Skip to main content
SpringerLink
Log in

UV and Skin: Photocarcinogenesis

  • Chapter
  • First Online:
Environment and Skin

Abstract

Because the annual incidence of nonmelanoma skin cancers (NMSCs), both basal cell carcinomas and squamous cell carcinomas, exceeds that of all other cancers combined, there is a need to understand the mechanisms by which these neoplasms occur in order to develop more effective methods for their prevention and therapy. Most are caused by overexposure to ultraviolet (UV) radiation; the discipline of photocarcinogenesis seeks to understand the pathogenesis of UV-induced skin cancers.

The sequence of events in which molecular and biochemical changes accumulate in keratinocytes over long periods of time has been divided into three distinct stages: initiation, promotion, and progression. During initiation, UV-induced DNA damage, primarily cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone 6-4 photoproducts (6-4PPs), form in keratinocytes. These photochemical changes cause mutations in TP53, Ptch, and other genes that control cell death, proliferation, and differentiation. During the promotion stage, repeated doses of UV cause chronic inflammation and encourage clonal expansion of initiated keratinocytes. The end results of promotion are premalignant actinic keratoses (AKs). In the progression stage, additional biochemical changes occur, such as epithelial-mesenchymal transition, which allows premalignant AKs to become invasive squamous cell carcinomas. In addition to these stages of photocarcinogenesis, UV radiation impairs host immune responses that have evolved to identify and neutralize mutant, premalignant, and malignant cells.

Recent advances in our understanding of photocarcinogenesis have resulted in new treatments, such as small molecule inhibitors of the hedgehog pathway. There are also many promising chemopreventive and chemotherapeutic agents under investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 99.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

6-4PP:

Pyrimidine-pyrimidone 6-4 photoproduct

8-oxoG:

8-Oxoguanine

AhR:

Arylhydrocarbon receptor

AK:

Actinic keratosis

AP:

Apurinic or apyrimidinic

AP-1:

Activator protein 1

APC:

Antigen-presenting cell

ARNT:

Aryl hydrocarbon receptor nuclear translocator

ATF:

Activating transcription factor

BCC:

Basal cell carcinoma

BER:

Base excision repair

CHS:

Contact hypersensitivity

CI:

Confidence interval

CK1-α:

Casein kinase 1 α

COX:

Cyclooxygenase

CPD:

Cyclobutane pyrimidine dimer

CS:

Cockayne syndrome

DAMP:

Damage associated molecular pattern

DFMO:

α-Difluoromethylornithine

DHH:

Desert Hedgehog

DNFB:

Dinitrofluorobenzene

DTH:

Delayed-type hypersensitivity

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular-signal-regulated kinase

FDA:

Food and Drug Administration

FICZ:

6-Formylindolo[3,2-b]carbazole

GG-NER:

Global genome nucleotide excision repair

GLI:

Glioma-associated oncogene

GSK3-β:

Glycogen synthase kinase 3 β

GWAS:

Genome-wide association study

HAF:

Hyaluronic acid fragments

HB-EGF:

Heparin-binding EGF

HCTZ:

Hydrochlorothiazide

Hh:

Hedgehog

IHH:

Indian Hedgehog

IKK:

IκB kinase

IL:

Interleukin

IRR:

Incidence rate ratio

IκB:

Inhibitor of NF-κB

JNK:

c-Jun amino-terminal kinase

LOX:

Lipoxygenase

MAF:

Musculoaponeurotic fibrosarcoma

MAPK:

Mitogen-activated protein kinase

MCR1:

Melanocortin 1 receptor

MM:

Malignant melanoma

MMP:

Matrix metalloproteinase

MyD88:

Myeloid differentiation factor-88

NAD:

Nicotinamide adenine dinucleotide

NBCCS:

Nevoid basal cell carcinoma syndrome

NEMO:

NF-κB Essential modulator

NER:

Nucleotide excision repair

NF-κB:

Nuclear factor κ-light-chain-enhancer of activated B cells

NK:

Natural killer

NMSC:

Nonmelanoma skin cancer

NSAID:

Nonsteroidal anti-inflammatory drug

ODC:

Ornithine decarboxylase

ONTRAC:

Oral Nicotinamide to Reduce Actinic Cancer

OR:

Odds ratio

PAMP:

Pathogen associated molecular pattern

PARP:

Poly-adenosine diphosphate ribose polymerase

PI3K:

Phosphoinositide 3-kinase

PKA:

Protein kinase A

PUVA:

Psoralen plus UVA

ROS:

Reactive oxygen species

RRR:

Relative rate reduction

SCC:

Squamous cell carcinoma

SCUP-h:

Skin Cancer Utrecht-Philadelphia-human

SCUP-m:

Skin Cancer Utrecht-Philadelphia-murine

SHH:

Sonic Hedgehog

SMO:

Smoothened

SPF:

Sun protection factor

SUFU:

Suppressor of fused

TC-NER:

Transcription-coupled nucleotide excision repair

TFIIH:

Transcription factor IIH

TGF:

Transforming growth factor

TLR:

Toll-like receptor

TNCB:

Trinitrochlorobenzene

TNF:

Tumor necrosis factor

Treg:

T regulatory cell, formerly known as suppressor T-cell

UV:

Ultraviolet

UVA:

Ultraviolet A (320–400 nm)

UVB:

Ultraviolet B (280–320 nm)

UVC:

Ultraviolet C (200–280 nm)

UVR:

Ultraviolet radiation

VATTC:

Veterans Affairs Topical Tretinoin Chemoprevention

VEGF:

Vascular endothelial growth factor

XP:

Xeroderma pigmentosum

References

  1. Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol. 2015;151(10):1081–6. doi:10.1001/jamadermatol.2015.1187.

    Article  PubMed  Google Scholar 

  2. American Cancer Society. Cancer facts & figures 2015. Atlanta: American Cancer Society; 2015.

    Google Scholar 

  3. Leiter U, Garbe C. Epidemiology of melanoma and nonmelanoma skin cancer—the role of sunlight. In: Reichrath J, editor. Sunlight, vitamin D and skin cancer. New York, NY: Springer; 2008. p. 89–103.

    Chapter  Google Scholar 

  4. Christenson LJ. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005;294:681. doi:10.1001/jama.294.6.681.

    Article  CAS  PubMed  Google Scholar 

  5. Collins GL, Nickoonahand N, Morgan MB. Changing demographics and pathology of nonmelanoma skin cancer in the last 30 years. Semin Cutan Med Surg. 2004;23:80–3.

    Article  PubMed  Google Scholar 

  6. Niederhuber JE, Armitage JO, Doroshow JH, et al. Abeloff’s clinical oncology. 5th ed. Philadelphia, PA: Elsevier; 2014.

    Google Scholar 

  7. Rhee JS, Matthews BA, Neuburg M, et al. Creation of a quality of life instrument for nonmelanoma skin cancer patients. Laryngoscope. 2005;115:1178–85. doi:10.1097/01.MLG.0000166177.98414.5E.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Guy GP, Machlin SR, Ekwueme DU, Yabroff KR. Prevalence and costs of skin cancer treatment in the U.S., 2002−2006 and 2007−2011. Am J Prev Med. 2015;48:183–7. doi:10.1016/j.amepre.2014.08.036.

    Article  PubMed  Google Scholar 

  9. Altmeyer P, Hoffmann K, Stücker M, editors. Skin cancer and UV radiation. Berlin, NY: Springer; 1997.

    Google Scholar 

  10. Norval M, Kellett P, Wright CY. The incidence and body site of skin cancers in the population groups of South Africa: skin cancers in South Africa. Photodermatol Photoimmunol Photomed. 2014;30:262–5. doi:10.1111/phpp.12106.

    Article  PubMed  Google Scholar 

  11. Madan V, Lear JT, Szeimies R-M. Non-melanoma skin cancer. Lancet. 2010;375:673–85. doi:10.1016/S0140-6736(09)61196-X.

    Article  CAS  PubMed  Google Scholar 

  12. Goldsmith LA, Fitzpatrick TB. Fitzpatrick’s dermatology in general medicine. New York: McGraw-Hill Medical; 2012.

    Google Scholar 

  13. Urbach F. The historical aspects of photocarcinogenesis. Front Biosci. 2002;7:e85–90.

    Article  CAS  PubMed  Google Scholar 

  14. Findlay GM. Ultra-violet light and skin cancer. CA Cancer J Clin. 1979;29:169–71.

    Article  CAS  PubMed  Google Scholar 

  15. Roffo A. Carcinomes et Sarcomes provoques par l’action du Soleil in toto. Bull Cancer. 1934;23:590–616.

    Google Scholar 

  16. Alberts B, editor. Molecular biology of the cell. 5th ed. Garland Science: New York; 2008.

    Google Scholar 

  17. Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol. 1996;122:135–40. doi:10.1007/BF01366952.

    Article  CAS  PubMed  Google Scholar 

  18. Schwab M (ed) (2011) Encyclopedia of cancer , 3rd ed. Springer, Heidelberg, NY.

    Google Scholar 

  19. National Institute of Environmental Health Sciences. National toxicology program (U.S.). 2014. Report on carcinogens.

    Google Scholar 

  20. Lim HW, Hönigsmann H, Hawk JLM. Photodermatology. New York: Informa Healthcare USA; 2007.

    Google Scholar 

  21. Strickland PT. Photocarcinogenesis by near-ultraviolet (UVA) radiation in Sencar mice. J Invest Dermatol. 1986;87:272–5.

    Article  CAS  PubMed  Google Scholar 

  22. Willis I, Menter JM, Whyte HJ. The rapid induction of cancers in the hairless mouse utilizing the principle of Photoaugmentation. J Invest Dermatol. 1981;76:404–8. doi:10.1111/1523-1747.ep12520945.

    Article  CAS  PubMed  Google Scholar 

  23. Cleaver JE. Defective repair replication of DNA in xeroderma pigmentosum. Nature. 1968;218(5142):652–6.

    Google Scholar 

  24. Cleaver JE. Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. 1969;63(2):428–35.

    Google Scholar 

  25. Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology (Williston Park). 2002;16:217–226, 229. discussion 230–232.

    Google Scholar 

  26. Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol. 1992;26:467–84.

    Article  CAS  PubMed  Google Scholar 

  27. Lee JM. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–81. doi:10.1083/jcb.200601018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Turro NJ, Ramamurthy V, Scaiano JC. Principles of molecular photochemistry: an introduction. Sausalito, CA: University Science Books; 2009.

    Google Scholar 

  29. Hsu TC, Young MR, Cmarik J, Colburn NH. Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-dependent transcriptional events in carcinogenesis. Free Radic Biol Med. 2000;28:1338–48.

    Article  CAS  PubMed  Google Scholar 

  30. Pfafflin JR, Ziegler EN. Encyclopedia of environmental science and engineering. New York: Taylor & Francis; 2006.

    Google Scholar 

  31. Preedy VR. Aging oxidative stress and dietary antioxidants. Burlington: Elsevier Science; 2014.

    Google Scholar 

  32. Blum H. Carcinogenesis by ultraviolet light. Princeton: Princeton University Press; 1959.

    Book  Google Scholar 

  33. Freeman RG. Data on the action spectrum for ultraviolet carcinogenesis. J Natl Cancer Inst. 1975;55:1119–22.

    Article  CAS  PubMed  Google Scholar 

  34. de Gruijl FR. Action spectrum for photocarcinogenesis. Recent Results Cancer Res. 1995;139:21–30.

    Article  PubMed  Google Scholar 

  35. de Gruijl FR, Sterenborg HJ, Forbes PD, et al. Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice. Cancer Res. 1993;53:53–60.

    PubMed  Google Scholar 

  36. Black HS, deGruijl FR, Forbes PD, et al. Photocarcinogenesis: an overview. J Photochem Photobiol B. 1997;40:29–47.

    Article  CAS  PubMed  Google Scholar 

  37. de Laat A, van der Leun JC, de Gruijl FR. Carcinogenesis induced by UVA (365-nm) radiation: the dose-time dependence of tumor formation in hairless mice. Carcinogenesis. 1997;18:1013–20.

    Article  PubMed  Google Scholar 

  38. van Weelden H, de Gruijl FR, van der Putte SC, et al. The carcinogenic risks of modern tanning equipment: is UV-A safer than UV-B? Arch Dermatol Res. 1988;280:300–7.

    Article  PubMed  Google Scholar 

  39. Setlow RB, Grist E, Thompson K, Woodhead AD. Wavelengths effective in induction of malignant melanoma. Proc Natl Acad Sci U S A. 1993;90:6666–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Colantonio S, Bracken MB, Beecker J. The association of indoor tanning and melanoma in adults: systematic review and meta-analysis. J Am Acad Dermatol. 2014;70:847–857.e1–18. doi:10.1016/j.jaad.2013.11.050.

    Article  PubMed  Google Scholar 

  41. Wehner MR, Shive ML, Chren M-M, et al. Indoor tanning and non-melanoma skin cancer: systematic review and meta-analysis. BMJ. 2012;345:e5909.

    Article  PubMed  PubMed Central  Google Scholar 

  42. de Gruijl FR, Van Der Meer JB, Van Der Leun JC. Dose-time dependency of tumor formation by chronic UV exposure. Photochem Photobiol. 1983;37:53–62. doi:10.1111/j.1751-1097.1983.tb04433.x.

    Article  PubMed  Google Scholar 

  43. Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B. 2001;63:8–18.

    Article  CAS  PubMed  Google Scholar 

  44. Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol. 1995;131:157–63.

    Article  CAS  PubMed  Google Scholar 

  45. Diffey BL. Solar ultraviolet radiation effects on biological systems. Phys Med Biol. 1991;36:299–328.

    Article  CAS  PubMed  Google Scholar 

  46. Urbach F. Ultraviolet radiation and skin cancer of humans. J Photochem Photobiol B. 1997;40:3–7.

    Article  CAS  PubMed  Google Scholar 

  47. Lee SG, Ko NY, Son SW, et al. The impact of ozone depletion on skin cancer incidence in Korea. Br J Dermatol. 2013;169:1164–5. doi:10.1111/bjd.12472.

    Article  CAS  PubMed  Google Scholar 

  48. US Environmental Protection Agency. Updating ozone calculations and emissions profiles for use in the atmospheric and health effects framework model. Washington, DC: U.S. Environmental Protection Agency; 2015.

    Google Scholar 

  49. Hill DJ, Elwood JM, English DR, editors. Prevention of skin cancer. Dordrecht; Boston: Kluwer Academic Publishers; 2004.

    Google Scholar 

  50. Wehner MR, Chren M-M, Nameth D, et al. International prevalence of indoor tanning: a systematic review and meta-analysis. JAMA Dermatol. 2014;150:390. doi:10.1001/jamadermatol.2013.6896.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cowan DO, Drisko RL. Elements of organic photochemistry. New York: Plenum Press; 1976.

    Book  Google Scholar 

  52. Beukers R, Eker APM, Lohman PHM. 50 years thymine dimer. DNA Repair. 2008;7:530–43. doi:10.1016/j.dnarep.2007.11.010.

    Article  CAS  PubMed  Google Scholar 

  53. You YH, Lee DH, Yoon JH, et al. Cyclobutane pyrimidine dimers are responsible for the vast majority of mutations induced by UVB irradiation in mammalian cells. J Biol Chem. 2001;276:44688–94. doi:10.1074/jbc.M107696200.

    Article  CAS  PubMed  Google Scholar 

  54. Sinha RP, Häder DP. UV-induced DNA damage and repair: a review. Photochem Photobiol Sci. 2002;1:225–36.

    Article  CAS  PubMed  Google Scholar 

  55. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol. 1995;33:551–73. quiz 574–576

    Article  CAS  PubMed  Google Scholar 

  56. Ley RD, Peak MJ, Lyon LL. Induction of pyrimidine dimers in epidermal DNA of hairless mice by UVB: an action spectrum. J Invest Dermatol. 1983;80:188–91.

    Article  CAS  PubMed  Google Scholar 

  57. de Gruijl FR, Van der Leun JC. Estimate of the wavelength dependency of ultraviolet carcinogenesis in humans and its relevance to the risk assessment of a stratospheric ozone depletion. Health Phys. 1994;67:319–25.

    Article  PubMed  Google Scholar 

  58. Young AR, Chadwick CA, Harrison GI, et al. The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema. J Invest Dermatol. 1998;111:982–8. doi:10.1046/j.1523-1747.1998.00436.x.

    Article  CAS  PubMed  Google Scholar 

  59. Bachelor MA, Bowden GT. UVA-mediated activation of signaling pathways involved in skin tumor promotion and progression. Semin Cancer Biol. 2004;14:131–8. doi:10.1016/j.semcancer.2003.09.017.

    Article  CAS  PubMed  Google Scholar 

  60. Mouret S, Baudouin C, Charveron M, et al. Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation. Proc Natl Acad Sci. 2006;103:13765–70. doi:10.1073/pnas.0604213103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tewari A, Sarkany RP, Young AR. UVA1 induces cyclobutane pyrimidine dimers but not 6-4 photoproducts in human skin in vivo. J Invest Dermatol. 2012;132:394–400. doi:10.1038/jid.2011.283.

    Article  CAS  PubMed  Google Scholar 

  62. de Gruijl FR. Skin cancer and solar UV radiation. Eur J Cancer. 1999;35:2003–9.

    Article  PubMed  Google Scholar 

  63. Pettijohn DE, Hanawalt PC. Deoxyribonucleic acid replication in bacteria following ultraviolet irradiation. Biochim Biophys Acta. 1963;72:127–9. doi:10.1016/0926-6550(63)90324-4.

    Article  CAS  PubMed  Google Scholar 

  64. Seeberg E, Eide L, Bjørås M. The base excision repair pathway. Trends Biochem Sci. 1995;20:391–7.

    Article  CAS  PubMed  Google Scholar 

  65. Ruven HJ, Seelen CM, Lohman PH, et al. Strand-specific removal of cyclobutane pyrimidine dimers from the p53 gene in the epidermis of UVB-irradiated hairless mice. Oncogene. 1994;9:3427–32.

    CAS  PubMed  Google Scholar 

  66. Bolognia J, Jorizzo JL, Schaffer JV. Dermatology. Philadelphia; London: Elsevier Saunders; 2012.

    Google Scholar 

  67. Burger A, Fix D, Liu H, et al. In vivo deamination of cytosine-containing cyclobutane pyrimidine dimers in E. coli: a feasible part of UV-mutagenesis. Mutat Res. 2003;522:145–56.

    Article  CAS  PubMed  Google Scholar 

  68. Choi J-H, Pfeifer GP. The role of DNA polymerase eta in UV mutational spectra. DNA Repair. 2005;4:211–20. doi:10.1016/j.dnarep.2004.09.006.

    Article  CAS  PubMed  Google Scholar 

  69. Lee D-H, Pfeifer GP. Deamination of 5-methylcytosines within cyclobutane pyrimidine dimers is an important component of UVB mutagenesis. J Biol Chem. 2003;278:10314–21. doi:10.1074/jbc.M212696200.

    Article  CAS  PubMed  Google Scholar 

  70. Song Q, Cannistraro VJ, Taylor J-S. Synergistic modulation of cyclobutane pyrimidine dimer photoproduct formation and deamination at a TmCG site over a full helical DNA turn in a nucleosome core particle. Nucleic Acids Res. 2014;42:13122–33. doi:10.1093/nar/gku1049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tu Y, Dammann R, Pfeifer GP. Sequence and time-dependent deamination of cytosine bases in UVB-induced cyclobutane pyrimidine dimers in vivo. J Mol Biol. 1998;284:297–311. doi:10.1006/jmbi.1998.2176.

    Article  CAS  PubMed  Google Scholar 

  72. Ziegler A, Leffell DJ, Kunala S, et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci U S A. 1993;90:4216–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Takasawa K. Chemical synthesis and translesion replication of a cis-syn cyclobutane thymine-uracil dimer. Nucleic Acids Res. 2004;32:1738–45. doi:10.1093/nar/gkh342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tessman I, Liu SK, Kennedy MA. Mechanism of SOS mutagenesis of UV-irradiated DNA: mostly error-free processing of deaminated cytosine. Proc Natl Acad Sci U S A. 1992;89:1159–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Stern RS. The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet a therapy: a 30-year prospective study. J Am Acad Dermatol. 2012;66:553–62. doi:10.1016/j.jaad.2011.04.004.

    Article  CAS  PubMed  Google Scholar 

  76. Karagas MR, Stukel TA, Umland V, et al. Reported use of photosensitizing medications and basal cell and squamous cell carcinoma of the skin: results of a population-based case-control study. J Invest Dermatol. 2007;127:2901–3. doi:10.1038/sj.jid.5700934.

    Article  CAS  PubMed  Google Scholar 

  77. Robinson SN, Zens MS, Perry AE, et al. Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study. J Invest Dermatol. 2013;133:1950–5. doi:10.1038/jid.2013.33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jensen AØ, Thomsen HF, Engebjerg MC, et al. Use of photosensitising diuretics and risk of skin cancer: a population-based case–control study. Br J Cancer. 2008;99:1522–8. doi:10.1038/sj.bjc.6604686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Schmidt SAJ, Schmidt M, Mehnert F, et al. Use of antihypertensive drugs and risk of skin cancer. J Eur Acad Dermatol Venereol. 2015;29:1545–54. doi:10.1111/jdv.12921.

    Article  CAS  PubMed  Google Scholar 

  80. Kaae J, Boyd HA, Hansen AV, et al. Photosensitizing medication use and risk of skin cancer. Cancer Epidemiol Biomarkers Prev. 2010;19:2942–9. doi:10.1158/1055-9965.EPI-10-0652.

    Article  CAS  PubMed  Google Scholar 

  81. Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62:31–7. doi:10.1016/j.jaad.2009.09.033.

    Article  CAS  PubMed  Google Scholar 

  82. Epaulard O, Saint-Raymond C, Villier C, et al. Multiple aggressive squamous cell carcinomas associated with prolonged voriconazole therapy in four immunocompromised patients. Clin Microbiol Infect. 2010;16:1362–4. doi:10.1111/j.1469-0691.2009.03124.x.

    Article  CAS  PubMed  Google Scholar 

  83. Ibrahim SF, Singer JP, Arron ST. Catastrophic squamous cell carcinoma in lung transplant patients treated with voriconazole. Dermatol Surg. 2010;36:1752–5. doi:10.1111/j.1524-4725.2010.01596.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. McCarthy KL, Playford EG, Looke DFM, Whitby M. Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged Voriconazole therapy. Clin Infect Dis. 2007;44:e55–6. doi:10.1086/511685.

    Article  CAS  PubMed  Google Scholar 

  85. Vadnerkar A, Nguyen MH, Mitsani D, et al. Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients. J Heart Lung Transplant. 2010;29:1240–4. doi:10.1016/j.healun.2010.05.022.

    Article  PubMed  Google Scholar 

  86. Vanacker A, Fabré G, Van Dorpe J, et al. Aggressive cutaneous squamous cell carcinoma associated with prolonged voriconazole therapy in a renal transplant patient. Am J Transplant. 2008;8:877–80. doi:10.1111/j.1600-6143.2007.02140.x.

    Article  CAS  PubMed  Google Scholar 

  87. Miller DD, Cowen EW, Nguyen JC, et al. Melanoma associated with long-term voriconazole therapy: a new manifestation of chronic photosensitivity. Arch Dermatol. 2010a;146:300–4. doi:10.1001/archdermatol.2009.362.

    CAS  PubMed  Google Scholar 

  88. Wikonkal NM, Brash DE. Ultraviolet radiation induced signature mutations in photocarcinogenesis. J Investig Dermatol Symp Proc. 1999;4:6–10.

    Article  CAS  PubMed  Google Scholar 

  89. Yin Y, Tainsky MA, Bischoff FZ, et al. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell. 1992;70:937–48.

    Article  CAS  PubMed  Google Scholar 

  90. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372:773–6. doi:10.1038/372773a0.

    Article  CAS  PubMed  Google Scholar 

  91. Berg RJ, van Kranen HJ, Rebel HG, et al. Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells. Proc Natl Acad Sci U S A. 1996;93:274–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–78.

    CAS  PubMed  Google Scholar 

  93. Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356:215–21. doi:10.1038/356215a0.

    Article  CAS  PubMed  Google Scholar 

  94. Jiang W, Ananthaswamy HN, Muller HK, Kripke ML. p53 protects against skin cancer induction by UV-B radiation. Oncogene. 1999;18:4247–53. doi:10.1038/sj.onc.1202789.

    Article  CAS  PubMed  Google Scholar 

  95. Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the hedgehog pathway in cancer. Nat Med. 2013;19:1410–22. doi:10.1038/nm.3389.

    Article  CAS  PubMed  Google Scholar 

  96. Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol. 2009;10:207–17. doi:10.1038/nrm2636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Burness CB. Sonidegib: first global approval. Drugs. 2015;75:1559–66. doi:10.1007/s40265-015-0458-y.

    Article  CAS  PubMed  Google Scholar 

  98. Rudin CM. Vismodegib. Clin Cancer Res. 2012;18:3218–22. doi:10.1158/1078-0432.CCR-12-0568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gorlin RJ. Nevoid basal cell carcinoma syndrome. Dermatol Clin. 1995;13:113–25.

    CAS  PubMed  Google Scholar 

  100. Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N Engl J Med. 1960;262:908–12. doi:10.1056/NEJM196005052621803.

    Article  CAS  PubMed  Google Scholar 

  101. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841–51.

    Article  CAS  PubMed  Google Scholar 

  102. Scales SJ, de Sauvage FJ. Mechanisms of hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30:303–12. doi:10.1016/j.tips.2009.03.007.

    Article  CAS  PubMed  Google Scholar 

  103. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743–54. doi:10.1038/nrc2503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Heitzer E, Lassacher A, Quehenberger F, et al. UV fingerprints predominate in the PTCH mutation spectra of basal cell carcinomas independent of clinical phenotype. J Invest Dermatol. 2007;127:2872–81. doi:10.1038/sj.jid.5700923.

    Article  CAS  PubMed  Google Scholar 

  105. Daya-Grosjean L, Sarasin A. The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors. Mutat Res. 2005;571:43–56. doi:10.1016/j.mrfmmm.2004.11.013.

    Article  CAS  PubMed  Google Scholar 

  106. Oro AE. Basal cell carcinomas in mice overexpressing Sonic hedgehog. Science. 1997;276:817–21. doi:10.1126/science.276.5313.817.

    Article  CAS  PubMed  Google Scholar 

  107. Athar M, Li C, Kim AL, et al. Sonic hedgehog signaling in basal cell nevus syndrome. Cancer Res. 2014;74:4967–75. doi:10.1158/0008-5472.CAN-14-1666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gober MD, Bashir HM, Seykora JT. Reconstructing skin cancers using animal models. Cancer Metastasis Rev. 2013;32:123–8. doi:10.1007/s10555-012-9410-8.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Grachtchouk M, Mo R, Yu S, et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet. 2000;24:216–7. doi:10.1038/73417.

    Article  CAS  PubMed  Google Scholar 

  110. Hutchin ME, Kariapper MST, Grachtchouk M, et al. Sustained hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev. 2005;19:214–23. doi:10.1101/gad.1258705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nilsson M, Undèn AB, Krause D, et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci U S A. 2000;97:3438–43. doi:10.1073/pnas.050467397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Xie J, Murone M, Luoh SM, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–2. doi:10.1038/34201.

    Article  CAS  PubMed  Google Scholar 

  113. Aszterbaum M, Epstein J, Oro A, et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med. 1999;5:1285–91. doi:10.1038/15242.

    Article  CAS  PubMed  Google Scholar 

  114. Soufir N, Molès JP, Vilmer C, et al. P16 UV mutations in human skin epithelial tumors. Oncogene. 1999;18:5477–81. doi:10.1038/sj.onc.1202915.

    Article  CAS  PubMed  Google Scholar 

  115. Saridaki Z, Liloglou T, Zafiropoulos A, et al. Mutational analysis of CDKN2A genes in patients with squamous cell carcinoma of the skin. Br J Dermatol. 2003;148:638–48.

    Article  CAS  PubMed  Google Scholar 

  116. Pierceall WE, Goldberg LH, Tainsky MA, et al. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog. 1991;4:196–202.

    Article  CAS  PubMed  Google Scholar 

  117. Van der Lubbe JL, Rosdorff HJ, Bos JL, Van der Eb AJ. Activation of N-ras induced by ultraviolet irradiation in vitro. Oncogene Res. 1988;3:9–20.

    PubMed  Google Scholar 

  118. Miller AJ, Tsao H. New insights into pigmentary pathways and skin cancer. Br J Dermatol. 2010;162:22–8. doi:10.1111/j.1365-2133.2009.09565.x.

    Article  CAS  PubMed  Google Scholar 

  119. Gudbjartsson DF, Sulem P, Stacey SN, et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet. 2008;40:886–91. doi:10.1038/ng.161.

    Article  CAS  PubMed  Google Scholar 

  120. Stacey SN, Sulem P, Masson G, et al. New common variants affecting susceptibility to basal cell carcinoma. Nat Genet. 2009;41:909–14. doi:10.1038/ng.412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wei YD, Helleberg H, Rannug U, Rannug A. Rapid and transient induction of CYP1A1 gene expression in human cells by the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. Chem Biol Interact. 1998;110:39–55.

    Article  CAS  PubMed  Google Scholar 

  122. Enan E, Matsumura F. Identification of c-Src as the integral component of the cytosolic ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochem Pharmacol. 1996;52:1599–612.

    Article  CAS  PubMed  Google Scholar 

  123. Kitagawa D, Tanemura S, Ohata S, et al. Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation. Its implication in an anti-apoptotic function. J Biol Chem. 2002;277:366–71. doi:10.1074/jbc.M107110200.

    Article  CAS  PubMed  Google Scholar 

  124. Köhle C, Gschaidmeier H, Lauth D, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells. Arch Toxicol. 1999;73:152–8.

    Article  PubMed  Google Scholar 

  125. Krutmann J, Morita A, Chung JH. Sun exposure: what molecular photodermatology tells us about its good and bad sides. J Invest Dermatol. 2012;132:976–84. doi:10.1038/jid.2011.394.

    Article  CAS  PubMed  Google Scholar 

  126. Fritsche E, Schäfer C, Calles C, et al. Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A. 2007;104:8851–6. doi:10.1073/pnas.0701764104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol. 2009;9:351–69. doi:10.1016/j.coph.2009.06.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Devary Y, Rosette C, DiDonato JA, Karin M. NF-kappa B activation by ultraviolet light not dependent on a nuclear signal. Science. 1993;261:1442–5.

    Article  CAS  PubMed  Google Scholar 

  129. Simon MM, Aragane Y, Schwarz A, et al. UVB light induces nuclear factor kappaB (NFkappaB) activity independently from chromosomal DNA damage in cell-free cytosolic extracts. J Invest Dermatol. 1994;102:422–7. doi:10.1111/1523-1747.ep12372194.

    Article  CAS  PubMed  Google Scholar 

  130. Vile GF, Tanew-Ilitschew A, Tyrrell RM. Activation of NF-kappa B in human skin fibroblasts by the oxidative stress generated by UVA radiation. Photochem Photobiol. 1995;62:463–8.

    Article  CAS  PubMed  Google Scholar 

  131. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–76. doi:10.1146/annurev.immunol.21.120601.141126.

    Article  CAS  PubMed  Google Scholar 

  132. Mills KHG. TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011;11:807–22. doi:10.1038/nri3095.

    CAS  PubMed  Google Scholar 

  133. Byrd-Leifer CA, Block EF, Takeda K, et al. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur J Immunol. 2001;31:2448–57. doi:10.1002/1521-4141(200108)31:8<2448::AID-IMMU2448>3.0.CO;2-N.

    Article  CAS  PubMed  Google Scholar 

  134. Okamura Y, Watari M, Jerud ES, et al. The extra domain a of fibronectin activates toll-like receptor 4. J Biol Chem. 2001;276:10229–33. doi:10.1074/jbc.M100099200.

    Article  CAS  PubMed  Google Scholar 

  135. Termeer C, Benedix F, Sleeman J, et al. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med. 2002;195:99–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ohashi K, Burkart V, FLohe S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol. 2000;164(2):558–61.

    Google Scholar 

  137. Kwon M-J, Han J, Kim BH, et al. Superoxide dismutase 3 suppresses hyaluronic acid fragments mediated skin inflammation by inhibition of toll-like receptor 4 signaling pathway: superoxide dismutase 3 inhibits reactive oxygen species-induced trafficking of toll-like receptor 4 to lipid rafts. Antioxid Redox Signal. 2012;16:297–313. doi:10.1089/ars.2011.4066.

    Article  CAS  PubMed  Google Scholar 

  138. Kurimoto I, Streilein JW. Characterization of the immunogenetic basis of ultraviolet-B light effects on contact hypersensitivity induction. Immunology. 1994;81:352–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Lewis W, Simanyi E, Li H, et al. Regulation of ultraviolet radiation induced cutaneous photoimmunosuppression by toll-like receptor-4. Arch Biochem Biophys. 2011;508:171–7. doi:10.1016/j.abb.2011.01.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yoshikawa T, Rae V, Bruins-Slot W, et al. Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans. J Invest Dermatol. 1990;95:530–6.

    Article  CAS  PubMed  Google Scholar 

  141. Ahmad I, Simanyi E, Guroji P, Tamimi IA, delaRosa HJ, Nagar A, Nagar P, Katiyar SK, Elmets CA, Yusuf N. Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism. J Invest Dermatol. 2014;134(6):1710–7.

    Google Scholar 

  142. Gao J, Li J, Ma L. Regulation of EGF-induced ERK/MAPK activation and EGFR internalization by G protein-coupled receptor kinase 2. Acta Biochim Biophys Sin. 2005;37:525–31.

    Article  CAS  PubMed  Google Scholar 

  143. Pastore S, Mascia F, Mariotti F, et al. ERK1/2 regulates epidermal chemokine expression and skin inflammation. J Immunol. 2005;174:5047–56.

    Article  CAS  PubMed  Google Scholar 

  144. Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 2004;68:320–44. doi:10.1128/MMBR.68.2.320-344.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 2004;23:2838–49. doi:10.1038/sj.onc.1207556.

    Article  CAS  PubMed  Google Scholar 

  146. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–6. doi:10.1038/ncb0502-e131.

    Article  CAS  PubMed  Google Scholar 

  147. Rosette C, Karin M. Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science. 1996;274:1194–7.

    Article  CAS  PubMed  Google Scholar 

  148. Chouinard N, Valerie K, Rouabhia M, Huot J. UVB-mediated activation of p38 mitogen-activated protein kinase enhances resistance of normal human keratinocytes to apoptosis by stabilizing cytoplasmic p53. Biochem J. 2002;365:133–45. doi:10.1042/BJ20020072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Muthusamy V, Piva TJ. The UV response of the skin: a review of the MAPK, NFkappaB and TNFalpha signal transduction pathways. Arch Dermatol Res. 2010;302:5–17. doi:10.1007/s00403-009-0994-y.

    Article  CAS  PubMed  Google Scholar 

  150. Assefa Z, Garmyn M, Bouillon R, et al. Differential stimulation of ERK and JNK activities by ultraviolet B irradiation and epidermal growth factor in human keratinocytes. J Invest Dermatol. 1997;108:886–91.

    Article  CAS  PubMed  Google Scholar 

  151. An KP, Athar M, Tang X, et al. Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches. Photochem Photobiol. 2002;76:73–80.

    Article  CAS  PubMed  Google Scholar 

  152. Rundhaug JE, Fischer SM. Cyclo-oxygenase-2 plays a critical role in UV-induced skin carcinogenesis. Photochem Photobiol. 2008;84:322–9. doi:10.1111/j.1751-1097.2007.00261.x.

    Article  CAS  PubMed  Google Scholar 

  153. Tang X, Kim AL, Kopelovich L, et al. Cyclooxygenase-2 inhibitor nimesulide blocks ultraviolet B-induced photocarcinogenesis in SKH-1 hairless mice. Photochem Photobiol. 2008;84:522–7. doi:10.1111/j.1751-1097.2008.00303.x.

    Article  CAS  PubMed  Google Scholar 

  154. Thiagalingam S, editor. Systems biology of cancer. Cambridge: Cambridge University Press; 2015.

    Google Scholar 

  155. Bachelor MA, Cooper SJ, Sikorski ET, Bowden GT. Inhibition of p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase decreases UVB-induced activator protein-1 and cyclooxygenase-2 in a SKH-1 hairless mouse model. Mol Cancer Res MCR. 2005;3:90–9. doi:10.1158/1541-7786.MCR-04-0065.

    Article  CAS  PubMed  Google Scholar 

  156. Chen W, Bowden GT. Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes. Oncogene. 1999;18:7469–76. doi:10.1038/sj.onc.1203210.

    Article  CAS  PubMed  Google Scholar 

  157. Tang Q, Gonzales M, Inoue H, Bowden GT. Roles of Akt and glycogen synthase kinase 3beta in the ultraviolet B induction of cyclooxygenase-2 transcription in human keratinocytes. Cancer Res. 2001;61:4329–32.

    CAS  PubMed  Google Scholar 

  158. Mahns A, Wolber R, Stäb F, et al. Contribution of UVB and UVA to UV-dependent stimulation of cyclooxygenase-2 expression in artificial epidermis. Photochem Photobiol Sci. 2004;3:257–62. doi:10.1039/b309067a.

    Article  CAS  PubMed  Google Scholar 

  159. Santos AL, Oliveira V, Baptista I, et al. Wavelength dependence of biological damage induced by UV radiation on bacteria. Arch Microbiol. 2013;195:63–74. doi:10.1007/s00203-012-0847-5.

    Article  CAS  PubMed  Google Scholar 

  160. Gilmour SK.Polyamines and nonmelanoma skin cancer. Toxicol Appl Pharmacol. 2007;224(3):249–56.

    Google Scholar 

  161. Hillebrand GG, Winslow MS, Benzinger MJ, Heitmeyer DA, Bissett DL. Acute and chronic ultraviolet radiation induction of epidermal ornithine decarboxylase activity in hairless mice. Cancer Res. 1990;50(5):1580–4.

    Google Scholar 

  162. Tang X, Kim AL, Feith DJ, Pegg AE, Russo J, Zhang H, Aszterbaum M, Kopelovich L, Epstein EH Jr, Bickers DR, Athar M. Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice. J Clin Invest. 2004;113(6):867–75.

    Google Scholar 

  163. Bailey HH, Kim K, Verma AK, et al. A randomized, double-blind, placebo-controlled phase 3 skin cancer prevention study of {alpha}-difluoromethylornithine in subjects with previous history of skin cancer. Cancer Prev Res (Phila). 2010;3:35–47. doi:10.1158/1940-6207.CAPR-09-0096.

    Article  CAS  Google Scholar 

  164. Elmets CA, Cala CM, Xu H. Photoimmunology. Dermatol Clin. 2014;32:277–290., vii. doi:10.1016/j.det.2014.03.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ullrich SE, Byrne SN. The immunologic revolution: photoimmunology. J Invest Dermatol. 2012;132:896–905. doi:10.1038/jid.2011.405.

    Article  CAS  PubMed  Google Scholar 

  166. Kripke ML. Antigenicity of murine skin tumors induced by ultraviolet light. J Natl Cancer Inst. 1974;53:1333–6.

    Article  CAS  PubMed  Google Scholar 

  167. Fisher MS, Kripke ML. Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis. Proc Natl Acad Sci U S A. 1977;74:1688–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Sreevidya CS, Fukunaga A, Khaskhely NM, et al. Agents that reverse UV-induced immune suppression and photocarcinogenesis affect DNA repair. J Invest Dermatol. 2010;130:1428–37. doi:10.1038/jid.2009.329.

    Article  CAS  PubMed  Google Scholar 

  169. Kripke ML, Fidler IJ. Enhanced experimental metastasis of ultraviolet light-induced fibrosarcomas in ultraviolet light-irradiated syngeneic mice. Cancer Res. 1980;40:625–9.

    CAS  PubMed  Google Scholar 

  170. Elmets CA, Bergstresser PR, Tigelaar RE, et al. Analysis of the mechanism of unresponsiveness produced by haptens painted on skin exposed to low dose ultraviolet radiation. J Exp Med. 1983;158:781–94.

    Article  CAS  PubMed  Google Scholar 

  171. Greene MI, Sy MS, Kripke M, Benacerraf B. Impairment of antigen-presenting cell function by ultraviolet radiation. Proc Natl Acad Sci U S A. 1979;76:6591–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Haniszko J, Suskind RR. The effect of ultraviolet radiation on experimental cutaneous sensitization in guinea pigs. J Invest Dermatol. 1963;40:183–91.

    Article  CAS  PubMed  Google Scholar 

  173. Jessup JM, Hanna N, Palaszynski E, Kripke ML. Mechanisms of depressed reactivity to dinitrochlorobenzene and ultraviolet-induced tumors during ultraviolet carcinogenesis in BALB/c mice. Cell Immunol. 1978;38:105–15. doi:10.1016/0008-8749(78)90036-9.

    Article  CAS  PubMed  Google Scholar 

  174. Morison WL, Parrish JA, Woehler ME, et al. Influence of PUVA and UVB radiation on delayed hypersensitivity in the guinea pig. J Invest Dermatol. 1981;76:484–8.

    Article  CAS  PubMed  Google Scholar 

  175. Morison WL, Pike RA, Kripke ML. Effect of sunlight and its component wavebands on contact hypersensitivity in mice and guinea pigs. Photo-Dermatology. 1985;2:195–204.

    CAS  PubMed  Google Scholar 

  176. Toews GB, Bergstresser PR, Streilein JW. Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J Immunol. 1980;124:445–53.

    CAS  PubMed  Google Scholar 

  177. Fukunaga A, Khaskhely NM, Sreevidya CS, et al. Dermal dendritic cells, and not Langerhans cells, play an essential role in inducing an immune response. J Immunol. 2008;180:3057–64. doi:10.4049/jimmunol.180.5.3057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Kaplan DH. In vivo function of Langerhans cells and dermal dendritic cells. Trends Immunol. 2010;31:446–51. doi:10.1016/j.it.2010.08.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Mathers AR, Larregina AT. Professional antigen-presenting cells of the skin. Immunol Res. 2006;36:127–36. doi:10.1385/IR:36:1:127.

    Article  CAS  PubMed  Google Scholar 

  180. Fisher MS, Kripke ML. Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice. Science. 1982;216:1133–4.

    Article  CAS  PubMed  Google Scholar 

  181. Fisher MS, Kripke ML. Further studies on the tumor-specific suppressor cells induced by ultraviolet radiation. J Immunol. 1978;121:1139–44.

    CAS  PubMed  Google Scholar 

  182. Kripke ML, Thorn RM, Lill PH, et al. Further characterization of immunological unresponsiveness induced in mice by ultraviolet radiation. Growth and induction of nonultraviolet-induced tumors in ultraviolet-irradiated mice. Transplantation. 1979;28:212–7.

    Article  CAS  PubMed  Google Scholar 

  183. Lehtimäki S, Lahesmaa R. Regulatory T cells control immune responses through their non-redundant tissue specific features. Front Immunol. 2013; doi:10.3389/fimmu.2013.00294.

  184. Fukunaga A, Khaskhely NM, Ma Y, et al. Langerhans cells serve as immunoregulatory cells by activating NKT cells. J Immunol. 2010;185:4633–40. doi:10.4049/jimmunol.1000246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Loser K, Mehling A, Loeser S, et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006;12:1372–9. doi:10.1038/nm1518.

    Article  CAS  PubMed  Google Scholar 

  186. Aubin F. Mechanisms involved in ultraviolet light-induced immunosuppression. Eur J Dermatol EJD. 2003;13:515–23.

    CAS  PubMed  Google Scholar 

  187. Clydesdale GJ, Dandie GW, Muller HK. Ultraviolet light induced injury: immunological and inflammatory effects. Immunol Cell Biol. 2001;79:547–68. doi:10.1046/j.1440-1711.2001.01047.x.

    Article  CAS  PubMed  Google Scholar 

  188. Cooper KD, Oberhelman L, Hamilton TA, et al. UV exposure reduces immunization rates and promotes tolerance to epicutaneous antigens in humans: relationship to dose, CD1a-DR+ epidermal macrophage induction, and Langerhans cell depletion. Proc Natl Acad Sci U S A. 1992;89:8497–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Kang K, Hammerberg C, Meunier L, Cooper KD. CD11b+ macrophages that infiltrate human epidermis after in vivo ultraviolet exposure potently produce IL-10 and represent the major secretory source of epidermal IL-10 protein. J Immunol. 1994;153:5256–64.

    CAS  PubMed  Google Scholar 

  190. Moodycliffe AM, Nghiem D, Clydesdale G, Ullrich SE. Immune suppression and skin cancer development: regulation by NKT cells. Nat Immunol. 2000;1:521–5. doi:10.1038/82782.

    Article  CAS  PubMed  Google Scholar 

  191. Starcher B. Role for tumour necrosis factor-alpha receptors in ultraviolet-induced skin tumours. Br J Dermatol. 2000;142:1140–7.

    Article  CAS  PubMed  Google Scholar 

  192. Bernard JJ, Cowing-Zitron C, Nakatsuji T, et al. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med. 2012;18:1286–90. doi:10.1038/nm.2861.

    Article  CAS  PubMed  Google Scholar 

  193. Elmets CA, LeVine MJ, Bickers DR. Action spectrum studies for induction of immunologic unresponsiveness to dinitrofluorobenzene following in vivo low dose ultraviolet radiation. Photochem Photobiol. 1985;42:391–7. doi:10.1111/j.1751-1097.1985.tb01586.x.

    Article  CAS  PubMed  Google Scholar 

  194. Kripke ML, Cox PA, Alas LG, Yarosh DB. Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice. Proc Natl Acad Sci U S A. 1992;89:7516–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Majewski S, Jantschitsch C, Maeda A, et al. IL-23 antagonizes UVR-induced immunosuppression through two mechanisms: reduction of UVR-induced DNA damage and inhibition of UVR-induced regulatory T cells. J Invest Dermatol. 2010;130:554–62. doi:10.1038/jid.2009.274.

    Article  CAS  PubMed  Google Scholar 

  196. Schmitt DA, Owen-Schaub L, Ullrich SE. Effect of IL-12 on immune suppression and suppressor cell induction by ultraviolet radiation. J Immunol. 1995;154:5114–20.

    CAS  PubMed  Google Scholar 

  197. Schwarz A, Grabbe S, Aragane Y, et al. Interleukin-12 prevents ultraviolet B-induced local immunosuppression and overcomes UVB-induced tolerance. J Invest Dermatol. 1996;106:1187–91.

    Article  CAS  PubMed  Google Scholar 

  198. Schwarz A, Maeda A, Ständer S, et al. IL-18 reduces ultraviolet radiation-induced DNA damage and thereby affects photoimmunosuppression. J Immunol. 2006;176:2896–901.

    Article  CAS  PubMed  Google Scholar 

  199. Schwarz A, Ständer S, Berneburg M, et al. Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. Nat Cell Biol. 2002;4:26–31. doi:10.1038/ncb717.

    Article  CAS  PubMed  Google Scholar 

  200. Schwarz T. 25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells. Photochem Photobiol. 2008;84:10–8. doi:10.1111/j.1751-1097.2007.00223.x.

    Article  CAS  PubMed  Google Scholar 

  201. Gaspari AA, Fleisher TA, Kraemer KH. Impaired interferon production and natural killer cell activation in patients with the skin cancer-prone disorder, xeroderma pigmentosum. J Clin Invest. 1993;92:1135–42. doi:10.1172/JCI116682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Walterscheid JP, Nghiem DX, Kazimi N, et al. Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor. Proc Natl Acad Sci U S A. 2006;103:17420–5. doi:10.1073/pnas.0603119103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Silverberg MJ, Leyden W, Warton EM, et al. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst. 2013;105:350–60. doi:10.1093/jnci/djs529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91. doi:10.1056/NEJMra022137.

    Article  PubMed  Google Scholar 

  205. Martinez J-C, Otley CC, Stasko T, et al. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139:301–6.

    Article  PubMed  Google Scholar 

  206. Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol. 1992;26:976–90. doi:10.1016/0190-9622(92)70144-5.

    Article  CAS  PubMed  Google Scholar 

  207. Kelly GE, Meikle W, Sheil AG. Scheduled and unscheduled DNA synthesis in epidermal cells of hairless mice treated with immunosuppressive drugs and UVB-UVA irradiation. Br J Dermatol. 1987;117:429–40.

    Article  CAS  PubMed  Google Scholar 

  208. Yarosh DB, Pena AV, Nay SL, et al. Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation. J Invest Dermatol. 2005;125:1020–5. doi:10.1111/j.0022-202X.2005.23858.x.

    Article  CAS  PubMed  Google Scholar 

  209. Adami J, Frisch M, Yuen J, et al. Evidence of an association between non-Hodgkin’s lymphoma and skin cancer. BMJ. 1995;310:1491–5. doi:10.1136/bmj.310.6993.1491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Weimar VM, Ceilley RI, Goeken JA. Cell-mediated immunity in patients with basal and squamous cell skin cancer. J Am Acad Dermatol. 1980;2:143–7.

    Article  CAS  PubMed  Google Scholar 

  211. Kaporis HG, Guttman-Yassky E, Lowes MA, et al. Human basal cell carcinoma is associated with Foxp3+ T cells in a Th2 dominant microenvironment. J Invest Dermatol. 2007;127:2391–8. doi:10.1038/sj.jid.5700884.

    Article  CAS  PubMed  Google Scholar 

  212. Volden G, Molin L, Thomsen K. PUVA-induced suppression of contact sensitivity to mustine hydrochloride in mycosis fungoides. Br Med J. 1978;2:865–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Morison WL, Wimberly J, Parrish JA, Bloch KJ. Abnormal lymphocyte function following long-term PUVA therapy for psoriasis. Br J Dermatol. 1983;108:445–50.

    Article  CAS  PubMed  Google Scholar 

  214. Moscicki RA, Morison WL, Parrish JA, et al. Reduction of the fraction of circulating helper-inducer T cells identified by monoclonal antibodies in psoriatic patients treated with long-term psoralen/ultraviolet-a radiation (PUVA). J Invest Dermatol. 1982;79:205–8.

    Article  CAS  PubMed  Google Scholar 

  215. Ad Hoc Task Force, Connolly SM, Baker DR, et al. AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol. 2012;67:531–50. doi:10.1016/j.jaad.2012.06.009.

    Article  Google Scholar 

  216. Cancer Council Australia, Australian Cancer Network. Clinical practice guide: basal cell carcinoma, squamous cell carcinoma (and related lesions): a guide to clinical management in Australia. Sydney, N.S.W: Cancer Council Australia; 2008.

    Google Scholar 

  217. Gupta AK, Paquet M, Villanueva E, Brintnell W. Interventions for actinic keratoses. In: The Cochrane collaboration, editor. Cochrane database of systematic reviews. Chichester: John Wiley & Sons, Ltd; 2012.

    Google Scholar 

  218. Miller SJ, Alam M, Andersen J, et al. Basal cell and squamous cell skin cancers. J Natl Compr Cancer Netw. 2010b;8:836–64.

    Article  Google Scholar 

  219. Stasko T, Brown MD, Carucci JA, et al. Guidelines for the Management of Squamous Cell Carcinoma in organ transplant recipients. Dermatol Surg. 2004;30:642–50. doi:10.1111/j.1524-4725.2004.30150.x.

    PubMed  Google Scholar 

  220. Stockfleth E, Ferrandiz C, Grob JJ, et al. Development of a treatment algorithm for actinic keratoses: a European consensus. Eur J Dermatol. 2008;18:651–9. doi:10.1684/ejd.2008.0514.

    PubMed  Google Scholar 

  221. Szeimies R-M, Bichel J, Ortonne J-P, et al. A phase II dose-ranging study of topical resiquimod to treat actinic keratosis. Br J Dermatol. 2008;159:205–10. doi:10.1111/j.1365-2133.2008.08615.x.

    Article  CAS  PubMed  Google Scholar 

  222. Zhang G, Dass CR, Sumithran E, et al. Effect of deoxyribozymes targeting c-Jun on solid tumor growth and angiogenesis in rodents. J Natl Cancer Inst. 2004;96:683–96.

    Article  CAS  PubMed  Google Scholar 

  223. Cho E-A, Moloney FJ, Cai H, et al. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER). Lancet. 2013;381:1835–43. doi:10.1016/S0140-6736(12)62166-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used antifungal that inhibits hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17:388–99. doi:10.1016/j.ccr.2010.02.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014;32:745–51. doi:10.1200/JCO.2013.49.9525.

    Article  CAS  PubMed  Google Scholar 

  226. Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Arch Dermatol. 2007;143:889–92. doi:10.1001/archderm.143.7.889.

    Article  CAS  PubMed  Google Scholar 

  227. Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol. 2011;29:3419–26. doi:10.1200/JCO.2010.34.1735.

    Article  CAS  PubMed  Google Scholar 

  228. Giacchero D, Barrière J, Benezery K, et al. Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma--a report of eight cases. Clin Oncol (R Coll Radiol). 2011;23:716–8. doi:10.1016/j.clon.2011.07.007.

    Article  CAS  Google Scholar 

  229. Eder J, Simonitsch-Klupp I, Trautinger F. Treatment of unresectable squamous cell carcinoma of the skin with epidermal growth factor receptor antibodies--a case series. Eur J Dermatol. 2013;23:658–62. doi:10.1684/ejd.2013.2153.

    CAS  PubMed  Google Scholar 

  230. Foote MC, McGrath M, Guminski A, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Ann Oncol. 2014;25:2047–52. doi:10.1093/annonc/mdu368.

    Article  CAS  PubMed  Google Scholar 

  231. Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012;18:1435–46. doi:10.1158/1078-0432.CCR-11-1951.

    Article  CAS  PubMed  Google Scholar 

  232. Khan N, Afaq F, Mukhtar H. Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal. 2008;10:475–510. doi:10.1089/ars.2007.1740.

    Article  CAS  PubMed  Google Scholar 

  233. Sambandan DR, Ratner D. Sunscreens: an overview and update. J Am Acad Dermatol. 2011;64:748–58. doi:10.1016/j.jaad.2010.01.005.

    Article  CAS  PubMed  Google Scholar 

  234. Green A, Williams G, Neale R, 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. doi:10.1016/S0140-6736(98)12168-2.

    Article  CAS  PubMed  Google Scholar 

  235. Naylor MF, Boyd A, Smith DW, et al. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol. 1995;131:170–5.

    Article  CAS  PubMed  Google Scholar 

  236. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med. 1993;329:1147–51. doi:10.1056/NEJM199310143291602.

    Article  CAS  PubMed  Google Scholar 

  237. Ulrich C, Jürgensen JS, Degen A, et al. Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study. Br J Dermatol. 2009;161(Suppl 3):78–84. doi:10.1111/j.1365-2133.2009.09453.x.

    Article  PubMed  Google Scholar 

  238. van der Pols JC, Williams GM, Pandeya N, et al. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomarkers Prev. 2006;15:2546–8. doi:10.1158/1055-9965.EPI-06-0352.

    Article  PubMed  Google Scholar 

  239. Harvey I, Frankel S, Marks R, et al. Non-melanoma skin cancer and solar keratoses II analytical results of the South Wales skin cancer study. Br J Cancer. 1996;74:1308–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Handel AE, Ramagopalan SV. The questionable effectiveness of sunscreen. Lancet. 2010;376:161–162.; author reply 162. doi:10.1016/S0140-6736(10)61104-X.

    Article  PubMed  Google Scholar 

  241. Hood WF, Gierse JK, Isakson PC, et al. Characterization of celecoxib and valdecoxib binding to cyclooxygenase. Mol Pharmacol. 2003;63:870–7.

    Article  CAS  PubMed  Google Scholar 

  242. Elmets CA, Viner JL, Pentland AP, et al. Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst. 2010;102:1835–44. doi:10.1093/jnci/djq442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Weinstock MA, Bingham SF, Lew RA, et al. Topical tretinoin therapy and all-cause mortality. Arch Dermatol. 2009;145:18–24. doi:10.1001/archdermatol.2008.542.

    Article  PubMed  Google Scholar 

  244. Kadakia KC, Barton DL, Loprinzi CL, et al. Randomized controlled trial of acitretin versus placebo in patients at high-risk for basal cell or squamous cell carcinoma of the skin (north central cancer treatment group study 969251). Cancer. 2012;118:2128–37. doi:10.1002/cncr.26374.

    Article  CAS  PubMed  Google Scholar 

  245. Cafardi JA, Shafi R, Athar M, Elmets CA. Prospects for skin cancer treatment and prevention: the potential contribution of an engineered virus. J Invest Dermatol. 2011;131:559–61. doi:10.1038/jid.2010.394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. DeBoyes T, Kouba D, Ozog D, et al. Reduced number of actinic keratoses with topical application of DNA repair enzyme creams. J Drugs Dermatol. 2010;9:1519–21.

    PubMed  Google Scholar 

  247. Yarosh D, Bucana C, Cox P, et al. Localization of liposomes containing a DNA repair enzyme in murine skin. J Invest Dermatol. 1994;103:461–8. doi:10.1111/1523-1747.ep12395551.

    Article  CAS  PubMed  Google Scholar 

  248. Yarosh D, Klein J, O’Connor A, et al. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet. 2001;357:926–9.

    Article  CAS  PubMed  Google Scholar 

  249. Zahid S, Brownell I. Repairing DNA damage in xeroderma pigmentosum: T4N5 lotion and gene therapy. J Drugs Dermatol. 2008;7:405–8.

    PubMed  Google Scholar 

  250. Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275:218–20.

    Article  CAS  PubMed  Google Scholar 

  251. Meeran SM, Mantena SK, Meleth S, et al. Interleukin-12-deficient mice are at greater risk of UV radiation-induced skin tumors and malignant transformation of papillomas to carcinomas. Mol Cancer Ther. 2006;5:825–32. doi:10.1158/1535-7163.MCT-06-0003.

    Article  CAS  PubMed  Google Scholar 

  252. Mittal A, Elmets CA, Katiyar SK. Dietary feeding of proanthocyanidins from grape seeds prevents photocarcinogenesis in SKH-1 hairless mice: relationship to decreased fat and lipid peroxidation. Carcinogenesis. 2003;24:1379–88. doi:10.1093/carcin/bgg095.

    Article  CAS  PubMed  Google Scholar 

  253. Roy AM, Baliga MS, Elmets CA, Katiyar SK. Grape seed Proanthocyanidins induce apoptosis through p53, Bax, and caspase 3 pathways. Neoplasia. 2005;7:24–36. doi:10.1593/neo.04412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Sharma SD, Katiyar SK. Dietary grape-seed proanthocyanidin inhibition of ultraviolet B-induced immune suppression is associated with induction of IL-12. Carcinogenesis. 2006;27:95–102. doi:10.1093/carcin/bgi169.

    Article  CAS  PubMed  Google Scholar 

  255. Yang Y, Paik JH, Cho D, et al. Resveratrol induces the suppression of tumor-derived CD4+CD25+ regulatory T cells. Int Immunopharmacol. 2008;8:542–7. doi:10.1016/j.intimp.2007.12.006.

    Article  CAS  PubMed  Google Scholar 

  256. Yusuf N, Nasti TH, Meleth S, Elmets CA. Resveratrol enhances cell-mediated immune response to DMBA through TLR4 and prevents DMBA induced cutaneous carcinogenesis. Mol Carcinog. 2009;48:713–23. doi:10.1002/mc.20517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Katiyar S, Elmets CA, Katiyar SK. Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. J Nutr Biochem. 2007;18:287–96. doi:10.1016/j.jnutbio.2006.08.004.

    Article  CAS  PubMed  Google Scholar 

  258. Hora JJ, Maydew ER, Lansky EP, Dwivedi C. Chemopreventive effects of pomegranate seed oil on skin tumor development in CD1 mice. J Med Food. 2003;6:157–61. doi:10.1089/10966200360716553.

    Article  CAS  PubMed  Google Scholar 

  259. Burton A. Chemoprevention: eat ginger, rub on pomegranate. Lancet Oncol. 2003;4:715.

    Article  PubMed  Google Scholar 

  260. Afaq F, Saleem M, Krueger CG, et al. Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice. Int J Cancer. 2005b;113:423–33. doi:10.1002/ijc.20587.

    Article  CAS  PubMed  Google Scholar 

  261. Afaq F, Malik A, Syed D, et al. Pomegranate fruit extract modulates UV-B-mediated phosphorylation of mitogen-activated protein kinases and activation of nuclear factor kappa B in normal human epidermal keratinocytes paragraph sign. Photochem Photobiol. 2005a;81:38–45. doi:10.1562/2004-08-06-RA-264.

    Article  CAS  PubMed  Google Scholar 

  262. Afaq F, Zaid MA, Khan N, et al. Protective effect of pomegranate-derived products on UVB-mediated damage in human reconstituted skin. Exp Dermatol. 2009;18:553–61. doi:10.1111/j.1600-0625.2008.00829.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Afaq F, Khan N, Syed DN, Mukhtar H. Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Photochem Photobiol. 2010;86:1318–26. doi:10.1111/j.1751-1097.2010.00815.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. de Vries E, Trakatelli M, Kalabalikis D, et al. Known and potential new risk factors for skin cancer in European populations: a multicentre case-control study. Br J Dermatol. 2012;167(Suppl 2):1–13. doi:10.1111/j.1365-2133.2012.11081.x.

    Article  PubMed  Google Scholar 

  265. Gensler HL, Williams T, Huang AC, Jacobson EL. Oral niacin prevents photocarcinogenesis and photoimmunosuppression in mice. Nutr Cancer. 1999;34:36–41. doi:10.1207/S15327914NC340105.

    Article  CAS  PubMed  Google Scholar 

  266. Schreiber V, Dantzer F, Ame J-C, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006;7:517–28. doi:10.1038/nrm1963.

    Article  CAS  PubMed  Google Scholar 

  267. Fisher AEO, Hochegger H, Takeda S, Caldecott KW. Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) Glycohydrolase. Mol Cell Biol. 2007;27:5597–605. doi:10.1128/MCB.02248-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Damian DL, Patterson CRS, Stapelberg M, et al. UV radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide. J Invest Dermatol. 2008;128:447–54. doi:10.1038/sj.jid.5701058.

    Article  CAS  PubMed  Google Scholar 

  269. Yiasemides E, Sivapirabu G, Halliday GM, et al. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis. 2009;30:101–5. doi:10.1093/carcin/bgn248.

    Article  CAS  PubMed  Google Scholar 

  270. Park J, Halliday GM, Surjana D, Damian DL. Nicotinamide prevents ultraviolet radiation-induced cellular energy loss. Photochem Photobiol. 2010;86:942–8. doi:10.1111/j.1751-1097.2010.00746.x.

    Article  CAS  PubMed  Google Scholar 

  271. Surjana D, Halliday GM, Martin AJ, et al. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J Invest Dermatol. 2012;132:1497–500. doi:10.1038/jid.2011.459.

    Article  CAS  PubMed  Google Scholar 

  272. Benavente CA, Schnell SA, Jacobson EL. Effects of niacin restriction on Sirtuin and PARP responses to photodamage in human skin. PLoS One. 2012;7:e42276. doi:10.1371/journal.pone.0042276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Martin AJ, Chen A, Penas PF, Halliday G, Dalziell R, McKenzie C, Scolyer RA, Dhillon HM, Vardy JL, George GS, Chinniah N, Damian D. Oral nicotinamide to reduce actinic cancer: a phase 3 double-blind randomized controlled trial. J Clin Oncol. 2015;33(15):9000. doi:10.1200/jco.2015.33.15.

    Google Scholar 

  274. Gu M, Dhanalakshmi S, Singh RP, Agarwal R. Dietary feeding of silibinin prevents early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Cancer Epidemiol Biomarkers Prev. 2005;14:1344–9. doi:10.1158/1055-9965.EPI-04-0664.

    Article  CAS  PubMed  Google Scholar 

  275. Vaid M, Katiyar SK. Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.) (review). Int J Oncol. 2010;36(5):1053–60. doi:10.3892/ijo_00000586.

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Vaid M, Prasad R, Singh T, et al. Silymarin inhibits ultraviolet radiation-induced immune suppression through DNA repair-dependent activation of dendritic cells and stimulation of effector T cells. Biochem Pharmacol. 2013;85:1066–76. doi:10.1016/j.bcp.2013.01.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Middelkamp-Hup MA, Pathak MA, Parrado C, et al. Oral polypodium leucotomos extract decreases ultraviolet-induced damage of human skin. J Am Acad Dermatol. 2004;51:910–8. doi:10.1016/j.jaad.2004.06.027.

    Article  PubMed  Google Scholar 

  278. Jańczyk A, Garcia-Lopez MA, Fernandez-Peñas P, et al. A Polypodium leucotomos extract inhibits solar-simulated radiation-induced TNF-alpha and iNOS expression, transcriptional activation and apoptosis. Exp Dermatol. 2007;16:823–9. doi:10.1111/j.1600-0625.2007.00603.x.

    Article  PubMed  Google Scholar 

  279. Philips N, Conte J, Chen Y-J, et al. Beneficial regulation of matrixmetalloproteinases and their inhibitors, fibrillar collagens and transforming growth factor-beta by Polypodium leucotomos, directly or in dermal fibroblasts, ultraviolet radiated fibroblasts, and melanoma cells. Arch Dermatol Res. 2009;301:487–95. doi:10.1007/s00403-009-0950-x.

    Article  PubMed  Google Scholar 

  280. Rodríguez-Yanes E, Juarranz Á, Cuevas J, et al. Polypodium leucotomos decreases UV-induced epidermal cell proliferation and enhances p53 expression and plasma antioxidant capacity in hairless mice. Exp Dermatol. 2012;21:638–40. doi:10.1111/j.1600-0625.2012.01544.x.

    Article  PubMed  CAS  Google Scholar 

  281. El-Haj N, Goldstein N. Sun protection in a pill: the photoprotective properties of Polypodium leucotomos extract. Int J Dermatol. 2015;54:362–6. doi:10.1111/ijd.12611.

    Article  PubMed  Google Scholar 

  282. Berman B, Ellis C, Elmets C. Polypodium Leucotomos – an overview of basic investigative findings. J Drugs Dermatol. 2016;15:224–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Howes LG. Selective COX-2 inhibitors, NSAIDs and cardiovascular events – is celecoxib the safest choice? Ther Clin Risk Manag. 2007;3:831–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  284. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study. JAMA. 2000;284:1247–55.

    Article  CAS  PubMed  Google Scholar 

  285. Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA. 2006;296:1619. doi:10.1001/jama.296.13.jrv60015.

    Article  CAS  PubMed  Google Scholar 

  286. Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13:1933–8.

    Article  CAS  PubMed  Google Scholar 

  287. George R, Weightman W, Russ GR, et al. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients. Australas J Dermatol. 2002;43:269–73.

    Article  PubMed  Google Scholar 

  288. Kraemer KH, DiGiovanna JJ, Moshell AN, et al. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988;318:1633–7. doi:10.1056/NEJM198806233182501.

    Article  CAS  PubMed  Google Scholar 

  289. Peck GL, DiGiovanna JJ, Sarnoff DS, et al. Treatment and prevention of basal cell carcinoma with oral isotretinoin. J Am Acad Dermatol. 1988;19:176–85.

    Article  CAS  PubMed  Google Scholar 

  290. Tangrea JA, Edwards BK, Taylor PR, et al. Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. Isotretinoin-basal cell carcinoma study group. J Natl Cancer Inst. 1992;84:328–32.

    Article  CAS  PubMed  Google Scholar 

  291. So P-L, Lee K, Hebert J, et al. Topical tazarotene chemoprevention reduces basal cell carcinoma number and size in Ptch1+/− mice exposed to ultraviolet or ionizing radiation. Cancer Res. 2004;64:4385–9. doi:10.1158/0008-5472.CAN-03-1927.

    Article  CAS  PubMed  Google Scholar 

  292. Peris K, Fargnoli MC, Chimenti S. Preliminary observations on the use of topical tazarotene to treat basal-cell carcinoma. N Engl J Med. 1999;341:1767–8. doi:10.1056/NEJM199912023412312.

    Article  CAS  PubMed  Google Scholar 

  293. Atigadda VR, Xia G, Desphande A, et al. Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity. J Med Chem. 2014;57:5370–80. doi:10.1021/jm5004792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Brtko J, Thalhamer J. Renaissance of the biologically active vitamin a derivatives: established and novel directed therapies for cancer and chemoprevention. Curr Pharm Des. 2003;9:2067–77.

    Article  CAS  PubMed  Google Scholar 

  295. Desphande A, Xia G, Boerma LJ, et al. Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention. Bioorg Med Chem. 2014;22:178–85. doi:10.1016/j.bmc.2013.11.039.

    Article  CAS  PubMed  Google Scholar 

  296. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618–26. doi:10.1056/NEJMoa1506197.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, University of Alabama at Birmingham, 1530 3rd Ave S, EFH 414, Birmingham, AL, 35294-0009, USA

    Allen S. W. Oak, Mohammad Athar, Nabiha Yusuf & Craig A. Elmets M.D.

Authors
  1. Allen S. W. Oak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Athar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nabiha Yusuf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Craig A. Elmets M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig A. Elmets M.D. .

Editor information

Editors and Affiliations

  1. IUF – Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

    Jean Krutmann

  2. Universitätsklinikum Aachen Klinik für Dermatologie u. Allergologie, Aachen, Germany

    Hans F. Merk

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Oak, A.S.W., Athar, M., Yusuf, N., Elmets, C.A. (2018). UV and Skin: Photocarcinogenesis. In: Krutmann, J., Merk, H. (eds) Environment and Skin. Springer, Cham. https://doi.org/10.1007/978-3-319-43102-4_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-43102-4_8

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-43100-0

  • Online ISBN: 978-3-319-43102-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation