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See related article on pg 2508 of cancers, including those of the colon, breast, and prostate (Bostick et al., 1993; Garland et al., 1985, 1990; Vitamin D , UVR, Hanchette and Schwartz, 1992; Kearney et al., 1996), is strong. However, sev- and Skin Cancer: A Potential eral large epidemiologic surveys have not demonstrated such a correlation Protective Mechanism with skin cancer (Hunter et al., 1992; Daniel D. Bikle1 van Dam et al., 2000; Weinstock et al., 1992). One potential complica- More than 1 million skin cancers occur annually in the United States—of tion is that UVB radiation has the dual

which 80% are basal-cell carcinoma (BCC), 16% are squamous-cell carcinoma effect of promoting vitamin D3 ­ synthesis (SCC), and 4% are melanomas—making skin cancer by far the most common in the skin (which can be further con-

cancer (Greenlee et al., 2001). UVR is the major etiologic agent. UV wave- verted to 1,25(OH)2D3) and increasing lengths shorter than 280 nm (UVC) are absorbed by the ozone layer and do DNA damage, leading to skin cancer. not reach the earth. UV wavelengths longer than 320 nm (UVA) have limited Thus, although UVR may be an effi- ability to induce the characteristic mutations in DNA seen in epidermal can- cient means of providing the nutritional cers. Thus, UVB, with a spectrum between 280 and 320 nm, is the major cause requirement for vitamin D, the advan- of these cancers (Freeman et al., 1989), but this is the same spectrum required tage to the skin may be countered by the for vitamin D production in the skin. Is there a link? increased risk of mutagenesis. However, Journal of Investigative Dermatology (2008), 128, 2357–2361. doi:10.1038/jid.2008.249 recent studies indicate that the skin has evolved a vitamin D signaling mecha- nism whereby the harmful effects of UVR may be mitigated. The principal genotoxic lesions SCCs (Danaee et al., 2006), and poly- The study by Ellison et al. (2008) induced by UVR are cyclobutane morphisms of the Ptch1 have in this issue demonstrates the protec- pyrimidine dimers and pyrimidine (6-4) altered the resistance to SCC formation tive role of VDR for UVR-induced skin pyrimidone photoproducts, which, if in mice expressing an activated ras tumors. Earlier studies indicated that not repaired, result in C-to-T or CC-to- (Wakabayashi et al., 2007). mice null for VDR were highly sus- TT mutations, the UVB “signature” Thus, alterations in the Hh signaling ceptible to epidermal tumor formation lesion (Hussein, 2005). Mutations in pathway contribute to the formation of induced by either the oral administra- are common (50–90%) in both both SCC and BCC. tion of the carcinogen 7,12-dimethyl-

BCC and SCC (Brash et al., 1991; 1,25-Dihydroxyvitamin D3 (1,25 benzanthracene (DMBA) (Zinser et al.,

Daya-Grosjean and Sarasin, 2005; (OH)2D3) has been evaluated for its 2002) or its topical application (Indra Ziegler et al., 1993, 1994), as well potential anticancer activity for approx- et al., 2007). In the former study, the as in actinic keratoses, the precur- imately 25 years (Eisman et al., 1979). tumors were mostly papillomas, but sor lesions to SCC (Bito et al., 1995). The list of malignant cells that express several BCCs were observed. No SCCs

Precursor lesions for BCC have not the receptor for 1,25(OH)2D3—vitamin were reported. In the latter study, only been identified, but BCCs are thought D receptor (VDR)—is now quite benign tumors were seen in the VDR to arise from interfollicular basal cells, extensive and for the purposes of this null mice, unlike RXRα null mice, hair follicles, and sebaceous glands. Commentary includes BCCs and SCCs which developed both BCCs and SCCs Mutations in ras are much more com- (Kamradt et al., 2003; Ratnam et al., (Indra et al., 2007). Ellison et al. (2008) mon in SCC than in BCC (Reifenberger 1996), as well as melanomas (Colston confirmed the report by Zinser et al. et al., 2005), whereas mutations in the et al., 1981). The accepted basis for (2002) demonstrating that oral admin-

hedgehog (Hh) signaling pathway— the promise of 1,25(OH)2D3 in the pre- istration of DMBA induced skin tumors in particular, in patched 1 (Ptch1)— vention and treatment of malignancy in all of the VDR null mice and none of characterize BCC (Aszterbaum et includes its antiproliferative, prodif- the wild-type mice. Furthermore, most al., 1998, 1999; Hahn et al., 1996; ferentiating effects on most cell types. of the tumors that formed appeared to Johnson et al., 1996). However, loss Epidemiologic evidence supporting originate from the folliculosebaceous of heterozygosity in the region includ- the importance of adequate vitamin unit. Importantly, Ellison et al. (2008) ing the Ptch1 gene has been reported D nutrition (including sunlight expo- did not report increased susceptibil- in a high percentage of both BCCs and sure) for the prevention of a number ity to DMBA-induced tumor forma- tion in mice lacking the enzyme for 1,25(OH) D production (CYP27B1). 1Department of Medicine, University of California San Francisco/VA Medical Center, San Francisco, 2 3 California, USA The authors thus concluded that, at Correspondence: Dr Daniel D. Bikle, Department of Medicine, University of California San Francisco/VA least for DMBA induction of tumors, Medical Center, 4150 Clement Street, San Francisco, California 94121, USA. VDR protection does not require its

E-mail: [email protected] principal ligand, 1,25(OH)2D3.

www.jidonline.org 2357 commentary

At this point the authors turned with earlier observations (De Haes et have mutations in Ptch1 or other alter-

their attention to UVR-induced skin al., 2003) that 1,25(OH)2D3 increases ations in Hh signaling (Aszterbaum tumors comparing VDR null mice with p53 levels and protects keratinocytes et al., 1999). This appreciation has wild-type controls. The mice were of from UVR-induced apoptosis (Gupta resulted in the development of the C57BL/6 background, a strain - et al., 2007), suggesting that VDR Ptch1+/– (Gorlin) mouse as the first

tively resistant to UVR-induced skin and 1,25(OH)2D3 might have oppo- practical model of murine BCC (Regl site effects in these responses to UVR. et al., 2004a). Treatment of these mice This possibility could be tested by (unlike treatment of Ptch1 wild-type comparing the responses in CYP27B1 mice) with UVR or ionizing radiation Protection by VDR for null mice to those in VDR null mice. produces BCC as well as SCC (Regl UVR-induced tumors. The proliferative response to UVR et al., 2004a). Ptch1 is the membrane was also slightly reduced in the VDR receptor for (Shh). | null , which, despite the In the absence of Shh, Ptch1 inhib- decrease in apoptosis, seems to have its the function of another membrane resulted in a thinner epidermis in the , (Smoh). Shh VDR null compared with wild-type reverses this inhibition, freeing Smoh tumors. Even at the very high doses of mice, although UVR induced epider- to enable the activation of a family of UVB used in these experiments, only mal thickening compared with the transcription factors, Gli1 and Gli2. 4 of 23 wild-type mice developed nonirradiated controls of either gen- Gli1 and -2 overexpression in keratin­ tumors by 45 weeks after the start of otype. This result is consistent with ocytes can increase the expression of UVR, 1 of which was classified as an earlier studies (De Haes et al., 2003; each other as well as Ptch1, the anti- SCC. In contrast, all 22 of the VDR null Gupta et al., 2007) demonstrating that apoptotic factor bcl2, cyclins D1 and

mice developed tumors, and 10 of the 1,25(OH)2D3 enhances cell survival in D2, , and cdc45 (all of which 27 tumors analyzed were classified as keratinocytes after UVR, but it again promote proliferation) while suppress- SCC, although markers to document raises the question of whether these ing associated with keratinocyte

this classification were not provided. are 1,25(OH)2D3-dependent or -inde- differentiation such as K1, K10, invo- Taken at face value, therefore, it would pendent actions of VDR. The finding of lucrin, loricrin and VDR (Grachtchouk appear that UVR-induced tumors in the thinner epidermis in the VDR null et al., 2000; Nilsson et al., 2000; Regl VDR null mice differ in type compared mouse relative to controls is surpris- et al., 2002, 2004a,b). Mice overex- with DMBA-induced tumors, with SCC ing, however, considering the higher pressing Gli1, Gli2, or Shh in their predominating following UVR and proliferation rates in the epidermis basal keratinocytes (Grachtchouk et BCC and folliculosebaceous tumors and underlying folliculosebaceous al., 2000; Nilsson et al., 2000; Oro et predominating after DMBA. unit of the VDR null mouse compared al., 1997) or grafted with human kera- Potential mechanisms were then with controls under basal conditions tinocytes overexpressing Shh (Fan et explored. The skin of VDR null mice (Bikle et al., 2006; Xie et al., 2002). al., 1997) develop BCC-like lesions. appeared to have greater cyclobutane What, then, might be the underlying Furthermore, BCCs demonstrate over- pyrimidine dimer formation following mechanisms? The DMBA studies pro- expression of Ptch1, Smoh, Gli1, and UVR, suggesting a DNA repair defi- ducing tumors primarily of folliculo­ Gli2 (Bonifas et al., 2001; Tojo et al., ciency. Previous studies with cultured sebaceous origin suggest that Hh 1999). A number of the Hh pathway keratinocytes have demonstrated that signaling might be altered in VDR null components, including both Gli1 and

1,25(OH)2D3 and analogs not thought skin. Appreciation of the pivotal role -2, have consensus vitamin D response to act via the nuclear configuration of of the Hh signaling pathway in epi- elements in their promoters (Palmer the VDR were also protective against dermal carcinogenesis began with the et al., 2008; Wang et al., 2005). We UVR-induced cyclobutane pyrimidine identification of the Ptch1 gene as the (A. Teichert, J. Welsh, and D. Bikle, dimer formation (or accelerated their site of mutations underlying the rare unpublished data) reported that the repair) (Dixon et al., 2005; Gupta et autosomal dominant heritable basal- epidermis and epidermal portion (utri- al., 2007). Ellison et al. (2008) did not cell nevus syndrome (Gorlin’s syn- cles) of the hair follicles of VDR null test whether CYP27B1 null mice were drome), one cardinal feature of which animals overexpress elements of the also predisposed to UVR-induced is a high susceptibility to the devel- Hh signaling pathway, suggesting that tumor formation, so the results in their opment of BCCs (Aszterbaum et al., one of the causes of the increased sus- article are silent as to whether this is 1998; Hahn et al., 1996). The BCCs in ceptibility of the epidermis to malig-

a 1,25(OH)2D3-independent action these subjects frequently lose function nant transformation is a loss of VDR of VDR. Apoptosis following a single of the inherited wild-type Ptch1 allele, regulation of Hh signaling. exposure to UVR was reduced in VDR leaving the tumor cells functionally The wnt signaling pathway may null mice, although no differences null of Ptch1. It has subsequently also be involved. In a recent paper, between wild-type and null mice were become clear that essentially all BCCs, Palmer et al. (2008) reported the inter- shown for p53 induction by UVR. whether arising in patients with basal action of VDR and wnt signaling in the These observations are discordant cell nevus syndrome or sporadically, regulation of differentiation

2358 Journal of Investigative Dermatology (2008), Volume 128 commentary

and tumor formation. The authors iden- trolled, and mutation rates and copy interaction with NER remains unclear. tified various combinations of puta- number changes increase by orders of However, when Moll et al. (2007) per- tive vitamin D response elements and magnitude (Bielas et al., 2006; Tlsty et formed microarray studies of kerati- lymphoid-enhancing factor/T-cell fac- al., 1989). nocytes treated with 1,25(OH)2D3 for tor response elements in a number of DDR from UV-induced photo- 24 hours, they observed an upregula- genes involved with epidermal and hair products has distinct G1 and S phase tion of two genes important for DDR: follicle differentiation, including com- responses. Nucleotide excision repair XPC and DDB2/XPE. Accordingly, ponents of the Hh signaling pathway (NER) in G1, for example, excises 1,25(OH)2D3 and VDR may be protec- such as Shh, Ptch2, and Gli1 and -2, UV photoproducts before onset of tive against UVR-induced epidermal as well as in LEF itself, the transcrip- DNA replication and thereby elimi- tumor formation by stimulating DDR tional partner for β-catenin critical for nates mutagenic lesions completely as well as by suppressing Hh and wnt wnt signaling. At least in colon cancer (Maher et al., 1979). The main sub- signaling. cells, 1,25(OH)2D3 inhibits the tumor- strates for NER are the UV photoprod- Ellison et al. (2008) make the impor- promoting properties of β-catenin ucts between adjacent pyrimidines: tant point that VDR serves as a tumor by inducing E-cadherin, to which cyclobutane pyrimidine dimers and suppressor not only for chemically β-catenin binds (Palmer et al., 2001), pyrimidine (6-4) pyrimidone photo- induced epidermal carcinogenesis but and promoting the binding of VDR products (Cleaver et al., 2005), lesions also for the more physiologically - to β-catenin (Shah et al., 2006), thus produced by UVB. Mutations in NER evant UVR-induced epidermal carcino- limiting its nuclear localization and genes are associated with several genesis. Although these authors have transcriptional activity. Palmer et al. human cancer and neurodegenerative convincingly demonstrated that the

(2008) demonstrated in skin that lack of diseases, especially xeroderma pig- former is a 1,25(OH)2D3-independent VDR predisposes the mouse to develop mentosum (XP) and Cockayne’s syn- action of VDR, this conclusion cannot BCC when active β-catenin was overex- drome (Hoeijmakers, 2001; Wood yet be extended to UVR-induced car- pressed, although the link to increased et al., 2001). Damage in transcribed cinogenesis. Earlier studies indicated Hh signaling was not explored. genes is recognized through the several mechanisms by which VDR,

In addition to suppression of Hh arrest of RNA Pol II, which is relieved with or without its ligand 1,25(OH)2D3, and wnt signaling, a third mechanism through the action of two , might be protective. These mechanisms may also be at work, the DNA damage CSA and CSB. Damage in the non- include altered Hh and wnt signal- response (DDR). Many endogenous transcribed or global regions of the ing and increased DDR. Future inves- and exogenous factors, including onco- genome is recognized by the binding tigations are required to determine genes, tumor suppressors, radiation, of two heterodimeric XP proteins, XPE which, if any, of these mechanisms are chemical carcinogens, and viral infec- (DDB1/DDB2) and XPC/HR23B, which involved and the degree to which VDR tions, impact a common, but complex, may act in concert to bind to damaged acts through these mechanisms in a set of pathways that regulate cellular DNA (Hoeijmakers, 2001). These con- 1,25(OH)2D3-dependent or -indepen- survival, apoptosis, and genomic sta- verge on a common pathway through dent manner. However, this publication bility: DDR and the cell cycle check- which the damage is verified (XPA/ establishes an important fact: the skin points (Bartkova et al., 2005, 2006). RPA), the DNA is unwound by the XPB has evolved a way of protecting itself DDR involves a cascade of damage and XPD helicase components of the from the deleterious actions of UVR recognition, repair, and signal trans- TFIIH, cleaved by using a key component of the pathway duction that coordinates the response structure-specific nucleases (XPG, promoted by UVR, namely, the VDR. of the cell cycle to DNA damage. DDR XPF/ERCC1), and the damage is activates checkpoints that delay the cell excised and replaced. The glob- CONFLICT OF INTEREST cycle, providing time for repair, and al branch of the NER (GGR: XP-A The author states no conflict of interest. directs damaged cells into senescent through G) pathway is strongly influ- ACKNOWLEDGMENTS or apoptotic pathways. DDR demon- enced by transactivation of the XPC The author appreciates helpful discussions strates wide variation in components, and XPE genes by p53 through DNA with James Cleaver, Dennis Oh, Yuko Oda, activation signals, and downstream damage-dependent increases in p53 and Arnaud Teichert regarding the content of the paper. The writing of the manuscript was consequences according to the cell expression. GGR defects increase car- supported in part by grants to the author from types, species, and damaging agents. cinogenesis (Berg et al., 2000). the National Institutes of Health (PO1 AR39448, DDR is tightly controlled and highly As noted above, recent studies have RO1 AR0550023), the Veterans Affairs Merit accurate in normal primary cells such shown that vitamin D may have a Review system, and the American Institute for Cancer Research. that the spontaneous mutation rate is strong regulatory effect on the capac- very low and changes in copy number ity of cells and skin to carry out DDR. References are negligible (Bielas et al., 2006; Tlsty, Treatment of the skin with 1,25(OH)2D3 Aszterbaum M, Rothman A, Johnson RL, Fisher 1990; Tlsty et al., 1989). During malig- rapidly increased photo­product exci- M, Xie J, Bonifas JM et al. (1998) Identification nant transformation, a DNA repair sion in human and mouse cells and of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients “barrier” is abrogated (Bartkova et al., tissues (Dixon et al., 2005; Gupta with the basal cell nevus syndrome. J Invest 2005, 2006), DDR becomes less con- et al., 2007), but the mechanism of Dermatol 110:885–8

www.jidonline.org 2359 commentary

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2360 Journal of Investigative Dermatology (2008), Volume 128 commentary

GLI is predominantly See related article on pg 2526 mediated by GLI2. Cancer Res 64:7724–31 Reifenberger J, Wolter M, Knobbe CB, Kohler B, Schonicke A, Scharwachter C et al. (2005) Oxidative Stress and “Senescent” Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 152:43–51 Fibroblasts in Non-Healing Wounds Shah S, Islam MN, Dakshanamurthy S, Rizvi I, Rao M, Herrell R et al. (2006) The molecular as Potential Therapeutic Targets basis of vitamin D receptor and beta-catenin 1 crossregulation. Mol Cell 21:799–809 Richard A.F. Clark Tlsty TD (1990) Normal diploid human and In chronic wounds, fibroblast dysfunctions, such as increased apoptosis, rodent cells lack a detectable frequency of premature senescence, senescence-like phenotype, or poor growth response in gene amplification. Proc Natl Acad Sci USA 87:3132–6 the absence of senescence markers, have been reported. Some of these differ- Tlsty TD, Margolin BH, Lum K (1989) Differences ential dysfunctions may be secondary to differences in patient age or sex, ulcer in the rates of gene amplification in size or duration, edge versus base sampling, or culture technique. Nevertheless, nontumorigenic and tumorigenic cell lines the entire spectrum of fibroblast dysfunction may exist and be secondary to, or as measured by Luria–Delbruck fluctuation a response to, different amounts of oxidative stress. analysis. Proc Natl Acad Sci USA 86:9441–5 Journal of Investigative Dermatology (2008), 128, 2361–2364. doi:10.1038/jid.2008.257 Tojo M, Mori T, Kiyosawa H, Honma Y, Tanno Y, Kanazawa KY et al. (1999) Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma. In their article entitled “Fibroblast group has identified a different chronic Pathol Int 49:687–94 dysfunction is a key factor in the non- wound fibroblast phenotype from the van Dam RM, Huang Z, Giovannucci E, Rimm healing of chronic venous leg ulcers,” ulcer bed than the previously described EB, Hunter DJ, Colditz GA et al. (2000) Diet Wall et al. (2008, this issue) demon- fibroblast phenotype from the ulcer and basal cell carcinoma of the skin in a strate that a telomere-independent margin. prospective cohort of men. Am J Clin Nutr 71:135–41 fibroblast abnormality occurs in chronic Nevertheless, the fibroblast pheno- venous leg ulcers and posit that oxida- types reported by all groups of investi- Wakabayashi Y, Mao JH, Brown K, Girardi M, Balmain A (2007) Promotion of Hras-induced tive stress underlies this dysfunctional gators are consistent with the variety of squamous carcinomas by a polymorphic behavior. Although it is dysfunctional, functional changes that can be induced variant of the Patched gene in FVB mice. the authors have clearly emphasized by oxidative stress on fibroblasts Nature 445:761–5 both here and in a previous publication (Wlaschek and Scharffetter-Kochanek, Wang TT, Tavera-Mendoza LE, Laperriere D, (Stephens et al., 2003) that the chronic 2005). As pointed out by Wall et al. Libby E, MacLeod NB, Nagai Y et al. (2005) wound fibroblast phenotype observed (2008), the oxidative effects on fibro- Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin by them does not represent the replica- blast phenotype and function depend D3 target genes. Mol Endocrinol 19:2685–95 tive senescence-like phenotype as has on the level and length of exposure Weinstock MA, Stampfer MJ, Lew RA, Willett been reported for chronic wound fibro- to reactive oxygen species (ROS). WC, Sober AJ (1992) Case–control study of blasts by a number of other investiga- Low-level, chronic exposure to ROS melanoma and dietary vitamin D: implications tors (Agren et al., 1999; Mendez et al., accelerates telomere shortening (von for advocacy of sun protection and sunscreen 1998; Stanley and Osler, 2001; Stanley Zglinicki, 2002), whereas high levels use. J Invest Dermatol 98:809–11 et al., 1997; Vande Berg et al., 1998, of ROS induce telomere-independent Wood RD, Mitchell M, Sgouros J, Lindahl T (2001) Human DNA repair genes. Science 2005). However, Stephens’s group iso- premature senescence (Song et al., 291:1284–9 lated their chronic wound fibroblasts 2005). Another important aspect of the Xie Z, Komuves L, Yu QC, Elalieh H, Ng DC, from biopsy specimens that come from cell “senescence” response to oxida- Leary C et al. (2002) Lack of the vitamin D the ulcer base while all other groups tive stress is cell age; aged human der- receptor is associated with reduced epidermal harvested chronic wound fibroblasts mal fibroblasts demonstrate increased differentiation and hair follicle growth. J Invest from the ulcer edge. Given the hetero- entrance into a senescent state com- Dermatol 118:11–6 geneity in growth response and other pared with their younger counter- Ziegler A, Leffell DJ, Kunala S, Sharma HW, functions among human fibroblasts parts when exposed to oxidative stress Gailani M, Simon JA et al. (1993) Mutation hotspots due to sunlight in the p53 gene of derived from either papillary or reticu- (Gurjala et al., 2005). Furthermore, nonmelanoma skin cancers. Proc Natl Acad lar dermis (Harper and Grove, 1979; depending on the physiologic state of Sci USA 90:4216–20 Sorrell et al., 2008; Sorrell and Caplan, the cell, oxidative stress can induce Ziegler A, Jonason AS, Leffell DJ, Simon JA, 2004), it is not surprising that Stephens’s apoptosis rather than senescence (Chen Sharma HW, Kimmelman J et al. (1994) Sunburn and p53 in the onset of skin cancer. Nature 372:773–6 1Departments of Biomedical Engineering, Dermatology, and Medicine, Stony Brook University, Stony Zinser GM, Sundberg JP, Welsh J (2002) Brook, New York, USA Vitamin D(3) receptor ablation sensitizes Correspondence: Dr Richard A.F. Clark, Center for Tissue Engineering, Department of Biomedical skin to chemically induced tumorigenesis. Engineering, Stony Brook University, HSC T-16, Room 060, Stony Brook, New York 11794-8165, USA. Carcinogenesis 23:2103–9 E-mail: [email protected]

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