Aging-Associated Nonmelanoma Skin Cancer: A Role for the Dermis

  • Davina A. Lewis
  • Aleksandar Krbanjevic
  • Jeffrey B. Travers
  • Dan F Spandau
Living reference work entry


The cocktail of sun’s ultraviolet (UVB) rays, and the hands of father time, can significantly increase the risk of skin cancers. However, genetic predisposition, certain skin diseases, and some viral infections can also increase the risk of skin cancers. Nonmelanoma skin cancer (NMSC), including basal cell (BCC) and squamous cell carcinoma (SCC), is thought to be based on a life time exposure to risk factors such as UV radiation combined with little sun protection in that life time. In fact, over 80 % of all skin cancers are found in people over the age of 60. NMSC tends to occur on highly visible areas such as the head, face, and neck. The treatment of these NMSC represents both a significant economic burden to health services and can cause significant morbidity especially as these occur on highly visible areas. Treatment is often invasive surgery which often leads to scaring and affects quality of life. Other treatments are based on chemotherapeutic, immunotherapies that can also affect quality of life. While very effective standard treatments have been developed to treat NMSC, very little is understood about the underlying cellular causes, and as such, alternative methods of treatment have not readily been developed. In this chapter, we explore the mechanisms of UVB-induced effects on skin and exciting new possible methods to treat NMSC.


Skin Cancer Dermal Fibroblast Cellular Senescence Senescent Cell Actinic Keratosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    ACS Cancer Facts and Figures 2015.Google Scholar
  2. 2.
    Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68:957–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Kripke ML. Carcinogenesis: ultraviolet radiation. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. New York: McGraw-Hill; 1993. p. 797–804.Google Scholar
  4. 4.
    Tyrrell RM. The molecular and cellular pathology of solar ultraviolet radiation. Mol Aspects Med. 1994;15:1–77.PubMedCrossRefGoogle Scholar
  5. 5.
    Clingen PH, Arlett CF, Roza L, Mori T, Nikaido O, Green MHL. Induction of cyclobutane pyrimidine dimers, pyrimidine(6-4) pyrimidone photoproducts, and Dewar valence isomers by natural sunlight in normal human mononuclear cells. Cancer Res. 1995;55:2245–8.PubMedGoogle Scholar
  6. 6.
    Wikonkal NM, Brash DE. Ultraviolet radiation induced signature mutations in photocarcinogenesis. J Investig Dermatol Symp Proc. 1999;4:6–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Brash DE, Heffernan T, Nghiem P. Carcinogenesis: ultraviolet radiation. In: Wolff K, editor. Fitzpatrick’s dermatology in general medicine. 6th ed. New York: McGraw-Hill Professional; 2003.Google Scholar
  8. 8.
    Kraemer KH. Sunlight and skin cancer: another link revealed. Proc Natl Acad Sci U S A. 1997;94:11–4.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kuhn C, Kumar M, Hurwitz SA, Cotton J, Spandau DF. Activation of the insulin-like growth factor-1 receptor promotes the survival of human keratinocytes following ultraviolet B irradiation. Int J Cancer. 1999;80:431–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Lewis DA, Spandau DF. UVB-induced activation of NF-κB is regulated by the IGF-1R and dependent on p38 MAPK. J Invest Dermatol. 2008;128:1022–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Lewis DA, Yi Q, Travers JB, Spandau DF. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53. Mol Biol Cell. 2008;19:1346–53.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lewis DA, Travers JB, Spandau DF. A new paradigm for the role of aging in the development of skin cancer. J Invest Dermatol. 2008;129:787–91.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Barreca A, De Luca M, Del Monte P, Bondanza S, Damonte G, Cariola G, et al. In vitro paracrine regulation of human keratinocyte growth by fibroblast derived insulin-like growth factors. J Cell Physiol. 1992;151:262–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Tavakkol A, Elder JT, Griffiths CE, Cooper KD, Talwar H, Fisher GJ, et al. Expression of growth hormone receptor, insulin-like growth factor 1 (IGF-1) and IGF-1 receptor mRNA and proteins in human skin. J Invest Dermatol. 1992;99:343–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Campisi J. Aging and cancer cell biology, 2008. Aging Cell. 2008;7:281–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Vasto S, Carruba G, Lio D, Colonna-Romano G, Di Bona D, Candore G, Caruso C. Inflammation, ageing and cancer. Mech Ageing Dev. 2009;130:40–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Anisimov VN. Carcinogenesis and aging 20 years after. Escaping horizon. Mech Ageing Dev. 2009;130:105–21.PubMedCrossRefGoogle Scholar
  18. 18.
    Moriwaki S, Ray S, Tarone RE, Kraemer KH, Grossman L. The effect of donor age on the processing of UV-damaged DNA by cultured human cells: reduced DNA repair capacity and increased DNA mutability. Mutat Res. 1996;364:117–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Ouhtit A, Ueda M, Nakazawa M, Dumaz N, Sarasin A, Yamasaki H. Quantitative detection of ultraviolet-specific p53 mutations in normal skin from Japanese patients. Cancer Epidemiol Biomarkers Prev. 1997;6:433–8.PubMedGoogle Scholar
  20. 20.
    Krtolica A, Parrinello S, Lockett S, Desprez P-Y, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A. 2001;98:12072–7.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Parrinello S, Coppe J-P, Krtolica A, Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci. 2005;118:485–96.PubMedCrossRefGoogle Scholar
  22. 22.
    Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005;120:513–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Jemal A, Tiwari RC, Murray T, et al. Cancer statistics. CA Cancer J Clin. 2004;54:8–29.PubMedCrossRefGoogle Scholar
  24. 24.
    Fuchs E, Raghavan S. Getting under the skin of epidermal morphogenesis. Nat Rev Genet. 2002;31:199–209.CrossRefGoogle Scholar
  25. 25.
    Mullenders LHF, Van Hoffen A, Vreeswijk MP, Gruven HJ, Vrieling H, van Zeeland AA. Ultraviolet-induced photolesions: repair and mutagenesis. Recent Results Cancer Res. 1997;143:89–99.PubMedCrossRefGoogle Scholar
  26. 26.
    Yuspa SH, Dlugosz AA. Cutaneous carinogenesis: natural and experimental. In: Goldsmith LA, editor. Physiology, biochemistry and molecular biology of the skin. New York: Oxford University Press; 1991. p. 1365–402.Google Scholar
  27. 27.
    Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–99.PubMedCrossRefGoogle Scholar
  28. 28.
    Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Stillman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JKV, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Campisi J. Suppressing cancer: the importance of being senescent. Science. 2005;309:886–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Dimri GP. What has senescence got to do with cancer? Cancer Cell. 2005;7:505–12.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Feng Z, Hu W, Teresky AK, Hernando E, Cordon-Cardo C, Levine AJ. Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. Proc Natl Acad Sci U S A. 2007;104:16633–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Melnikova VO, Ananthaswamy HN. Cellular and molecular events leading to the development of skin cancer. Mutat Res. 2005;571:91–106.PubMedCrossRefGoogle Scholar
  33. 33.
    Ichihashi M, Ueda M, Budiyanto A, Bito T, Oka M, Fukunaga M, et al. UV-induced skin damage. Toxicology. 2003;189:21–37.PubMedCrossRefGoogle Scholar
  34. 34.
    Nishigori C. Cellular aspects of photocarcinogenesis. Photochem Photobiol Sci. 2006;5:208–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Mathon NF, Lloyd AC. Cell senescence and cancer. Nat Rev Cancer. 2001;1:203–13.PubMedCrossRefGoogle Scholar
  36. 36.
    Krtolica A, Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol. 2002;34:1401–14.PubMedCrossRefGoogle Scholar
  37. 37.
    Campisi J. Cancer and ageing: rival demons? Nat Rev Cancer. 2003;3:339–49.PubMedCrossRefGoogle Scholar
  38. 38.
    Matsumura Y, Ananthaswammy HN. Toxic effects of ultraviolet radiation on the skin. Toxicol Appl Pharmacol. 2004;195:298–308.PubMedCrossRefGoogle Scholar
  39. 39.
    Ramos J, Villa J, Ruiz A, Armstrong R, Matta A. UV dose determines key characteristics of non-melanoma skin cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:2006–11.PubMedGoogle Scholar
  40. 40.
    Brash DE. Roles of the transcription factor p53 keratinocyte carcinomas. Br J Dermatol. 2006;154:8–10.PubMedCrossRefGoogle Scholar
  41. 41.
    Benjamin CL, Anathaswamy HN. p53 and the pathogenesis of skin cancer. Toxicol Appl Pharmacol. 2007;224:241–8.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, et al. Frequent clones of p53 -mutated in keratinocytes in normal skin. Proc Natl Acad Sci U S A. 1996;93:14025–9.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rodier F, Campisi J, Bhaumik D. Two faces of p53: aging and tumor suppression. Nucleic Acids Res. 2007;35:7475–84.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Halliday GM, Rana S. Wave band and dose dependency of sunlightinduced immunomodulation and cellular changes. Photochem Photobiol. 2008;84:35–46.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang Q, Yao Y, Konger RL, Sinn A, Cai S, Pollok KE, Travers JB. Platelet-activating factor mediates ultraviolet B radiation-mediated inhibition of delayed-type contact hypersensitivity reactions. J Invest Dermatol. 2008;128:1780–7.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Aubin F. Mechanisms involved in ultraviolet light-induced immunesuppression. Eur J Dermatol. 2003;13:515–23.PubMedGoogle Scholar
  47. 47.
    Schwartz T. Photoimmunosupression. Photodermatol Photoimmunol Photomed. 2002;18:141–5.CrossRefGoogle Scholar
  48. 48.
    Marathe GK, Johnson C, Billings SD, Southall MD, Pei Y, Spandau DF, Murphy RC, Zimmerman GA, McIntyre TM, Travers JB. Ultraviolet B radiation generates platelet-activating factor-like phospholipids underlying cutaneous damage. J Biol Chem. 2005;280:35448–57.PubMedCrossRefGoogle Scholar
  49. 49.
    Halliday GM. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res. 2005;571:107–20.PubMedCrossRefGoogle Scholar
  50. 50.
    Chung JH, Hanft VN, Kang S. Aging and photoaging. J Am Acad Dermatol. 2003;49:690–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Cooper SJ, Bowen GT. Ultraviolet B regulation of transcription factor families: role of the nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) in UVB-induced skin carcinogenesis. Curr Cancer Drug Targets. 2007;7:325–34.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Madson JG, Hansen LA. Multiple mechanisms of erbB2 action after ultraviolet irradiation of the skin. Mol Carcinog. 2007;46:624–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Gallagher RP, Hill GB, Bajdik CD, Fincham S, Coldman AJ, McLean DI, Threlfall WJ. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer I. Basal cell carcinoma. Arch Dermatol. 1995;131:157–63.PubMedCrossRefGoogle Scholar
  54. 54.
    MacKie RM. Long-term health risk to the skin of ultraviolet radiation. Prog Biophys Mol Biol. 2006;92:92–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol. 2006;126:2565–75.PubMedCrossRefGoogle Scholar
  56. 56.
    Chen J-H, Hales N, Ozanne SE. DNA damage, cellular senescence and organismal ageing: causal or correlative. Nucleic Acids Res. 2007;35:7417–28.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Bertram C, Hass R. Cellular responses to ROS-induced DNA damage and aging. Biol Chem. 2008;389:211–20.PubMedCrossRefGoogle Scholar
  58. 58.
    Burhans WC, Weinberger M. DNA replication stress, genome instability and aging. Nucleic Acids Res. 2007;35:7545–56.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Yamada M, Udono M, Hori M, Hirose R, Sato S, Mori T, et al. Aged human skin removes UVB-induced pryimidine dimers from the epidermis more slowly than younger adult skin in vivo. Arch Dermatol Res. 2006;297:294–302.PubMedCrossRefGoogle Scholar
  60. 60.
    Kenyon J, Gerson SL. The role of DNA damage repair in aging of adult stem cells. Nucleic Acids Res. 2007;35:7557–65.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Sunderkotter C, Kalden H, Luger TA. Aging and the skin immune system. Arch Dermatol. 1997;133:1256–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211:144–56.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Witkowski JM, Soroczynska-Cybula M, Bryl E, Smolenska Z, Jozwik A. Klotho-a common link in physiological and rheumatoid arthritis related aging of human CD4 lymphocytes. J Immunol. 2007;178:771–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Hayflick L, Moorhead P. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:385–621.CrossRefGoogle Scholar
  65. 65.
    Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60.PubMedCrossRefGoogle Scholar
  66. 66.
    Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol. 2005;2005(37):961–76.CrossRefGoogle Scholar
  67. 67.
    Blackburn EH. Telomeres and telomerase: their mechanisms of action and the effects of altering their function. FEBS Lett. 2005;579:859–62.PubMedCrossRefGoogle Scholar
  68. 68.
    Herbig U, Jobling WA, Chen BPC, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53 and p21CIP1 but not p16INK4a. Mol Cell. 2004;14:501–13.PubMedCrossRefGoogle Scholar
  69. 69.
    Dimiri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarkers that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92:9363–7.CrossRefGoogle Scholar
  70. 70.
    Herbig U, Ferreira M, Carey D, Sedivy JM. Cellular senescence in aging primates. Science. 2006;311:1257.PubMedCrossRefGoogle Scholar
  71. 71.
    Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007;128:36–44.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Lewis DA, Travers JB, Machado C, Somani AK, Spandau DF. Reversing the aging stromal phenotype prevents carcinoma initiation. Aging. 2011;3:407–16.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Evolution. 1957;11:398–411.CrossRefGoogle Scholar
  74. 74.
    Hornsby PJ. Senescence as an anticancer mechanism. J Clin Oncol. 2007;14:1852–7.CrossRefGoogle Scholar
  75. 75.
    Dilley T, Bowden G, Chen Q. Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confer tumor promoter activity. Exp Cell Res. 2003;290:38–48.PubMedCrossRefGoogle Scholar
  76. 76.
    Collado M, Blasco MA, Serrao M. Cellular senescence in cancer and aging. Cell. 2007;130:223–31.PubMedCrossRefGoogle Scholar
  77. 77.
    Sorrell JM, Baber MA, Caplan AI. Site-matched papillary and reticular human dermal fibroblasts differ in their release of specific growth factors/cytokines and in their interaction with keratinocytes. J Cell Physiol. 2004;200:134–45.PubMedCrossRefGoogle Scholar
  78. 78.
    El-Ghalbzouri A, Gibbs S, Lamme E, Van Blitterswijk CA, Ponec M. Effect of fibroblasts on epidermal regeneration. Br J Dermatol. 2002;147:230–43.PubMedCrossRefGoogle Scholar
  79. 79.
    Kneilling M, Rocken M. Mast cells: novel clinical perspectives from recent insights. Exp Dermatol. 2009;18:488–96.PubMedCrossRefGoogle Scholar
  80. 80.
    Sharp L, Jameson J, Cauvi G, Havran W. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat Immun. 2004;6:73–9.CrossRefGoogle Scholar
  81. 81.
    Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence associated secretory phenotypes reveal cell non-autonomous functions of oncogenic RAS and p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.PubMedCrossRefGoogle Scholar
  82. 82.
    Nolte SV, Xu Weiguo W, Rennekampff HO, Rodemann HP. Diversity of fibroblasts – a review on implications for skin tissue engineering. Cell Tissues Organs. 2008;187:165–76.CrossRefGoogle Scholar
  83. 83.
    Eming Sabine A, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127:514–25.PubMedCrossRefGoogle Scholar
  84. 84.
    Spiekstra SW, Breetveld M, Rustemeyer T, Scheper RJ, Gibbs S. Wound-healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes. Wound Repair Regen. 2007;15:708–17.PubMedCrossRefGoogle Scholar
  85. 85.
    Haniffa MA, Wang XN, Holtick U, Rae M, Isaacs JD, Dickinson AM, Hilkens CMU, Collin MP. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol. 2007;179:1595–604.PubMedCrossRefGoogle Scholar
  86. 86.
    Flavell SJ, Hou TZ, Lax AD, Salmon M, Buckley CD. Fibroblasts as novel therapeutic targets in chronic inflammation. Br J Pharmacol. 2008;153:s241–6.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Campisi J, Fagagna F. Cellular senescence: when bad things happen to good cells. Mol Cell Biol. 2007;8:729–40.Google Scholar
  88. 88.
    Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298–300.PubMedCrossRefGoogle Scholar
  89. 89.
    Sohal RS, Orr WC. Oxidative stress may be a causal factor in senescence. Age. 1998;21:81–2.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Hamilton ML, Remmen HV, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A. Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A. 2001;98:10469–74.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Lin MT, Flint BM. The oxidative theory of aging. Clin Neurosci Res. 2003;2:305–15.CrossRefGoogle Scholar
  92. 92.
    Shelton DN, Chang E, Whittier PS, Choi D, Funk WD. Microarray analysis of replicative senescence. Curr Biol. 1999;9:939–45.PubMedCrossRefGoogle Scholar
  93. 93.
    Wall IB, Moseley R, Briard DM, Kipling D, Giles P, Laffafian I, et al. Fibroblast dysfunction is a key factor in non-healing of chronic venous leg ulcers. J Invest Dermatol. 2008;128:2526–40.PubMedCrossRefGoogle Scholar
  94. 94.
    Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Child BG, van de Sluis B, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232–6.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Farage MA, Miller KW, Elsner P, Maibach HI. Intrinsic and extrinsic factors in aging: a review. Int J Cosmet Sci. 2008;30:87–95.PubMedCrossRefGoogle Scholar
  96. 96.
    Bol DK, Kigucji K, Gimenez-Conti I, Rupp T, DiGiovanni J. Overexpression of the insulin-like growth factor-1 induces hyperplasia, dermal abnormalities and spontaneous tumor formation in transgenic mice. Oncogene. 1997;14:1725–34.PubMedCrossRefGoogle Scholar
  97. 97.
    Wilker E, Bol D, Kiguchi K, Rupp T, Beltran L, Di Giovanni J. Enhancement for susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice. Mol Carcinog. 1999;25:122–31.PubMedCrossRefGoogle Scholar
  98. 98.
    DiGiovanni J, Bol DK, Wilker E, Beltran L, Carbajal S, Moats S, et al. Constitutive expression of insulin-like growth factor-1 in epidermal basal cells of transgenic mice leads to spontaneous tumor promotion. Cancer Res. 2000;60:1561–70.PubMedGoogle Scholar
  99. 99.
    Sadagurski M, Yakar S, Weingarten G, Holzenberger M, Rhodes C, Breikreutz D, et al. Insulin-like growth factor receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. Mol Cell Biol. 2006;26:2675–87.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Lin K, Hsin H, Libina N, Kenyon C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF1 and germline signaling. Nat Genet. 2001;28:139–45.PubMedCrossRefGoogle Scholar
  101. 101.
    Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003;21:182–7.CrossRefGoogle Scholar
  102. 102.
    Kruso H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone Klotho. Science. 2005;309:1829–33.CrossRefGoogle Scholar
  103. 103.
    Ikushima M, Rakugi H, Ishidawa K, Maedawa Y, Yamamoto K, Ohta J, et al. Anti-apoptotic and anti-senescent effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun. 2006;339:827–32.PubMedCrossRefGoogle Scholar
  104. 104.
    Chuang T-Y, Lewis DA, Spandau DF. Decreased incidence of nonmelanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study. Br J Dermatol. 2005;153:552–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Ferber A, Chang C, Sells C, Ptasznik A, Cristofalo V, Hubbard K, et al. Failure of senescent human fibroblasts to express insulin-like growth factor-1 gene. J Biol Chem. 1993;268:17883–8.PubMedGoogle Scholar
  106. 106.
    Pollak M. Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer. 2008;8:915–28.PubMedCrossRefGoogle Scholar
  107. 107.
    Lann D, LeRoith D. The role of endocrine insulin-like growth factor-1 and insulin in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:371–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Dziadziuszko R, Camidge DR, Hirsch FR. The insulin-like growth factor in lung cancer. J Thorac Oncol. 2008;3:815–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Donovan EA, Kummar S. Role of the insulin-like growth factor-1R system in colorectal carcinogenesis. Crit Rev Oncol Hematol. 2008;66:91–8.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Thompson SC, Jolley D, Marks R. Reduction of solar keratosis by regular sunscreen use. N Engl J Med. 1993;329:1147–51.PubMedCrossRefGoogle Scholar
  111. 111.
    Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, Marks G, Gaffney P, Battistath D, Frost C, Lang C, Russell A. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomized controlled trial. Lancet. 1999;354:723–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Neale R, Williams G, Green A. Application patterns among participants randomized to daily sunscreen use in a skin cancer prevention trial. Arch Dermatol. 2002;138:1319–25.PubMedCrossRefGoogle Scholar
  113. 113.
    Travers JB, Spandau DF, Lewis DA, Machado C, Kingsley M, Mousdicas N, Somani AK. Fibroblast senescence and squamous cell carcinoma: how wounding therapies could be protective. Dermatol Surg. 2013;39:967–73.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Cooley JE, Casey DL, Kauffman CL. Manual resurfacing and trichloracetic acid for the treatment of patients with widespread actinic damage. Dermatol Surg. 1997;23:373–9.PubMedGoogle Scholar
  115. 115.
    Hantash BM, Stewart DB, Cooper AZ, Rehmus WE, Koch RJ, Setter SM. Facial resurfacing for nonmelanoma skin cancer prophylaxis. Arch Dermatol. 2006;142:976–82.PubMedGoogle Scholar
  116. 116.
    Ostertag JU, Quaedvlieg PJF, Neumann MHAM, Kerkels GA. Recurrence rates and long-term follow-up after laser resurfacing as a treatment for widespread actinic dermatoses in the face and on the scalp. Dermatol Surg. 2006;32:261–7.PubMedGoogle Scholar
  117. 117.
    Halachmi S, Lapidoth M. Lasers in skin cancer prophylaxis. Expert Rev Anticancer Ther. 2008;8:1713–5.PubMedCrossRefGoogle Scholar
  118. 118.
    Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma. Arch Dermatol. 2009;145:1431–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Loesch MM, Somani AK, Kingsley MM, Travers JB, Spandau DF. Skin resurfacing procedures: new and emerging options. Clin Cosmet Investig Dermatol. 2014;28:231–41.Google Scholar
  120. 120.
    Gye J, Ahn SK, Kwon JE, Hong SP. Use of fractional CO2 laser decreases the risk of skin cancer development during ultraviolet exposure in hairless mice. Dermatol Surg. 2015;41:378–86.PubMedCrossRefGoogle Scholar
  121. 121.
    Spandau DF, Lewis DA, Somani AK, Travers JB. Fractionated laser resurfacing corrects the inappropriate UVB response in geriatric skin. J Invest Dermatol. 2012;132:1591–6.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Meshkinpour A, Ghasri P, Pope K, Lyubovitsky JG, Risteli J, Krasieva TB, Kelly KM. Treatment of hypertrophic scars and keloids with a radiofrequency device: a study of collagen effects. Lasers Surg Med. 2005;37:343–9.PubMedCrossRefGoogle Scholar
  123. 123.
    DeHoratius DM, Dover JS. Nonablative tissue remodeling and photorejuvenation. Clin Dermatol. 2007;25:474–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Sachs DL, Kang S, Hammerberg C, Helfrich Y, Karimipour D, Orringer J, Johnson T, Hamilton TA, Fisher G, Voorhees JJ. Topical fluorouracil for actinic keratoses and photoaging: a clinical and molecular analysis. Arch Dermatol. 2009;145:659–66.PubMedCrossRefGoogle Scholar
  125. 125.
    Collett-Solberg PF, Misra M, Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. The role of recombinant human insulin-like growth factor-I in treating children with short stature. J Clin Endocrinol Metabol. 2008;93:10–8.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Davina A. Lewis
    • 1
  • Aleksandar Krbanjevic
    • 2
  • Jeffrey B. Travers
    • 3
  • Dan F Spandau
    • 4
  1. 1.Department of Anatomic Pathology & HistologyCovance CLSIndianapolisUSA
  2. 2.Department of DermatologyIndiana University School of MedicineIndianapolisUSA
  3. 3.Departments of Pharmacology & Toxicology and DermatologyBoonshoft School of Medicine at Wright State UniversityDaytonUSA
  4. 4.Departments of Dermatology and Biochemistry & Molecular BiologyIndiana University School of MedicineIndianapolisUSA

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