P h o t o c a rc i n o g e n e s i s An Epidemiologic Perspective on Ultraviolet Light and Skin Cancer Bonita Kozma, MDa,*, Melody J. Eide, MD, MPHa,b KEYWORDS Melanoma Nonmelanoma skin cancer Photocarcinogenesis Ultraviolet radiation Epidemiology
KEY POINTS Ultraviolet (UV) light exposure is a well-known risk factor for developing skin cancer. Indoor tanning has been shown to increase cumulative UV exposure and risk of skin cancers, especially in younger fair-skinned populations. Cutaneous photocarcinogenesis involves a complex interplay between ultraviolet radiation, cells of the skin, molecular pathways, DNA, and the immune system.
Skin cancer is the most common malignancy worldwide, with increasing incidence seen in many countries, including the United States. In 2013, it is estimated that there will be 3.5 million new cases of nonmelanoma skin cancer (NMSC) and approximately 76,000 new cases of melanoma in the United States alone.1 It is estimated that around 9000 deaths will occur in the United States because of melanoma in 2013.1,2 Ultraviolet (UV) light exposure is a well-known risk factor for the development of skin cancer. Although UV exposure occurs on a daily basis, it is increased through recreational and occupational choices; thus, heightened awareness and understanding of factors and avoidable exposures are key factors to reducing this risk. The International Agency for Research on Cancer (IARC) has classified solar radiation as carcinogenic to humans.3 This article discusses a brief overview of UV and its biologic effects on cells of the skin
that can lead to mutagenesis and ultimately carcinogenesis. NMSC and melanoma are discussed separately in regards to epidemiology, genetic conditions predisposing patients to each type of skin cancer, and the initiation and propagation of tumors. In addition, public health issues related to UV exposure, such as tanning, workplace exposures, and vitamin D deficiency, are discussed briefly.
BIOLOGIC EFFECTS OF UV Solar radiation contains UV, visible light, and infrared radiation. The UV spectrum is divided into UVC (200–290 nm), UVB (290–320 nm), UVA2 (320–340 nm), and UVA1 (340–400 nm). Most all of the UVC wavelength is absorbed by the Earth’s ozone, with UVB and UVA reaching the Earth’s surface. The wavelength corresponds to level of penetration into the skin, with longer wavelengths penetrating deeper. UVB penetrates to the basal layer of the epidermis and superficial
No relationships to disclose. a Department of Dermatology, Henry Ford Hospital, 3031 West Grand Boulevard, Detroit, MI 48202, USA; b Department of Public Health Sciences, Henry Ford Hospital, 3031 West Grand Boulevard, Detroit, MI 48202, USA * Corresponding author. Department of Dermatology, Henry Ford Health System, 3031 West Grand Boulevard, Suite 800, Detroit, MI 48202. E-mail address: [email protected] Dermatol Clin 32 (2014) 301–313 http://dx.doi.org/10.1016/j.det.2014.03.004 0733-8635/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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Kozma & Eide dermis, with UVA penetrating into the deep dermis.4 Apart from DNA damage, UVA and UVB also exert different effects on the skin. UVB is more effective than UVA in causing sunburn, whereas UVA leads to immediate (lasting minutes after exposure) and persistent (lasting hours after exposure) pigment darkening. UVA is also responsible for most photoallergic and phototoxic reactions and is capable of penetrating window glass. Both UVA and UVB are involved in photocarcinogenesis.5 Fig. 1 overviews photocarcinogenesis.
DNA Damage Biologic effects of UV light on the skin occur after the absorption of UV light by chromophores, which are molecules in the skin that absorb photons. The most important chromophore in photocarcinogenesis is DNA. UVB induces the formation of pyrimidine dimers and 4,6 photoproducts. Often there are C to T and CC to TT mutations, which are known as UVB signature mutations. UVA is thought to contribute to carcinogenesis through the formation of free radicals that then cause indirect damage to DNA. Oxidation of guanine to 8-hydroxyguanine is a common mutation from UVA irradiation.6 However, it is now known that UVA can also form pyrimidine dimers. Singlestrand breaks, double-strand breaks, and crosslinks between DNA strands can occur as a result of ultraviolet radiation (UVR) exposure.7 Once a mutation forms, it may be repaired, or the cell may be targeted for apoptosis if the damage is too severe. This is accomplished through p53, a tumor suppressor gene that plays a central role in cell repair, apoptosis, and cell-cycle arrest to
Fig. 1. Mechanisms of UV-induced photocarcinogenesis.
allow time for repairs. The levels of p53 are increased in normal keratinocytes after UVR exposure.6 If the p53 gene is mutated, the cell may not be able to repair itself, leading to permanent damage. The cell may also become resistant to apoptosis.8 P53 mutations have been demonstrated in sun-exposed skin, actinic keratoses (AKs), squamous cell carcinoma (SCCs), basal cell carcinoma (BCCs), and melanomas.6 It may be more harmful for mutations of p53 to occur in basal keratinocytes than fully differentiated keratinocytes because basal keratinocytes have the ability to express a stem-cell-like phenotype. Basal keratinocytes with mutated p53 can give rise to differentiated keratinocytes that also contain mutated p53. Clones of cells with mutated p53 are often found in normal chronically sunexposed skin, which suggests mutations in p53 are an early event in photocarcinogenesis.9,10
Cell-Cycle Arrest For the cell to repair a mutation accurately, it must have time for repair. The cell cycle is divided into G1 (Gap phase), S (DNA synthesis), G2, and M (mitosis) phases. The cell cycle can undergo arrest at various points to allow repair of DNA damage. The G1 checkpoint is important because it prevents a cell from progressing to S phase with a damaged DNA template, which would lead to a mutation formation with DNA replication. Progression to S phase depends on the phosphorylation of retinoblastoma (Rb) by cyclin-dependent kinases (CDK), specifically D-CDK4 (6) kinases. Unphosphorylated Rb is bound by E2F, a transcription factor. Increased levels of p-53 following UVR
Photocarcinogenesis exposure leads to induction of p21, a cyclin kinase inhibitor, and to cell-cycle arrest at the G1 checkpoint,11 which can also occur independent of p53. DNA damage is thought to be sensed by ataxia telangiectasia mutated (ATM) and ATM-Rad3related protein (ATR), which are protein kinases that signal via other molecules to effectors of cellular repair. ATM and ATR are thought to exhibit some specificity to the type of DNA damage they detect. Because UVA and UVB can produce differing proportions of photoproducts, it is thought that UVA and UVB induce different mechanisms of repair through the transduction paths of ATM and/or ATR. ATM depends on functional p53, whereas ATR does not.12 Some phases of the cell cycle are more resistant to UV-mediated damage. S phase is the most resistant phase to damage from UVR. ATM phosphorylates Chk2, BRCA1, and NBS1, which are molecules responsible for DNA repair response and the S-phase checkpoint. G2 phase is also comparatively resistant to photodamage. This phase represents the last opportunity to prevent damaged DNA from replicating and being passed on to daughter cells in mitosis. If cells are damaged in G2, they undergo arrest that depends on ATM and BRCA1. If cells are damaged in S phase and passed onto G2, they are arrested in an ATM-independent manner through ATR. Multiple pathways regulating G2 arrest ultimately contribute to regulating CDK1 activity through phosphorylation and subsequent activation or inactivation.12
DNA Repair Once the cell cycle has been arrested, DNA damage is repaired. Base excision repair (BER) involves the recognition and removal of damaged bases, which may not cause significant distortion of the DNA helix. BER is important in protection from oxidative damage of DNA, which is mainly attributed to UVA. Larger strings of nucleotide damage, such as pyrimidine dimers and 6,4 photoproducts caused commonly by UVB, are repaired by nucleotide excision repair (NER). Two groups of NER are used, depending on if the damage has occurred in a transcriptionally active or transcriptionally silent gene.12 Repair speed varies by mechanism. Transcription coupled repair corrects damage quickly in active genes, whereas global genome repair works at a slower pace in inactive genes.13 There are also differences in repair speed between pyrimidine dimers and 6,4 photoproducts. Young and colleagues14 demonstrated that bulky dimers were repaired slowly and had a half-life of 33.3 hours
in human skin following irradiation. In contrast, 6,4 photoproducts had a half-life of only 2.3 hours. It is postulated that these differences occur because of the difference in degree of distortion the 2 types of products generated on the DNA helix. Although the 6,4 lesion is smaller, it causes more distortion in the helix than the dimer.15
Apoptosis If cells have sustained too much damage to be repaired, apoptosis is a mechanism in place to prevent mutation formation. The p53 tumor suppressor protein plays a role in mediating apoptosis, with p53-deficient mice showing decreased apoptotic cells after UVR compared with wildtype mice.9 p53 increases the transcription of Bax, a pro-apoptotic protein, and bcl-2 can inhibit Bax when the 2 molecules form a heterodimer.13 Although keratinocytes readily undergo apoptosis through this pathway after exposure to UVR, melanocytes are less likely to undergo apoptosis following UVR exposure. This difference is likely due to the higher concentrations of bcl-2 found in melanocytes compared with keratinocytes.16 After exposure to UVR, bcl-2 expression is reduced in normal skin cells, which leads to a state favoring apoptosis. High levels of bcl-2 are seen in the tumors of melanoma, SCC, BCC, and AKs, which gives the tumor cells a selective survival advantage over normal cells that undergo apoptosis following UVR damage.13 Park and Lee17 demonstrated decreased expression of Bcl-Xl after UVB irradiation, which likely occurs through proteasomemediated degradation. Pro-apoptotic agents may potentially provide alternative treatment modalities for patients with NMSC.
UV Effects on the Immune System In addition to causing DNA damage, UV can also indirectly increase the risk of carcinogenesis through effects on the immune system. UV exposure decreases the detection of damaged cells by the immune system as demonstrated by Kripke.18 Tumor cells were transplanted onto irradiated and unexposed mice. The tumor cells grew when placed in the radiation-exposed mice, but did not progress in the unexposed mice. Immune suppression is accomplished through alterations of cytokines, soluble factors, and effects on Langerhans cells and T cells of the skin. Proinflammatory cytokines and prostaglandins, such as interleukin (IL)-10, tumor necrosis factor a, and prostaglandin E2 are increased following irradiation of keratinocytes.19 Simon and colleagues20 demonstrated that Langerhans cells exposed to UVR could present antigen to Th2 cells but could
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Kozma & Eide not present antigen to Th1 cells. Increased Th2 cytokines such as IL-4, IL-5, IL-6, and IL-10 resulted, which reduced the presentation of antigens to T cells. Trans-urocanic acid is found in the outer layers of the skin and isomerizes to cis-urocanic acid following UVB exposure. Cis-urocanic acid can also decrease antigen presentation to T cells, in addition to inducing the formation of suppressor T cells.21 Free radicals can also contribute to immune suppression through peroxidation of lipid membranes. Generated free radicals cause release of platelet activating factor (PAF) from the epidermis. Free radicals and PAF attack mainly unsaturated fatty acids in the lipid membrane. Lipids are damaged through the direct oxidation of their double bonds or by free radical-induced chain reactions. The peroxidation of lipids impacts prostaglandin synthesis and cytokine release, which results in active regulatory T cells and immune suppression.19,22
NONMELANOMA SKIN CANCER Epidemiology Nonmelanoma skin cancer largely consists of BCC and SCC. Although NMSC is found mainly in elderly individuals,23 the incidence has been increasing, especially among younger women.24 BCC is the most common NMSC, comprising about 80% of skin cancers. BCCs are slowgrowing and locally invasive, reflected in the low mortality rate. Established risk factors for sporadic BCC include intermittent UV exposure in childhood and adolescence, skin types I and II, exposure to ionizing radiation, arsenic exposure, immunosuppression, family history, male sex, and older age.25 Increasing attention has focused on BCCs in younger individuals. Risk factors for BCC occurring in those under the age of 40 were examined by Bakos and colleagues.26 They found that women were more likely than men to be affected, and that most tumors occurred on the neck and face. Tanning bed use and smoking were found to be associated with increased risk for sporadic BCC before the age of 40. Sunscreen use was found to be a protective factor. Although BCC incidence is increasing in this age group, the overall frequency of BCC in this age group remains low. SCCs have a stronger link to cumulative UV exposure and tend to occur on sun-exposed surfaces, frequently the head and neck. Unlike BCC, they have a higher mortality rate and are more likely to metastasize if not treated.27 Additional risk factors for developing SCC are similar to the risk factors for developing BCC, with immunosuppression
(including organ transplant) being a stronger risk factor for SCC than BCC.28
Genetic Predisposition for NMSC Some patients have an increased risk for NMSC because of genetic predisposition, which may be amplified by UV exposure. Nevoid basal cell carcinoma syndrome, or Gorlin syndrome, is inherited in an autosomal-dominant manner. In Gorlin syndrome, there is a mutation in patched (PTCH), a tumor suppressor gene; the product of this gene, Patched, inhibits the G protein-coupled receptor Smoothened (SMO) at baseline. Sonic Hedgehog can bind to Patched, which releases SMO from inhibition; downstream signaling results in activation of the transcription factor Gli, and subsequent cellular proliferation (Fig. 2).29 Patients characteristically have palmoplantar pits, odontogenic keratocysts, calcification of the dura, rib anomalies, ovarian fibromas, and medulloblastomas.30 There is no increase in photocarcinogenesis in Gorlin syndrome, although some disorders with increased skin cancers do have an increase in photocarcinogenesis.31 Another genetic disorder, xeroderma pigmentosum (XP), can predispose patients to BCC, SCC, and melanoma through increased photocarcinogenesis. The disorder is autosomal-recessive, and there are several types of XP (XPA-XPG) and XP variant. In XP, the mutations are related to excision repair, which is responsible for removing the 6,4 photoproducts and pyrimidine dimers induced by UVR. Inability or decreased efficacy in removing the DNA damage leads to mutations, which can then progress to carcinomas.15 In a proof of concept study, application of liposomes containing DNA repair enzyme T4 endonuclease V to skin of patients with XP resulted in lower development of BCCs and AKs.32
Sporadic Formation of NMSC Acquired (noninherited) DNA mutations, such as those induced by UV, are responsible for sporadic NMSC. Sporadic BCCs arise when mutations accrue in the basal keratinocytes and give selective survival advantage to these cells. Sporadic SCCs occur when keratinocytes with the potential to proliferate acquire mutations that lead to malignant transformation. As discussed earlier, UVR can damage DNA directly or indirectly, interfere with cell-cycle arrest, alter apoptosis, and affect the immune system.6 Prolonged and intermittent exposure to high levels of UVR are responsible for BCC development, with intermittent exposure being the most important. BCC most commonly develops on the head and neck.33 The tumor
Photocarcinogenesis
Fig. 2. Sonic hedgehog pathway. Under normal conditions, patched inhibits smoothened. When sonic hedgehog binds, it releases smoothened from inhibition of patched. Gli is then activated and translocated to the nucleus and acts on target genes resulting in proliferation. (Data from Bale AE, Yu K. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet 2001;10(7):757–62.)
suppressor genes PTCH and p53 are the most common mutations found in BCC, with PTCH mutations being the most prevalent.6 The function of Patched protein is to relay growth regulatory signals to the nucleus of the cell.26 Mutations found in BCC’s PTCH gene are often C to T UVB signature mutations. It is thought that the mutation of PTCH is an earlier event in the initiation of BCC than the mutation of p53.34 Unlike BCC, SCC can be preceded by precursor lesions, such as AKs and Bowen’s disease. Cumulative UV exposure seems to be important in SCC.27 The rate of progression from AK to SCC in a given year ranges from 0.025% to 16%, whereas roughly 25% of AKs resolve in a given year.35 Similar to BCC, SCC may develop p53 mutations, as supported by studies that demonstrate increased mutated p53 in normal sun-exposed skin compared with non-sun-exposed skin. This increase may predispose cells in sun-exposed skin to carcinogenesis. As many as 58% of SCC have UVB signature mutations in p53.36
Occupational Exposure and NMSC Although BCC is the most common cancer and UVR has been proven to contribute to its
pathogenesis, little has been published in the literature regarding occupational exposure and preventative measures in the workplace. Stronger associations between workplace exposure and SCC have been established.26 A meta-analysis by Bauer and colleagues37 included 23 epidemiologic studies and found a pooled odds ratio (OR) of 1.43 for the association between outdoor work and risk of BCC (95% confidence interval 1.23–1.66; P 5 .0001). An inverse relationship between geographic latitude and risk of BCC was also found. However, there were limitations including incomplete distinction in some studies between occupational and nonoccupational UV exposures, and classification of indoor and outdoor occupations. Some studies also failed to consider Fitzpatrick skin type, recall bias, and self-selection bias (ie, phenotypic characteristics of workers selecting outdoor occupations). The authors speculated the risk may be higher than what was found in the meta-analysis. A meta-analysis of 18 studies was also performed on SCC and workplace UV exposure and found a pooled OR of 1.77 for the association between outdoor work and risk of SCC (95% confidence interval 1.40–2.22; P
KEY POINTS Ultraviolet (UV) light exposure is a well-known risk factor for developing skin cancer. Indoor tanning has been shown to increase cumulative UV exposure and risk of skin cancers, especially in younger fair-skinned populations. Cutaneous photocarcinogenesis involves a complex interplay between ultraviolet radiation, cells of the skin, molecular pathways, DNA, and the immune system.
Skin cancer is the most common malignancy worldwide, with increasing incidence seen in many countries, including the United States. In 2013, it is estimated that there will be 3.5 million new cases of nonmelanoma skin cancer (NMSC) and approximately 76,000 new cases of melanoma in the United States alone.1 It is estimated that around 9000 deaths will occur in the United States because of melanoma in 2013.1,2 Ultraviolet (UV) light exposure is a well-known risk factor for the development of skin cancer. Although UV exposure occurs on a daily basis, it is increased through recreational and occupational choices; thus, heightened awareness and understanding of factors and avoidable exposures are key factors to reducing this risk. The International Agency for Research on Cancer (IARC) has classified solar radiation as carcinogenic to humans.3 This article discusses a brief overview of UV and its biologic effects on cells of the skin
that can lead to mutagenesis and ultimately carcinogenesis. NMSC and melanoma are discussed separately in regards to epidemiology, genetic conditions predisposing patients to each type of skin cancer, and the initiation and propagation of tumors. In addition, public health issues related to UV exposure, such as tanning, workplace exposures, and vitamin D deficiency, are discussed briefly.
BIOLOGIC EFFECTS OF UV Solar radiation contains UV, visible light, and infrared radiation. The UV spectrum is divided into UVC (200–290 nm), UVB (290–320 nm), UVA2 (320–340 nm), and UVA1 (340–400 nm). Most all of the UVC wavelength is absorbed by the Earth’s ozone, with UVB and UVA reaching the Earth’s surface. The wavelength corresponds to level of penetration into the skin, with longer wavelengths penetrating deeper. UVB penetrates to the basal layer of the epidermis and superficial
No relationships to disclose. a Department of Dermatology, Henry Ford Hospital, 3031 West Grand Boulevard, Detroit, MI 48202, USA; b Department of Public Health Sciences, Henry Ford Hospital, 3031 West Grand Boulevard, Detroit, MI 48202, USA * Corresponding author. Department of Dermatology, Henry Ford Health System, 3031 West Grand Boulevard, Suite 800, Detroit, MI 48202. E-mail address: [email protected] Dermatol Clin 32 (2014) 301–313 http://dx.doi.org/10.1016/j.det.2014.03.004 0733-8635/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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INTRODUCTION
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Kozma & Eide dermis, with UVA penetrating into the deep dermis.4 Apart from DNA damage, UVA and UVB also exert different effects on the skin. UVB is more effective than UVA in causing sunburn, whereas UVA leads to immediate (lasting minutes after exposure) and persistent (lasting hours after exposure) pigment darkening. UVA is also responsible for most photoallergic and phototoxic reactions and is capable of penetrating window glass. Both UVA and UVB are involved in photocarcinogenesis.5 Fig. 1 overviews photocarcinogenesis.
DNA Damage Biologic effects of UV light on the skin occur after the absorption of UV light by chromophores, which are molecules in the skin that absorb photons. The most important chromophore in photocarcinogenesis is DNA. UVB induces the formation of pyrimidine dimers and 4,6 photoproducts. Often there are C to T and CC to TT mutations, which are known as UVB signature mutations. UVA is thought to contribute to carcinogenesis through the formation of free radicals that then cause indirect damage to DNA. Oxidation of guanine to 8-hydroxyguanine is a common mutation from UVA irradiation.6 However, it is now known that UVA can also form pyrimidine dimers. Singlestrand breaks, double-strand breaks, and crosslinks between DNA strands can occur as a result of ultraviolet radiation (UVR) exposure.7 Once a mutation forms, it may be repaired, or the cell may be targeted for apoptosis if the damage is too severe. This is accomplished through p53, a tumor suppressor gene that plays a central role in cell repair, apoptosis, and cell-cycle arrest to
Fig. 1. Mechanisms of UV-induced photocarcinogenesis.
allow time for repairs. The levels of p53 are increased in normal keratinocytes after UVR exposure.6 If the p53 gene is mutated, the cell may not be able to repair itself, leading to permanent damage. The cell may also become resistant to apoptosis.8 P53 mutations have been demonstrated in sun-exposed skin, actinic keratoses (AKs), squamous cell carcinoma (SCCs), basal cell carcinoma (BCCs), and melanomas.6 It may be more harmful for mutations of p53 to occur in basal keratinocytes than fully differentiated keratinocytes because basal keratinocytes have the ability to express a stem-cell-like phenotype. Basal keratinocytes with mutated p53 can give rise to differentiated keratinocytes that also contain mutated p53. Clones of cells with mutated p53 are often found in normal chronically sunexposed skin, which suggests mutations in p53 are an early event in photocarcinogenesis.9,10
Cell-Cycle Arrest For the cell to repair a mutation accurately, it must have time for repair. The cell cycle is divided into G1 (Gap phase), S (DNA synthesis), G2, and M (mitosis) phases. The cell cycle can undergo arrest at various points to allow repair of DNA damage. The G1 checkpoint is important because it prevents a cell from progressing to S phase with a damaged DNA template, which would lead to a mutation formation with DNA replication. Progression to S phase depends on the phosphorylation of retinoblastoma (Rb) by cyclin-dependent kinases (CDK), specifically D-CDK4 (6) kinases. Unphosphorylated Rb is bound by E2F, a transcription factor. Increased levels of p-53 following UVR
Photocarcinogenesis exposure leads to induction of p21, a cyclin kinase inhibitor, and to cell-cycle arrest at the G1 checkpoint,11 which can also occur independent of p53. DNA damage is thought to be sensed by ataxia telangiectasia mutated (ATM) and ATM-Rad3related protein (ATR), which are protein kinases that signal via other molecules to effectors of cellular repair. ATM and ATR are thought to exhibit some specificity to the type of DNA damage they detect. Because UVA and UVB can produce differing proportions of photoproducts, it is thought that UVA and UVB induce different mechanisms of repair through the transduction paths of ATM and/or ATR. ATM depends on functional p53, whereas ATR does not.12 Some phases of the cell cycle are more resistant to UV-mediated damage. S phase is the most resistant phase to damage from UVR. ATM phosphorylates Chk2, BRCA1, and NBS1, which are molecules responsible for DNA repair response and the S-phase checkpoint. G2 phase is also comparatively resistant to photodamage. This phase represents the last opportunity to prevent damaged DNA from replicating and being passed on to daughter cells in mitosis. If cells are damaged in G2, they undergo arrest that depends on ATM and BRCA1. If cells are damaged in S phase and passed onto G2, they are arrested in an ATM-independent manner through ATR. Multiple pathways regulating G2 arrest ultimately contribute to regulating CDK1 activity through phosphorylation and subsequent activation or inactivation.12
DNA Repair Once the cell cycle has been arrested, DNA damage is repaired. Base excision repair (BER) involves the recognition and removal of damaged bases, which may not cause significant distortion of the DNA helix. BER is important in protection from oxidative damage of DNA, which is mainly attributed to UVA. Larger strings of nucleotide damage, such as pyrimidine dimers and 6,4 photoproducts caused commonly by UVB, are repaired by nucleotide excision repair (NER). Two groups of NER are used, depending on if the damage has occurred in a transcriptionally active or transcriptionally silent gene.12 Repair speed varies by mechanism. Transcription coupled repair corrects damage quickly in active genes, whereas global genome repair works at a slower pace in inactive genes.13 There are also differences in repair speed between pyrimidine dimers and 6,4 photoproducts. Young and colleagues14 demonstrated that bulky dimers were repaired slowly and had a half-life of 33.3 hours
in human skin following irradiation. In contrast, 6,4 photoproducts had a half-life of only 2.3 hours. It is postulated that these differences occur because of the difference in degree of distortion the 2 types of products generated on the DNA helix. Although the 6,4 lesion is smaller, it causes more distortion in the helix than the dimer.15
Apoptosis If cells have sustained too much damage to be repaired, apoptosis is a mechanism in place to prevent mutation formation. The p53 tumor suppressor protein plays a role in mediating apoptosis, with p53-deficient mice showing decreased apoptotic cells after UVR compared with wildtype mice.9 p53 increases the transcription of Bax, a pro-apoptotic protein, and bcl-2 can inhibit Bax when the 2 molecules form a heterodimer.13 Although keratinocytes readily undergo apoptosis through this pathway after exposure to UVR, melanocytes are less likely to undergo apoptosis following UVR exposure. This difference is likely due to the higher concentrations of bcl-2 found in melanocytes compared with keratinocytes.16 After exposure to UVR, bcl-2 expression is reduced in normal skin cells, which leads to a state favoring apoptosis. High levels of bcl-2 are seen in the tumors of melanoma, SCC, BCC, and AKs, which gives the tumor cells a selective survival advantage over normal cells that undergo apoptosis following UVR damage.13 Park and Lee17 demonstrated decreased expression of Bcl-Xl after UVB irradiation, which likely occurs through proteasomemediated degradation. Pro-apoptotic agents may potentially provide alternative treatment modalities for patients with NMSC.
UV Effects on the Immune System In addition to causing DNA damage, UV can also indirectly increase the risk of carcinogenesis through effects on the immune system. UV exposure decreases the detection of damaged cells by the immune system as demonstrated by Kripke.18 Tumor cells were transplanted onto irradiated and unexposed mice. The tumor cells grew when placed in the radiation-exposed mice, but did not progress in the unexposed mice. Immune suppression is accomplished through alterations of cytokines, soluble factors, and effects on Langerhans cells and T cells of the skin. Proinflammatory cytokines and prostaglandins, such as interleukin (IL)-10, tumor necrosis factor a, and prostaglandin E2 are increased following irradiation of keratinocytes.19 Simon and colleagues20 demonstrated that Langerhans cells exposed to UVR could present antigen to Th2 cells but could
303
304
Kozma & Eide not present antigen to Th1 cells. Increased Th2 cytokines such as IL-4, IL-5, IL-6, and IL-10 resulted, which reduced the presentation of antigens to T cells. Trans-urocanic acid is found in the outer layers of the skin and isomerizes to cis-urocanic acid following UVB exposure. Cis-urocanic acid can also decrease antigen presentation to T cells, in addition to inducing the formation of suppressor T cells.21 Free radicals can also contribute to immune suppression through peroxidation of lipid membranes. Generated free radicals cause release of platelet activating factor (PAF) from the epidermis. Free radicals and PAF attack mainly unsaturated fatty acids in the lipid membrane. Lipids are damaged through the direct oxidation of their double bonds or by free radical-induced chain reactions. The peroxidation of lipids impacts prostaglandin synthesis and cytokine release, which results in active regulatory T cells and immune suppression.19,22
NONMELANOMA SKIN CANCER Epidemiology Nonmelanoma skin cancer largely consists of BCC and SCC. Although NMSC is found mainly in elderly individuals,23 the incidence has been increasing, especially among younger women.24 BCC is the most common NMSC, comprising about 80% of skin cancers. BCCs are slowgrowing and locally invasive, reflected in the low mortality rate. Established risk factors for sporadic BCC include intermittent UV exposure in childhood and adolescence, skin types I and II, exposure to ionizing radiation, arsenic exposure, immunosuppression, family history, male sex, and older age.25 Increasing attention has focused on BCCs in younger individuals. Risk factors for BCC occurring in those under the age of 40 were examined by Bakos and colleagues.26 They found that women were more likely than men to be affected, and that most tumors occurred on the neck and face. Tanning bed use and smoking were found to be associated with increased risk for sporadic BCC before the age of 40. Sunscreen use was found to be a protective factor. Although BCC incidence is increasing in this age group, the overall frequency of BCC in this age group remains low. SCCs have a stronger link to cumulative UV exposure and tend to occur on sun-exposed surfaces, frequently the head and neck. Unlike BCC, they have a higher mortality rate and are more likely to metastasize if not treated.27 Additional risk factors for developing SCC are similar to the risk factors for developing BCC, with immunosuppression
(including organ transplant) being a stronger risk factor for SCC than BCC.28
Genetic Predisposition for NMSC Some patients have an increased risk for NMSC because of genetic predisposition, which may be amplified by UV exposure. Nevoid basal cell carcinoma syndrome, or Gorlin syndrome, is inherited in an autosomal-dominant manner. In Gorlin syndrome, there is a mutation in patched (PTCH), a tumor suppressor gene; the product of this gene, Patched, inhibits the G protein-coupled receptor Smoothened (SMO) at baseline. Sonic Hedgehog can bind to Patched, which releases SMO from inhibition; downstream signaling results in activation of the transcription factor Gli, and subsequent cellular proliferation (Fig. 2).29 Patients characteristically have palmoplantar pits, odontogenic keratocysts, calcification of the dura, rib anomalies, ovarian fibromas, and medulloblastomas.30 There is no increase in photocarcinogenesis in Gorlin syndrome, although some disorders with increased skin cancers do have an increase in photocarcinogenesis.31 Another genetic disorder, xeroderma pigmentosum (XP), can predispose patients to BCC, SCC, and melanoma through increased photocarcinogenesis. The disorder is autosomal-recessive, and there are several types of XP (XPA-XPG) and XP variant. In XP, the mutations are related to excision repair, which is responsible for removing the 6,4 photoproducts and pyrimidine dimers induced by UVR. Inability or decreased efficacy in removing the DNA damage leads to mutations, which can then progress to carcinomas.15 In a proof of concept study, application of liposomes containing DNA repair enzyme T4 endonuclease V to skin of patients with XP resulted in lower development of BCCs and AKs.32
Sporadic Formation of NMSC Acquired (noninherited) DNA mutations, such as those induced by UV, are responsible for sporadic NMSC. Sporadic BCCs arise when mutations accrue in the basal keratinocytes and give selective survival advantage to these cells. Sporadic SCCs occur when keratinocytes with the potential to proliferate acquire mutations that lead to malignant transformation. As discussed earlier, UVR can damage DNA directly or indirectly, interfere with cell-cycle arrest, alter apoptosis, and affect the immune system.6 Prolonged and intermittent exposure to high levels of UVR are responsible for BCC development, with intermittent exposure being the most important. BCC most commonly develops on the head and neck.33 The tumor
Photocarcinogenesis
Fig. 2. Sonic hedgehog pathway. Under normal conditions, patched inhibits smoothened. When sonic hedgehog binds, it releases smoothened from inhibition of patched. Gli is then activated and translocated to the nucleus and acts on target genes resulting in proliferation. (Data from Bale AE, Yu K. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet 2001;10(7):757–62.)
suppressor genes PTCH and p53 are the most common mutations found in BCC, with PTCH mutations being the most prevalent.6 The function of Patched protein is to relay growth regulatory signals to the nucleus of the cell.26 Mutations found in BCC’s PTCH gene are often C to T UVB signature mutations. It is thought that the mutation of PTCH is an earlier event in the initiation of BCC than the mutation of p53.34 Unlike BCC, SCC can be preceded by precursor lesions, such as AKs and Bowen’s disease. Cumulative UV exposure seems to be important in SCC.27 The rate of progression from AK to SCC in a given year ranges from 0.025% to 16%, whereas roughly 25% of AKs resolve in a given year.35 Similar to BCC, SCC may develop p53 mutations, as supported by studies that demonstrate increased mutated p53 in normal sun-exposed skin compared with non-sun-exposed skin. This increase may predispose cells in sun-exposed skin to carcinogenesis. As many as 58% of SCC have UVB signature mutations in p53.36
Occupational Exposure and NMSC Although BCC is the most common cancer and UVR has been proven to contribute to its
pathogenesis, little has been published in the literature regarding occupational exposure and preventative measures in the workplace. Stronger associations between workplace exposure and SCC have been established.26 A meta-analysis by Bauer and colleagues37 included 23 epidemiologic studies and found a pooled odds ratio (OR) of 1.43 for the association between outdoor work and risk of BCC (95% confidence interval 1.23–1.66; P 5 .0001). An inverse relationship between geographic latitude and risk of BCC was also found. However, there were limitations including incomplete distinction in some studies between occupational and nonoccupational UV exposures, and classification of indoor and outdoor occupations. Some studies also failed to consider Fitzpatrick skin type, recall bias, and self-selection bias (ie, phenotypic characteristics of workers selecting outdoor occupations). The authors speculated the risk may be higher than what was found in the meta-analysis. A meta-analysis of 18 studies was also performed on SCC and workplace UV exposure and found a pooled OR of 1.77 for the association between outdoor work and risk of SCC (95% confidence interval 1.40–2.22; P
