highoutput UVA-emitting lamps were introduced and used in
combination with topical/oral photoactive agents such as 8-methoxypsoralen (25). This combination was termed “psoralen UVA range” (PUVA) treatment, which proved to be an effective option for patients with psoriasis (26). In 1978, broadband UVB (280–320 nm) phototherapy was reintroduced, but proved to be less effective at treating psoriasis than PUVA therapy. A breakthrough came in 1988 when narrowband-UVB (310–311 nm) phototherapy replaced broadband UVB light, and was found to be efficient for treating psoriasis (24, 27). Currently, the use of PUVA therapy has largely decreased due to the increased risk of developing skin cancers; however, it continues to be useful for treating conditions such as atopic dermatitis, psoriasis, and mycosis fungoides. Narrowband-UVB has widely replaced PUVA therapy and is one of the most widely used forms of light treatment (28). Phototherapy, like many other treatments, is associated with short- and long-term adverse events. In the short-term, patients who undergo light treatment may experience sunburns, erythema, and skin dryness (29). In the long-term, phototherapy may play a role in photoaging and, possibly, photocarcinogenesis. However, despite these adverse effects, phototherapy is still considered a safe option for most individuals due to the highly regulated manner in which it is administered (30).
Transmission of solar UV radiation The spectrum and intensity of UV light that reaches the Earth’s surface is a function of geographic and environmental variations. Agents in the environment and the atmosphere can modulate UV light transmission and ultimately impact how much UV radiation humans are exposed to.
Environmental agents Ozone is a naturally occurring photo-absorbing molecule found in the stratosphere. It protects life on Earth from the harmful effects of UV radiation by filtering almost all UVC radiation and nearly 95% of UVB radiation emitted by the sun. Ozone minimally filters UVA radiation, and for this reason, UVA accounts for more than 95% of UV light reaching the surface of the Earth (Figure 2) (3). Starting in the 1980s and continuing into the 1990s, increased production of chemicals such as chlorofluorocarbons, hydrochlorofluorocarbons, and carbon tetrachloride has led to the depletion of the stratospheric ozone, resulting in increased UVB transmission (1, 2). Successful regulations
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Mancebo and Wang: Role of UV radiation in skin cancer 267
at a particular location. Snow can reflect up to 90% of UV radiation reaching its surface (2). Trees are known to protect from UV radiation, but foliage density creates great variability in the amount of UV light attenuated (37). Air quality also impacts solar transmission. Air pollution and smog in urban areas result in large reductions of UV irradiance compared to areas that are less polluted (38). A study conducted in Beijing, China showed a substantial reduction in UV radiation of up to 50% on days with high levels of air pollution. In particular, this study showed a strong reduction in UV radiation in areas with increased levels of nitrogen oxide in the air (39). Figure 2 Ozone filters almost all UVC radiation and 95% of UVB radiation emitted from the sun. The composition of UV light reaching the Earth’s surface is 95% UVA and 5% UVB rays.
have reduced the production of ozone-depleting substances and greenhouse gases, and the ozone layer is no longer deteriorating. Gradual recovery is expected in the near future (31). Once solar UV light penetrates the stratosphere, other agents in the surrounding environment can influence the quality and quantity of UV light that reaches the skin. Clouds, in particular, can reduce the amount of UV light reaching the ground. Almost all UV light is transmitted under clear-sky conditions, whereas under overcast skies, approximately 31% of UV light reaches the surface level (32, 33). Furthermore, differences have been identified in the type of UV radiation transmitted by clouds. Seckemeyer et al. (34) conducted an experiment to measure the amount of UV radiation that penetrates dense (i.e., overcast) clouds. They found that 60% of UVB rays were transmitted compared to only 45% of UVA rays. In 2002, these findings were confirmed by Schwander et al. (35) who found that waves of 310–315 nm maximally pass through clouds, compared to wavelengths in the range of 300–380 nm. The increased transmission of shorter wavelengths in overcast conditions is caused by photons scattered back to the upper atmosphere at the top of clouds surface and then scattered back downward again (i.e., Rayleigh scattering) (36). Due to increasing optical depth of air molecules with decreasing wavelengths, photos in range 310–315 nm have a higher chance of downward scattering. However, at wavelenghts below 310 nm, this effect is overcompensated by increased absorption of photons by tropospheric ozone (35). Other environmental agents are also known to modify UV light transmission. Snow, ice, and sand are agents that reflect UV light; therefore, they can increase UV exposure
Geographic variations Solar UV exposure varies with the time of day, geographic location, and season. UV radiation is greatest at the equator and for every degree increase in latitude, there is a 3% decrease in UVB transmission (40). Areas located at higher altitudes have thinner atmosphere, which filters less UVB light. For every 1000-foot increase in elevation, there is a 4%–10% increase in UVB transmission (40). UV radiation is most intense between 10AM and 2PM, with increased transmission around the solar zenith, when the path length for UV rays is the shortest (32). Finally, seasonal variations resulting from the revolution of the Earth around the sun cause differences in UV light. The summer time is when UV transmission is most intense due to direct exposure to radiation emitted by the sun (41).
Acute exposure to UV radiation The biological events that occur after exposure to UV radiation can be schematically classified into immediate and long-term effects (Table 1). Acute UV exposure results in Vitamin D synthesis and adaptive mechanisms to prevent UV damage, including the development of redness (erythema), immediate pigment darkening, and thickening of the skin. At a molecular level, there is DNA damage, formation of reactive oxygen species, and induction of the tumor suppressor gene p53 (42, 43).
Erythema Sunburning and erythema are the most recognizable acute clinical effects of UV exposure. UVB rays, and to a lesser extent UVA-II, are responsible for sunburns and
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268 Mancebo and Wang: Role of UV radiation in skin cancer Table 1 Immediate vs. long-term effects of UV light exposure.
Pigment darkening
Biological effects of ultraviolet light exposure
UV irradiation causes a biphasic response in skin pigmentation. Initially, there is an immediate reaction causing transient changes in skin color, followed by delayed tanning—a process that leads to new pigment formation (44). Immediate pigment darkening (IPD) and persistent pigment darkening (PPD) are two processes that occur soon after sun exposure ( 10 J/cm2) (52). Clinically, PPD manifests with brown skin pigmentation that can persist up to 24 h. Both IPD and PPD are reversible processes that result from oxidation and redistribution of existing melanin moieties (43, 52). Delayed tanning is associated with the synthesis of new melanin. This process is induced by both UVA and UVB radiation (52). UVB causes melanogenesis, resulting in increased activity of melanocytes. UVA increases melanin density and promotes the transfer of melanin granules to other cells in the epidermis (44, 53). Clinically, delayed tanning causes changes in pigmentation that become visible 3 days after sun exposure. These changes in skin color eventually fade as the surface layer of the skin is shed (52).
Acute exposure to UV eadiation Vitamin D synthesis Erythema Pigment darkening Epidermal hyperplasia DNA damage Free radical oxygen species formation Induction of tumor suppressor gene p53 Upregulation of pro-apoptotic genes and proteins Chronic exposure to UV radiation Chronic inflammation Immune suppression Photoaging Unrepaired DNA mutations predisposing to development of skin cancer, including: Basal cell carcinoma Squamous cell carcinoma Melanoma
induction of short-term erythema, which peaks between 6 and 24 h after exposure. High doses of UVA light can also induce short-term erythema that can last up to 72 h (32). The degree of erythema formation depends on both host and environmental factors. Host factors, including skin color, age and anatomic site determine the severity of erythema formation. Individuals with darker skin pigmentation require up to 30 times more UV exposure to induce erythema compared to individuals with fair skin (44). Furthermore, infants and elderly individuals are known to have a lower threshold for erythema formation, particularly at anatomic sites with decreased skin thickness (44, 45). Environmental factors like latitude, altitude, and time of day may affect erythema formation by modulating UV light transmission (refer to previous section). To date, the biological mechanism resulting in erythema formation has yet to be completely delineated. However, various studies provide insights into the pathway leading to blood vessel dilation (vasodilation) after sun exposure (44). Upon UV irradiation, the principal event leading to erythema formation appears to be direct damage to DNA by UVB and UVAII, and indirect oxidative damage by longer-wavelength UVA rays (46–48). As a result of DNA damage, many cytokines and inflammatory mediators are synthesized and released into the skin. These mediators include prostaglandins, histamine, kinins, nitric oxide, IL-1, IL-6, and TNF-α (49–51). Together, these substances regulate the expression of adhesion molecules on blood vessels and keratinocytes, resulting in the recruitment and activation of inflammatory cells that cause vasodilation and inflammation.
Epidermal hyperplasia Epidermal hyperplasia is an adaptive process, which protects the skin from further UV damage. Upon exposure to acute UV irradiation, the cells in the epidermis and dermis undergo a transient period of cellular arrest that allows for cellular and DNA repair of acute injury. About 24–48 h after this transient period, the epidermal and dermal skin cells increase their reproductive rates (52). This increased reproductive activity is associated with increased synthesis of DNA, RNA, and proteins (54). Epidermal hyperplasia is a reversible and transient process. In the absence of further UV exposure, the cells return to a normal state within 1–2 weeks (52). Furthermore, the extent of cellular proliferation that occurs is an age-dependent process. Haratake et al. (55) demonstrated that aged mouse epidermis has a decreased ability to induce epidermal hyperplasia compared with epidermis from younger mice. These investigators suggest that aging skin may be less sensitive to UVB-induced damage due to the inherent changes in aging skin that include decreased inflammatory response, impaired immune function, and decreased epidermal turnover (55).
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Mancebo and Wang: Role of UV radiation in skin cancer 269
DNA damage UVB radiation induces a series of photochemical reactions that directly affect DNA pyrimidine bases. These photochemical reactions primarily result in the production of dimers such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (56). Both types of lesions occur in runs of tandemly located pyrimidine bases, which are considered “hot spots” for UVB-induced DNA damage (57, 58). In most cases, DNA repair mechanisms detect and replace these dimers, thus preventing downstream DNA mutations. If these lesions are not repaired, they result in C→T and CC→TT transitions, which are recognized as “UVB signature mutations” (43). In addition to the formation of dimers, UVB radiation can cause other types of DNA lesions, including single-strand breaks in DNA (56, 59). In recent years, UVA radiation has been recognized for the potential to indirectly damage DNA. UVA light induces the formation of reactive oxygen species (ROS) that cross-link DNA to proteins, resulting in single-strand breaks and alteration of DNA bases (60). Here, 8-hydroxyguanine is the signature DNA mutation induced by UVA radiation (61).
Free radical formation Oxidative stress plays a central role in initiating and driving the cellular response following UV exposure (62). UV light induces the production of superoxide anion (O2-), peroxide (H2O2), and hydroxyl radicals (OH·) within 15 min of exposure (63). These short-lived molecules have the capacity to damage DNA, proteins, and cellular membranes through oxidative reactions that occur in the epidermis and dermis. In addition, ROS activate matrix metalloproteinases and release inflammatory cytokines, ultimately leading to degradation of normal skin architecture and decreased cutaneous function (42, 63, 64).
Induction of p53 Previous studies have identified p53 as a tumor-suppressor protein that controls the cell cycle and maintains cellular normalcy by preventing DNA mutations (65–67). DNA damage resulting from UV exposure induces high levels of p53 leading to cell cycle arrest at G1 (68). This allows for repair of DNA lesions before the cell continues with DNA synthesis. When there is excessive DNA damage, p53 triggers apoptosis (i.e., programmed cellular death)
by up-regulating the expression of proapoptotic genes, including bax, bak and noxa, which belong to the Bcl-2 family (69). This results in the recruitment and activation of pro-apoptotic proteins known as caspases, which culminate in the disruption of mitochondrial membranes, eventually leading to cellular death (67, 68, 70).
Chronic exposure to UV radiation Long-term UV light exposure causes the gradual deterioration of cutaneous structures and function. Cumulative damage resulting from chronic inflammation and recurrent acute injury leads to the development of skin cancers through a multi-step process, which involves DNA mutations and escape from immune surveillance (43). In this section, we will focus our discussion on the role of UV radiation in the development of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. Other long-term effects of UV exposure like photoaging will be discussed in other sections of the book.
Mechanism of carcinogenesis: unrepaired DNA mutations and immunosuppression Whereas acute UV irradiation results in adaptive processes, chronic UV irradiation leads to deregulation of biological mechanisms, which promote abnormal proliferation of cells containing DNA damage (68). Long-term exposure to UV radiation is associated with mutations that inactivate tumor suppressor genes or activate protooncogenes. Tumor suppressor genes are negative regulators of the cell cycle that require inactivation of both copies of the gene before progression to uncontrolled cell growth (43, 59). Proto-oncogenes are positive regulators of the cell cycle that allow for cellular proliferation and differentiation. These genes require a mutation of only one copy of the gene to have a tumorigenic effect. UV-induced mutations in skin cancers have been identified among tumor suppressor genes p53, CDKN2A and PTCH, as well as in proto-oncogene ras (43). A second component in the development of skin cancer is escape from immune surveillance. UV irradiation induces immune suppression by altering cutaneous cellmediated immunity. Following multiple exposures to UV light, Langerhans cells in the epidermis are depleted and may undergo changes in morphology, eventually leading to decreased function (71, 72). T-helper and T-cytotoxic lymphocytes are also depleted and there is a simultaneous
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270 Mancebo and Wang: Role of UV radiation in skin cancer increase in T-regulatory cells, which contribute to self-tolerance (72–74). Ultimately, these alterations favor both the development and metastasis of skin tumors.
Carcinogenesis of NMSC Total cumulative sun exposure is associated with the development of SCC and BCC (75). Acute UVB exposure creates CPDs and (6-4) photoproducts that are mostly repaired effectively. However, long-term UVB exposure often leads to incorrect repair of these lesions, rendering cells to accumulate DNA mutations, which eventually result in malignant transformation (59). The tumor suppressor p53 gene is a frequent target of UVB genetic alterations. UVB signature mutations in p53 have been identified in about 90% of SCCs (76). It appears that these mutations are an early event in UV-induced carcinogenesis. Studies by Taguchi et al. (77) and Zigler et al. (78) have demonstrated p53 mutations in nearly 50% of actinic keratosis, which are precancerous skin lesions. BCCs are biologically different from SCCs and harbor different DNA lesions. Mutations in p53 have been identified in only 50% of BCCs (79). However, other genes are thought to play a role in BCC tumorigenesis. PTCH is an inhibitor of the hedgehog signal pathway, which transmits extracellular growth and differentiation signals to the nucleus (80). UVB-induced mutations in the PTCH gene have been detected among variable numbers of BCCs (81, 82). Other genes, including the ras family of proto-oncogenes, which promote cell survival and differentiation, have also been found to harbor UVB-signature mutations among BCCs (83). Further evidence for the role of UV light in the development of NMSC comes from epidemiological studies. A randomized control trial among 1621 adults in a subtropical community in Queensland, Australia compared the daily use of SPF 16 sunscreen with discretionary use of sunscreen (84). After a 4.5-year intervention, the study showed a 40% reduction in the incidence of SCC tumors among participants assigned to the sunscreen group. The study also assessed the incidence of BCC tumors, but there was no statistical difference between the two groups. A follow-up study conducted 8 years later on the same cohort showed a trend towards decreased BCC tumors among participants who used daily sunscreen (85). Both studies provide indirect evidence for the role of UV light in the development of NMSC. Protection from sunlight confers a protective effect on SCCs and on BCCs, although further studies are needed to fully delineate the role of UV light in BCC tumorigenesis.
Carcinogenesis of melanoma skin cancers Melanoma results from a multi-factorial process involving genetic, phenotypic, and environmental predispositions. People with fair skin, red hair, blue eyes, and proclivity to sunburn are at a higher risk of developing melanoma (75). The only environmental risk factor that has been shown to be relevant is UV light exposure. A history of sunburns and high-dose intermittent sun exposure has a direct relationship with lifetime relative risk of developing melanoma (86). In addition, studies analyzing the risk associated with artificial tanning devices suggest a modest but significantly increased risk of developing melanoma among users (15). The gene mutations that have been implicated in melanoma tumorigenesis include the tumor suppressor genes p16/CDKN2A and PTEN, and proto-oncogenes BRAF and N-RAS (72). These mutations do not show the typical ultraviolet “fingerprint” seen among BCCs and SCCs, thus reinforcing the notion that melanoma results from a multi-factorial process. With regards to epidemiologic studies, a 10-year follow-up study conducted by the Australian group on the cohort of 1621 patients in Queensland, demonstrated that daily use of sunscreens with SPF16 can reduce the risk of melanoma by 50% (87). These findings indirectly confirm that UV light exposure plays a role in the development of melanoma skin cancers.
Conclusion UV radiation is a carcinogen known to play a role in the development of non-melanoma and melanoma skin cancers. Acute exposure to UV radiation causes clinical and biological effects that are often repaired effectively. However, long-term or recurrent exposure leads to unrepaired DNA lesions, which promote the unregulated proliferation of skin cells. Recent changes in the environment have led to increased UV light transmission. These alterations may be implicated in the increased incidence of skin cancers. Conflict of interest: The authors report no conflict of interest.
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272 Mancebo and Wang: Role of UV radiation in skin cancer 42. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol 2005;52:937–58;quiz 59–62. 43. Matsumura Y, Ananthaswamy HN. Toxic effects of ultraviolet radiation on the skin. Toxicology and applied pharmacology 2004;195:298–308. 44. Hönigsmann H. Erythema and pigmentation. Photodermatol Photoimmunol Photomed 2002;18:75–81. 45. Gilchrest BA, Stoff JS, Soter NA. Chronologic aging alters the response to ultraviolet-induced inflammation in human skin. J Invest Dermatol 1982;79:11–5. 46. Brash DE. Sunlight and the onset of skin cancer. Trends Genet 1997;13:410–4. 47. Kraemer KH. Sunlight and skin cancer: another link revealed. Proc Natl Acad Sci USA 1997;94:11–4. 48. Young AR, Potten CS, Nikaido O, Parsons PG, Boenders J, et al. Human melanocytes and keratinocytes exposed to UVB or UVA in vivo show comparable levels of thymine dimers. J Invest Dermatol 1998;111:936–40. 49. Clydesdale GJ, Dandie GW, Muller HK. Ultraviolet light induced injury: immunological and inflammatory effects. Immunol Cell Biol 2001;79:547–68. 50. Deliconstantinos G, Villiotou V, Stravrides JC. Release by ultraviolet B (u.v.B) radiation of nitric oxide (NO) from human keratinocytes: a potential role for nitric oxide in erythema production. Br J Pharmacol 1995;114:1257–65. 51. Abeyama K, Eng W, Jester JV, Vink AA, Edelbaum D, et al. A role for NF-kappaB-dependent gene transactivation in sunburn. J Clin Invest 2000;105:1751–9. 52. Lim HW, Honigsmann H, Hawk J. Photodermatology. New York, NY, USA: CRC Press; 2013. 53. Fitzpatrick T. Ultraviolet-induced pigmentary changes: benefits and hazards. Current problems in dermatology 1986;15:25. 54. Epstein JH, Fukuyama K, Fye K. Effects of ultraviolet radiation on the mitotic cycle and DNA, RNA and protein synthesis in mammalian epidermis in vivo. Photochem Photobiol 1970;12:57–65. 55. Haratake A, Uchida Y, Mimura K, Elias PM, Holleran WM. Intrinsically aged epidermis displays diminished UVB-induced alterations in barrier function associated with decreased proliferation. J Invest Dermatol 1997;108:319–23. 56. Ananthaswamy HN, Pierceall WE. Molecular mechanisms of ultraviolet radiation carcinogenesis. Photochem Photobiol 1990;52:1119–36. 57. Black H, DeGruijl F, Forbes P, Cleaver J, Ananthaswamy H, et al. Photocarcinogenesis: an overview. J Photochem Photobiol B: Biol 1997;40:29–47. 58. Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 1991;88:10124–8. 59. Ichihashi M, Ueda M, Budiyanto A, Bito T, Oka M, et al. UVinduced skin damage. Toxicology 2003;189:21–39. 60. Cadet J, Sage E, Douki T. Ultraviolet radiation-mediated damage to cellular DNA. Mutat Res 2005;571:3–17. 61. Zhang X, Rosenstein BS, Wang Y, Lebwohl M, Mitchell DM, et al. Induction of 8-oxo-7,8-dihydro-2’-deoxyguanosine by ultraviolet radiation in calf thymus DNA and HeLa cells. Photochem Photobiol 1997;65:119–24.
62. Rittié L, Fisher GJ. UV-light-induced signal cascades and skin aging. Ageing Res Rev 2002;1:705–20. 63. Chen L, Hu JY, Wang SQ. The role of antioxidants in photoprotection: a critical review. J Am Acad Dermatol 2012;67:1013–24. 64. Runger TM, Kappes UP. Mechanisms of mutation formation with long-wave ultraviolet light (UVA). Photodermatol Photoimmunol Photomed 2008;24:2–10. 65. Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature 1991;351:453–6. 66. Vogelstein B, Kinzler KW. p53 function and dysfunction. Cell 1992;70:523–6. 67. Harris CC. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst 1996;88:1442–55. 68. Melnikova VO, Ananthaswamy HN. Cellular and molecular events leading to the development of skin cancer. Mutat ResFund Mol M 2005;571:91–106. 69. Shen Y, White E. p53-dependent apoptosis pathways. Adv Cancer Res 2001;82:55–84. 70. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995;80:293–9. 71. Taguchi K, Fukunaga A, Ogura K, Nishigori C. The role of epidermal Langerhans cells in NB-UVB-induced immunosuppression. Kobe J Med Sci 2013;59:E1–9. 72. Calzavara-Pinton P, Sala R, Arisi MC, Bussoletti C, Celleno L. Photobiology, photodermatology and sunscreens: a comprehensive overview. Part 1: damage from acute and chronic solar exposure. G Ital Dermatol Venereol 2013;148:89–106. 73. Ullrich SE. Mechanisms underlying UV-induced immune suppression. Mutat Res 2005;571:185–205. 74. Kuhn A, Beissert S, Krammer PH. CD4(+)CD25 (+) regulatory T cells in human lupus erythematosus. Arch Dermatol Res 2009;301:71–81. 75. Mulliken JS, Russak JE, Rigel DS. The effect of sunscreen on melanoma risk. Dermatol Clin 2012;30:369–76. 76. Agar NS, Halliday GM, Barnetson RS, Ananthaswamy HN, Wheeler M, et al. The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci USA 2004;101:4954–9. 77. Taguchi M, Watanabe S, Yashima K, Murakami Y, Sekiya T, et al. Aberrations of the tumor suppressor p53 gene and p53 protein in solar keratosis in human skin. J Invest Dermatol 1994;103:500–3. 78. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, et al. Sunburn and p53 in the onset of skin cancer. Nature 1994;372:773–6. 79. Rady P, Scinicariello F, Wagner RF, Tyring SK. p53 mutations in basal cell carcinomas. Cancer research 1992;52:3804–6. 80. Toftgård R. Hedgehog signalling in cancer. Cell Mol Life Sci CMLS 2000;57:1720–31. 81. Zhang H. Role of PTCH and p53 genes in early-onset basal cell carcinoma. Am J Path 2001;158:381–5. 82. Reifenberger J, Wolter M, Knobbe C, Köhler B, Schönicke A, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005;152:43–51.
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Mancebo and Wang: Role of UV radiation in skin cancer 273 83. van der Schroeff JG, Evers LM, Boot AJ, Bos JL. Ras oncogene mutations in basal cell carcinomas and squamous cell carcinomas of human skin. J Invest Dermatol 1990;4:423–5. 84. Green A, Williams G, Neale R, Hart V, Leslie D, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354:723–9. 85. van der Pols JC, Williams GM, Pandeya N, Logan V, Green AC. Prolonged prevention of squamous cell carcinoma of the skin
by regular sunscreen use. Cancer Epidemiol Biomarkers Prev 2006;15:2546–8. 86. Dennis LK, Vanbeek MJ, Beane Freeman LE, Smith BJ, Dawson DV, et al. Sunburns and risk of cutaneous melanoma: does age matter? A comprehensive meta-analysis. Ann Epidemiol 2008;18:614–27. 87. Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol 2011;29:257–63.
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Silvia E. Mancebo and Steven Q. Wang*
Skin cancer: role of ultraviolet radiation in carcinogenesis Abstract: UV radiation is a carcinogen known to play a role in the development of non-melanoma and melanoma skin cancers. Acute and chronic exposure to UV radiation causes clinical and biological effects that promote the unregulated proliferation of skin cells. In recent decades, changes in climate and increased air pollution have led to environmental changes that increase UV light transmission. In this chapter, we discuss sources of UV radiation that are relevant to human health, as well as the acute and chronic effects that result from UV radiation exposure.
DOI 10.1515/reveh-2014-0041 Received May 15, 2014; accepted August 21, 2014; previously published online September 24, 2014
of DNA mutations, which promote the uncontrolled replication of skin cells (4). Although there are other risk factors for carcinogenesis, UV light has been attributed to the development of nearly 90% of non-melanoma skin cancers (NMSC) and about 65% of melanoma skin cancers (5, 6). Therefore, changes in the environment leading to increased UV light transmission have direct implications on human health. In this chapter, we will focus on the role of UV light in the development of skin cancer. We describe the sources of UV radiation, which are relevant to human health, and also review the impact of geographic and environmental variations on the transmission of solar UV light. Furthermore, we aim to describe the biological events resulting from acute and long-term UV light exposure and explain how these processes promote carcinogenesis.
Introduction
Sources of UV radiation
The environment plays an important role in regulating the amount of ultraviolet (UV) radiation that reaches the surface of the Earth. Changes in stratospheric ozone as well as climate and air pollution impact UV light transmission. In recent decades, increased air pollution with ozone-depleting chemicals has led to the deterioration of the ozone layer, particularly in areas of high latitude (1). Although regulations have been implemented to restore the ozone layer and prevent further depletion, these largescale environmental changes have led to increased solar UV light transmission (2). UV radiation is a known carcinogen involved in the development of non-melanoma and melanoma skin cancers (3). Acute exposure to UV light can lead to transient biological events that can be repaired. However, longterm or recurrent exposure to UV radiation causes chronic inflammation, immune suppression and ineffective repair
Solar UV radiation
Keywords: carcinogenesis; skin cancer; UV light.
*Corresponding author: Steven Q. Wang, MD, Dermatology Service, Memorial Sloan Kettering Cancer Center, 136 Mountainview Blvd, Basking Ridge, NJ 07920, USA, Phone: +(908) 542-3400, Fax: +(908) 542-3216, E-mail: [email protected] Silvia E. Mancebo: Memorial Sloan Kettering Cancer Center, Dermatology Service, New York, NY, USA
Sunlight is a continuous spectra of electromagnetic radiation composed of UV radiation (200–400 nm), visible light (400–700 nm), and infrared radiation ( > 700 nm) (3). Within the spectrum of UV radiation, biological effects vary with wavelength, resulting in the classification of three distinct regions. Among environmental and dermatological photobiologists, these regions are defined as UVA (400–320 nm), UVB (320–290 nm), and UVC (290–200 nm) (Figure 1) (7). With regards skin health, UVC radiation is a non-factor because it does not reach the surface of the earth. UVA and UVB radiation are divided at 320 nm due to inherent differences in their photobiological activities. UVA radiation has been further divided into UVA-I (340–400 nm) and UVA-II (320–340 nm) due to similarities that have been identified in the properties of short-wavelength UVA light and UVB light.
Artificial UV radiation Artificial sources of UV radiation have become increasingly relevant to human health. Indoor tanning with
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266 Mancebo and Wang: Role of UV radiation in skin cancer
Figure 1 Spectrum of ultraviolet radiation. UV radiation is divided into three wavebands: UVC (200–290 nm), UVB (290–320 nm), and UVA (320–400 nm). UVA radiation is further classified into UVAII (320–340 nm) and UVAI (340–400 nm). Note that electromagnetic wavelength increases and frequency decreases as the UV spectrum progresses from UVC to UVA radiation.
devices that produce radiation similar or stronger than sunlight has been identified as a risk factor for the development of non-melanoma and melanoma skin cancer (8–12). Currently, it is estimated that over 28 million Americans undergo indoor tanning annually, including 2.3 million teenagers (13, 14). Over the years, there have been shifts in the types of devices used for indoor tanning. Prior to the 1980s, devices available were known to emit higher levels of UVB radiation compared with natural sunlight (15). However, these devices were quickly replaced by UVA-emitting lamps due to growing concerns that UVB radiation was implicated in the development of skin cancer and induction of sunburn (16, 17). In the 1990s, UVB lamps were reintroduced with high-intensity or high-speed devices, which were marketed for their ability to produce deeper tans. UVA lamps were also upgraded with high-pressure fluorescent lamps that could emit up to ten times more UVA light than natural sunlight (18). In general, the devices that are available today vary from predominantly emitting UVA light to producing a mixture of UVA and UVB radiation (15). As of June 2014, the U.S. Food and Drug Administration (FDA) has reclassified tanning beds as moderate-risk (i.e., class II) medical devices due to the increased association with the development of skin cancers. This new classification allows the FDA to review the design and safety before the manufacturers can sell the devices (19). Artificial UV radiation is also employed in medical settings for therapeutic purposes. Phototherapy is a form of light treatment, which can be particularly useful for skin conditions such as eczema, psoriasis, and vitiligo (20–22). The instruments used to administer phototherapy have also changed over the years. In 1925, William Goeckerman reported the successful use of broadband UV radiation combined with topical crude coal tar for the treatment of psoriasis (23). In the 1960s and early 1970s, there was a shift towards administering phototherapy with low-output UVA-emitting lamps (24). In 1974, highoutput UVA-emitting lamps were introduced and used in
combination with topical/oral photoactive agents such as 8-methoxypsoralen (25). This combination was termed “psoralen UVA range” (PUVA) treatment, which proved to be an effective option for patients with psoriasis (26). In 1978, broadband UVB (280–320 nm) phototherapy was reintroduced, but proved to be less effective at treating psoriasis than PUVA therapy. A breakthrough came in 1988 when narrowband-UVB (310–311 nm) phototherapy replaced broadband UVB light, and was found to be efficient for treating psoriasis (24, 27). Currently, the use of PUVA therapy has largely decreased due to the increased risk of developing skin cancers; however, it continues to be useful for treating conditions such as atopic dermatitis, psoriasis, and mycosis fungoides. Narrowband-UVB has widely replaced PUVA therapy and is one of the most widely used forms of light treatment (28). Phototherapy, like many other treatments, is associated with short- and long-term adverse events. In the short-term, patients who undergo light treatment may experience sunburns, erythema, and skin dryness (29). In the long-term, phototherapy may play a role in photoaging and, possibly, photocarcinogenesis. However, despite these adverse effects, phototherapy is still considered a safe option for most individuals due to the highly regulated manner in which it is administered (30).
Transmission of solar UV radiation The spectrum and intensity of UV light that reaches the Earth’s surface is a function of geographic and environmental variations. Agents in the environment and the atmosphere can modulate UV light transmission and ultimately impact how much UV radiation humans are exposed to.
Environmental agents Ozone is a naturally occurring photo-absorbing molecule found in the stratosphere. It protects life on Earth from the harmful effects of UV radiation by filtering almost all UVC radiation and nearly 95% of UVB radiation emitted by the sun. Ozone minimally filters UVA radiation, and for this reason, UVA accounts for more than 95% of UV light reaching the surface of the Earth (Figure 2) (3). Starting in the 1980s and continuing into the 1990s, increased production of chemicals such as chlorofluorocarbons, hydrochlorofluorocarbons, and carbon tetrachloride has led to the depletion of the stratospheric ozone, resulting in increased UVB transmission (1, 2). Successful regulations
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Mancebo and Wang: Role of UV radiation in skin cancer 267
at a particular location. Snow can reflect up to 90% of UV radiation reaching its surface (2). Trees are known to protect from UV radiation, but foliage density creates great variability in the amount of UV light attenuated (37). Air quality also impacts solar transmission. Air pollution and smog in urban areas result in large reductions of UV irradiance compared to areas that are less polluted (38). A study conducted in Beijing, China showed a substantial reduction in UV radiation of up to 50% on days with high levels of air pollution. In particular, this study showed a strong reduction in UV radiation in areas with increased levels of nitrogen oxide in the air (39). Figure 2 Ozone filters almost all UVC radiation and 95% of UVB radiation emitted from the sun. The composition of UV light reaching the Earth’s surface is 95% UVA and 5% UVB rays.
have reduced the production of ozone-depleting substances and greenhouse gases, and the ozone layer is no longer deteriorating. Gradual recovery is expected in the near future (31). Once solar UV light penetrates the stratosphere, other agents in the surrounding environment can influence the quality and quantity of UV light that reaches the skin. Clouds, in particular, can reduce the amount of UV light reaching the ground. Almost all UV light is transmitted under clear-sky conditions, whereas under overcast skies, approximately 31% of UV light reaches the surface level (32, 33). Furthermore, differences have been identified in the type of UV radiation transmitted by clouds. Seckemeyer et al. (34) conducted an experiment to measure the amount of UV radiation that penetrates dense (i.e., overcast) clouds. They found that 60% of UVB rays were transmitted compared to only 45% of UVA rays. In 2002, these findings were confirmed by Schwander et al. (35) who found that waves of 310–315 nm maximally pass through clouds, compared to wavelengths in the range of 300–380 nm. The increased transmission of shorter wavelengths in overcast conditions is caused by photons scattered back to the upper atmosphere at the top of clouds surface and then scattered back downward again (i.e., Rayleigh scattering) (36). Due to increasing optical depth of air molecules with decreasing wavelengths, photos in range 310–315 nm have a higher chance of downward scattering. However, at wavelenghts below 310 nm, this effect is overcompensated by increased absorption of photons by tropospheric ozone (35). Other environmental agents are also known to modify UV light transmission. Snow, ice, and sand are agents that reflect UV light; therefore, they can increase UV exposure
Geographic variations Solar UV exposure varies with the time of day, geographic location, and season. UV radiation is greatest at the equator and for every degree increase in latitude, there is a 3% decrease in UVB transmission (40). Areas located at higher altitudes have thinner atmosphere, which filters less UVB light. For every 1000-foot increase in elevation, there is a 4%–10% increase in UVB transmission (40). UV radiation is most intense between 10AM and 2PM, with increased transmission around the solar zenith, when the path length for UV rays is the shortest (32). Finally, seasonal variations resulting from the revolution of the Earth around the sun cause differences in UV light. The summer time is when UV transmission is most intense due to direct exposure to radiation emitted by the sun (41).
Acute exposure to UV radiation The biological events that occur after exposure to UV radiation can be schematically classified into immediate and long-term effects (Table 1). Acute UV exposure results in Vitamin D synthesis and adaptive mechanisms to prevent UV damage, including the development of redness (erythema), immediate pigment darkening, and thickening of the skin. At a molecular level, there is DNA damage, formation of reactive oxygen species, and induction of the tumor suppressor gene p53 (42, 43).
Erythema Sunburning and erythema are the most recognizable acute clinical effects of UV exposure. UVB rays, and to a lesser extent UVA-II, are responsible for sunburns and
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268 Mancebo and Wang: Role of UV radiation in skin cancer Table 1 Immediate vs. long-term effects of UV light exposure.
Pigment darkening
Biological effects of ultraviolet light exposure
UV irradiation causes a biphasic response in skin pigmentation. Initially, there is an immediate reaction causing transient changes in skin color, followed by delayed tanning—a process that leads to new pigment formation (44). Immediate pigment darkening (IPD) and persistent pigment darkening (PPD) are two processes that occur soon after sun exposure ( 10 J/cm2) (52). Clinically, PPD manifests with brown skin pigmentation that can persist up to 24 h. Both IPD and PPD are reversible processes that result from oxidation and redistribution of existing melanin moieties (43, 52). Delayed tanning is associated with the synthesis of new melanin. This process is induced by both UVA and UVB radiation (52). UVB causes melanogenesis, resulting in increased activity of melanocytes. UVA increases melanin density and promotes the transfer of melanin granules to other cells in the epidermis (44, 53). Clinically, delayed tanning causes changes in pigmentation that become visible 3 days after sun exposure. These changes in skin color eventually fade as the surface layer of the skin is shed (52).
Acute exposure to UV eadiation Vitamin D synthesis Erythema Pigment darkening Epidermal hyperplasia DNA damage Free radical oxygen species formation Induction of tumor suppressor gene p53 Upregulation of pro-apoptotic genes and proteins Chronic exposure to UV radiation Chronic inflammation Immune suppression Photoaging Unrepaired DNA mutations predisposing to development of skin cancer, including: Basal cell carcinoma Squamous cell carcinoma Melanoma
induction of short-term erythema, which peaks between 6 and 24 h after exposure. High doses of UVA light can also induce short-term erythema that can last up to 72 h (32). The degree of erythema formation depends on both host and environmental factors. Host factors, including skin color, age and anatomic site determine the severity of erythema formation. Individuals with darker skin pigmentation require up to 30 times more UV exposure to induce erythema compared to individuals with fair skin (44). Furthermore, infants and elderly individuals are known to have a lower threshold for erythema formation, particularly at anatomic sites with decreased skin thickness (44, 45). Environmental factors like latitude, altitude, and time of day may affect erythema formation by modulating UV light transmission (refer to previous section). To date, the biological mechanism resulting in erythema formation has yet to be completely delineated. However, various studies provide insights into the pathway leading to blood vessel dilation (vasodilation) after sun exposure (44). Upon UV irradiation, the principal event leading to erythema formation appears to be direct damage to DNA by UVB and UVAII, and indirect oxidative damage by longer-wavelength UVA rays (46–48). As a result of DNA damage, many cytokines and inflammatory mediators are synthesized and released into the skin. These mediators include prostaglandins, histamine, kinins, nitric oxide, IL-1, IL-6, and TNF-α (49–51). Together, these substances regulate the expression of adhesion molecules on blood vessels and keratinocytes, resulting in the recruitment and activation of inflammatory cells that cause vasodilation and inflammation.
Epidermal hyperplasia Epidermal hyperplasia is an adaptive process, which protects the skin from further UV damage. Upon exposure to acute UV irradiation, the cells in the epidermis and dermis undergo a transient period of cellular arrest that allows for cellular and DNA repair of acute injury. About 24–48 h after this transient period, the epidermal and dermal skin cells increase their reproductive rates (52). This increased reproductive activity is associated with increased synthesis of DNA, RNA, and proteins (54). Epidermal hyperplasia is a reversible and transient process. In the absence of further UV exposure, the cells return to a normal state within 1–2 weeks (52). Furthermore, the extent of cellular proliferation that occurs is an age-dependent process. Haratake et al. (55) demonstrated that aged mouse epidermis has a decreased ability to induce epidermal hyperplasia compared with epidermis from younger mice. These investigators suggest that aging skin may be less sensitive to UVB-induced damage due to the inherent changes in aging skin that include decreased inflammatory response, impaired immune function, and decreased epidermal turnover (55).
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Mancebo and Wang: Role of UV radiation in skin cancer 269
DNA damage UVB radiation induces a series of photochemical reactions that directly affect DNA pyrimidine bases. These photochemical reactions primarily result in the production of dimers such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (56). Both types of lesions occur in runs of tandemly located pyrimidine bases, which are considered “hot spots” for UVB-induced DNA damage (57, 58). In most cases, DNA repair mechanisms detect and replace these dimers, thus preventing downstream DNA mutations. If these lesions are not repaired, they result in C→T and CC→TT transitions, which are recognized as “UVB signature mutations” (43). In addition to the formation of dimers, UVB radiation can cause other types of DNA lesions, including single-strand breaks in DNA (56, 59). In recent years, UVA radiation has been recognized for the potential to indirectly damage DNA. UVA light induces the formation of reactive oxygen species (ROS) that cross-link DNA to proteins, resulting in single-strand breaks and alteration of DNA bases (60). Here, 8-hydroxyguanine is the signature DNA mutation induced by UVA radiation (61).
Free radical formation Oxidative stress plays a central role in initiating and driving the cellular response following UV exposure (62). UV light induces the production of superoxide anion (O2-), peroxide (H2O2), and hydroxyl radicals (OH·) within 15 min of exposure (63). These short-lived molecules have the capacity to damage DNA, proteins, and cellular membranes through oxidative reactions that occur in the epidermis and dermis. In addition, ROS activate matrix metalloproteinases and release inflammatory cytokines, ultimately leading to degradation of normal skin architecture and decreased cutaneous function (42, 63, 64).
Induction of p53 Previous studies have identified p53 as a tumor-suppressor protein that controls the cell cycle and maintains cellular normalcy by preventing DNA mutations (65–67). DNA damage resulting from UV exposure induces high levels of p53 leading to cell cycle arrest at G1 (68). This allows for repair of DNA lesions before the cell continues with DNA synthesis. When there is excessive DNA damage, p53 triggers apoptosis (i.e., programmed cellular death)
by up-regulating the expression of proapoptotic genes, including bax, bak and noxa, which belong to the Bcl-2 family (69). This results in the recruitment and activation of pro-apoptotic proteins known as caspases, which culminate in the disruption of mitochondrial membranes, eventually leading to cellular death (67, 68, 70).
Chronic exposure to UV radiation Long-term UV light exposure causes the gradual deterioration of cutaneous structures and function. Cumulative damage resulting from chronic inflammation and recurrent acute injury leads to the development of skin cancers through a multi-step process, which involves DNA mutations and escape from immune surveillance (43). In this section, we will focus our discussion on the role of UV radiation in the development of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. Other long-term effects of UV exposure like photoaging will be discussed in other sections of the book.
Mechanism of carcinogenesis: unrepaired DNA mutations and immunosuppression Whereas acute UV irradiation results in adaptive processes, chronic UV irradiation leads to deregulation of biological mechanisms, which promote abnormal proliferation of cells containing DNA damage (68). Long-term exposure to UV radiation is associated with mutations that inactivate tumor suppressor genes or activate protooncogenes. Tumor suppressor genes are negative regulators of the cell cycle that require inactivation of both copies of the gene before progression to uncontrolled cell growth (43, 59). Proto-oncogenes are positive regulators of the cell cycle that allow for cellular proliferation and differentiation. These genes require a mutation of only one copy of the gene to have a tumorigenic effect. UV-induced mutations in skin cancers have been identified among tumor suppressor genes p53, CDKN2A and PTCH, as well as in proto-oncogene ras (43). A second component in the development of skin cancer is escape from immune surveillance. UV irradiation induces immune suppression by altering cutaneous cellmediated immunity. Following multiple exposures to UV light, Langerhans cells in the epidermis are depleted and may undergo changes in morphology, eventually leading to decreased function (71, 72). T-helper and T-cytotoxic lymphocytes are also depleted and there is a simultaneous
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270 Mancebo and Wang: Role of UV radiation in skin cancer increase in T-regulatory cells, which contribute to self-tolerance (72–74). Ultimately, these alterations favor both the development and metastasis of skin tumors.
Carcinogenesis of NMSC Total cumulative sun exposure is associated with the development of SCC and BCC (75). Acute UVB exposure creates CPDs and (6-4) photoproducts that are mostly repaired effectively. However, long-term UVB exposure often leads to incorrect repair of these lesions, rendering cells to accumulate DNA mutations, which eventually result in malignant transformation (59). The tumor suppressor p53 gene is a frequent target of UVB genetic alterations. UVB signature mutations in p53 have been identified in about 90% of SCCs (76). It appears that these mutations are an early event in UV-induced carcinogenesis. Studies by Taguchi et al. (77) and Zigler et al. (78) have demonstrated p53 mutations in nearly 50% of actinic keratosis, which are precancerous skin lesions. BCCs are biologically different from SCCs and harbor different DNA lesions. Mutations in p53 have been identified in only 50% of BCCs (79). However, other genes are thought to play a role in BCC tumorigenesis. PTCH is an inhibitor of the hedgehog signal pathway, which transmits extracellular growth and differentiation signals to the nucleus (80). UVB-induced mutations in the PTCH gene have been detected among variable numbers of BCCs (81, 82). Other genes, including the ras family of proto-oncogenes, which promote cell survival and differentiation, have also been found to harbor UVB-signature mutations among BCCs (83). Further evidence for the role of UV light in the development of NMSC comes from epidemiological studies. A randomized control trial among 1621 adults in a subtropical community in Queensland, Australia compared the daily use of SPF 16 sunscreen with discretionary use of sunscreen (84). After a 4.5-year intervention, the study showed a 40% reduction in the incidence of SCC tumors among participants assigned to the sunscreen group. The study also assessed the incidence of BCC tumors, but there was no statistical difference between the two groups. A follow-up study conducted 8 years later on the same cohort showed a trend towards decreased BCC tumors among participants who used daily sunscreen (85). Both studies provide indirect evidence for the role of UV light in the development of NMSC. Protection from sunlight confers a protective effect on SCCs and on BCCs, although further studies are needed to fully delineate the role of UV light in BCC tumorigenesis.
Carcinogenesis of melanoma skin cancers Melanoma results from a multi-factorial process involving genetic, phenotypic, and environmental predispositions. People with fair skin, red hair, blue eyes, and proclivity to sunburn are at a higher risk of developing melanoma (75). The only environmental risk factor that has been shown to be relevant is UV light exposure. A history of sunburns and high-dose intermittent sun exposure has a direct relationship with lifetime relative risk of developing melanoma (86). In addition, studies analyzing the risk associated with artificial tanning devices suggest a modest but significantly increased risk of developing melanoma among users (15). The gene mutations that have been implicated in melanoma tumorigenesis include the tumor suppressor genes p16/CDKN2A and PTEN, and proto-oncogenes BRAF and N-RAS (72). These mutations do not show the typical ultraviolet “fingerprint” seen among BCCs and SCCs, thus reinforcing the notion that melanoma results from a multi-factorial process. With regards to epidemiologic studies, a 10-year follow-up study conducted by the Australian group on the cohort of 1621 patients in Queensland, demonstrated that daily use of sunscreens with SPF16 can reduce the risk of melanoma by 50% (87). These findings indirectly confirm that UV light exposure plays a role in the development of melanoma skin cancers.
Conclusion UV radiation is a carcinogen known to play a role in the development of non-melanoma and melanoma skin cancers. Acute exposure to UV radiation causes clinical and biological effects that are often repaired effectively. However, long-term or recurrent exposure leads to unrepaired DNA lesions, which promote the unregulated proliferation of skin cells. Recent changes in the environment have led to increased UV light transmission. These alterations may be implicated in the increased incidence of skin cancers. Conflict of interest: The authors report no conflict of interest.
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