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A New Paradigm for the Role of Aging in the Development of Skin Cancer

2008; Elsevier BV; Volume: 129; Issue: 3 Linguagem: Inglês

10.1038/jid.2008.293

1523-1747

Davina A. Lewis, Jeffrey B. Travers, Dan F. Spandau,

melanin and skin pigmentation

non-melanoma skin cancer ultraviolet B Cancers of the skin are the most common cancers to afflict Americans in the United States with over 1,000,000 new cases estimated to occur in 2008 (American Cancer Society, 2008American Cancer Society Cancer Facts & Figures. American Cancer Society, Atlanta2008Google Scholar). The primary environmental factor that influences the development of skin cancer is exposure to sunlight, in the ultraviolet B (UVB) wavelengths. Notably, a dramatic increase in the incidence of skin cancers is seen with increasing age (American Cancer Society, 2008American Cancer Society Cancer Facts & Figures. American Cancer Society, Atlanta2008Google Scholar), as evidenced by the fact that a majority of skin malignancies are found in people over the age of 60 years (Kraemer, 1997Kraemer K.H. Sunlight and skin cancer.Proc Natl Acad Sci USA. 1997; 94: 11-14Crossref PubMed Scopus (340) Google Scholar; American Cancer Society, 2008American Cancer Society Cancer Facts & Figures. American Cancer Society, Atlanta2008Google Scholar). However, the mechanisms underpinning the correlation between age and skin cancer are not well understood. New ideas on the link between age and skin cancer have arisen based on age-related accumulation of stromal senescent cells that can lead to a tumor-promoting environment (Krtolica et al., 2001Krtolica 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 USA. 2001; 98: 12072-12077Crossref PubMed Scopus (1190) Google Scholar; Krtolica and Campisi, 2002Krtolica A. Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma.Int J Biochem Cell Biol. 2002; 34: 1401-1414Crossref PubMed Scopus (254) Google Scholar; Dilley et al., 2003Dilley 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: 38-48Crossref PubMed Scopus (47) Google Scholar; Parinello et al., 2005Parinello 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: 485-496Crossref PubMed Scopus (450) Google Scholar; Collado et al., 2007Collado M. Blasco M.A. Serrao M. Cellular senescence in cancer and aging.Cell. 2007; 130: 223-231Abstract Full Text Full Text PDF PubMed Scopus (1262) Google Scholar. Combining these recent data from others with data from our laboratory leads us to propose a new paradigm for the role of aging in the development of skin cancer involving the insulin-like growth factor-1 receptor (IGF-1R) pathway (Kuhn et al., 1999Kuhn C. Kumar M. Hurwitz S.A. Cotton J. Spandau D.F. Activation of the insulin-like growth factor-1 receptor promotes the survival of human keratinocytes following ultraviolet B irradiation.Int J Cancer. 1999; 80: 431-438Crossref PubMed Scopus (102) Google Scholar; Chuang et al., 2005Chuang T.-Y. Lewis D.A. Spandau D.F. Decreased incidence of non-melanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study.Br J Derm. 2005; 153: 552-557Crossref PubMed Scopus (28) Google Scholar; Heemst et al., 2005Heemst D.V. Beekman M. Mooijaart S.P. Heijmans B.T. Brandt B.W. Zwaan B.J. et al.Reduced insulin/IGF-1 signalling and human longevity.Aging Cell. 2005; 4: 79-85Crossref PubMed Scopus (251) Google Scholar; Kurosu et al., 2005Kurosu H. Yamamoto M. Clark J.D. Pastor J.V. Nandi A. Gurnani P. et al.Suppression of aging in mice by the hormone Klotho.Science. 2005; 309: 1829-1833Crossref PubMed Scopus (1389) Google Scholar; Samani et al., 2005Samani A.A. Shoshana Y. LeRoith D. Brodt P. The role of the IGF1 system in cancer growth and metastasis: overview and recent highlights.Endocr Rev. 2005; 28: 20-47Crossref Scopus (856) Google Scholar; Lewis and Spandau, 2008Lewis D.A. Spandau D.F. UVB-induced activation of NF kappa B is regulated by the IGF-1R and dependent on p38 MAPK.J Invest Dermatol. 2008; 128: 1022-1029Crossref PubMed Scopus (30) Google Scholar; Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar). The historical explanation for the correlation between skin cancer and aging is that UVB-induced skin damage during childhood and early adolescence initiates mutations in keratinocytes (Kraemer, 1997Kraemer K.H. Sunlight and skin cancer.Proc Natl Acad Sci USA. 1997; 94: 11-14Crossref PubMed Scopus (340) Google Scholar; Whiteman et al., 2001Whiteman D.C. Whiteman C.A. Green A.C. Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies.Cancer Causes Control. 2001; 12: 69-82Crossref PubMed Scopus (506) Google Scholar; Krtolica and Campisi, 2002Krtolica A. Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma.Int J Biochem Cell Biol. 2002; 34: 1401-1414Crossref PubMed Scopus (254) Google Scholar; MacKie, 2006MacKie R.M. Long-term health risk to the skin of ultraviolet radiation.Prog Biophys Mol Biol. 2006; 92: 92-96Crossref PubMed Scopus (74) Google Scholar; Feng et al., 2007Feng Z. Hu W. Teresky A.K. Hernando E. Cordon-Cardo C. Levine A.J. Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older population.Proc Natl Acad Sci USA. 2007; 104: 16633-16638Crossref PubMed Scopus (204) Google Scholar). Subsequently, these keratinocytes containing mutations acquire a growth advantage that over many decades generates enough genetic change to become carcinogenic. However, can we presume that time is the sole contributor to UVB-induced skin cancers? It is reasonable to consider that the physiology of aging also lends a hand to carcinogenic events. Recent data from a variety of labs have demonstrated a modification on the theory of skin cancer and aging based on changes in stromal fibroblasts of aged individuals. There are age-related increases in the number of senescent dermal fibroblasts and epidermal keratinocytes in human skin (Dimiri et al., 1995Dimiri G.P. 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.Pro Natl Acad Sci USA. 1995; 92: 9363-9367Crossref PubMed Scopus (5719) Google Scholar). In a study involving aging primates, an age-dependent increase in markers of senescence in skin fibroblasts was observed (Herbig et al., 2006Herbig U. Ferreira M. Carey D. Sedivy J.M. Cellular senescence in aging primates.Science. 2006; 311: 1257Crossref PubMed Scopus (813) Google Scholar; Jeyapalan et al., 2007Jeyapalan J.C. Ferreira M. Sedivy J.M. Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates.Mech Ageing Dev. 2007; 128: 36-44Crossref PubMed Scopus (456) Google Scholar). Given this age-associated accumulation of senescent cells, it is reasonable to propose that cellular senescence may contribute to age-related cancers by altering the surrounding tissue into a neoplasia-promoting environment. The paradoxical effect of cellular senescence on an organism's well-being has been called antagonistic pleiotropy (Williams, 1957Williams G.C. Pleiotropy, natural selection and the evolution of senescence.Evolution. 1957; 11: 398-411Crossref Google Scholar; Krtolica and Campisi, 2002Krtolica A. Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma.Int J Biochem Cell Biol. 2002; 34: 1401-1414Crossref PubMed Scopus (254) Google Scholar). However, cellular senescence is a powerful tumor suppressor limiting cell life span and removing damaged cells from a proliferative state preventing formation of clonal tumors (Campisi, 2005Campisi J. Senescent cells, tumor suppression and organismal aging: good citizens, bad neighbors.Cell. 2005; 120: 513-522Abstract Full Text Full Text PDF PubMed Scopus (1820) Google Scholar; Hornsby, 2007Hornsby P.J. Senescence as an anticancer mechanism.J Clin Oncol. 2007; 14: 1852-1857Crossref Scopus (66) Google Scholar; Rodier et al., 2007Rodier F. Campisi J. Bhaumik D. Two faces of -53: aging and tumor suppression.Nucleic Acids Res. 2007; 35: 7475-7484Crossref PubMed Scopus (292) Google Scholar). Conversely, the accumulation of senescent cells may contribute to aging and provide a tumor-promoting environment due to their altered properties such as stromal matrix reorganization and/or degradation, secretion of growth factors, and inflammatory cytokines (Krtolica and Campisi, 2002Krtolica A. Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma.Int J Biochem Cell Biol. 2002; 34: 1401-1414Crossref PubMed Scopus (254) Google Scholar; Parinello et al., 2005Parinello 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: 485-496Crossref PubMed Scopus (450) Google Scholar). Here we present our data proposing a new paradigm to explain non-melanoma skin carcinogenesis that further substantiates the importance of stromal interactions in the progression of carcinogenic events. The stromal interactions discussed demonstrate that IGF-1 and the IGF-1R are critical in the interactions between dermal fibroblast and epidermal keratinocytes and that they play an important role in aging and the response of skin to UVB irradiation. The stroma and some basement membrane components are synthesized by stromal fibroblasts that also produce soluble factors that promote survival and growth of the skin. The health and proper functioning of the skin is highly dependent on the synergistic interactions between the dermal fibroblasts and epidermal keratinocyte. One factor regulating the interaction between dermal fibroblasts and epidermal keratinocytes is IGF-1 (Barreca et al., 1992Barreca 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: 262-268Crossref PubMed Scopus (129) Google Scholar; Tavakkol et al., 1992Tavakkol A. Elder J.T. Griffiths C.E. Cooper K.D. Talwar H. Fisher G.J. 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: 343-349Abstract Full Text PDF PubMed Scopus (184) Google Scholar). In the skin, keratinocytes express the IGF-1R but do not synthesize IGF-1. Dermal fibroblasts support the appropriate development of epidermal keratinocytes by secreting IGF-1. The mature IGF-1R consists of four subunits, two identical extracellular α- and two identical transmembrane β-subunits linked by disulfide bridges. IGF-1, IGF-2, and high concentrations of insulin can activate the IGF-1R resulting in tyrosine kinase activity. Subsequently, binding or phosphorylation of cellular substrates in close proximity through SH2 binding domain leads to downstream signaling (Figure S1). The importance of IGF-1R signaling in skin development is clearly evident from a variety of studies. Transgenic mice overexpressing IGF-1 in the basal layer of skin epidermis exhibited epidermal hyperplasia, hyperkeratosis, and squamous papillomas (Bol et al., 1997Bol D.K. 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: 1725-1734Crossref PubMed Scopus (126) Google Scholar; Wilker et al., 1999Wilker 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: 122-131Crossref PubMed Scopus (34) Google Scholar; DiGiovanni et al., 2000DiGiovanni J. Bol D.K. 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: 1561-1570PubMed Google Scholar). Conversely, IGF-1R knockout mice demonstrate severe hypoplasia (Lui et al., 1993Lui J.P. Baker J. Perkins A.S. Robertson E.J. Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I and type 1 IGF receptor.Cell. 1993; 75: 59-72PubMed Google Scholar). The IGF-1R has also been shown to be important in normal epidermal differentiation (Sadagurski et al., 2006Sadagurski 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: 2675-2687Crossref PubMed Scopus (104) Google Scholar) whereas other reports have identified a key role for the IGF-1R in regulating the response of cells to oxidative stress (Holzenberger et al., 2003Holzenberger M. Dupont J. Ducos B. Leneuve P. Geloen A. Even P.C. et al.IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice.Nature. 2003; 21: 182-187Crossref Scopus (1622) Google Scholar; Ikushima et al., 2006Ikushima 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: 827-832Crossref PubMed Scopus (185) Google Scholar). Therefore, the activation of the IGF-1R can influence all stages of epidermal homeostasis. Download .jpg (.04 MB) Help with files Supplementary Figure S1IGF-1R signal transduction cascade. ASK1, apoptosis signal-regulating kinase 1; ERK, extracellular signal-regulated kinase; IGF-1, insulin-like growth factor 1; IRS1, insulin receptor substrate 1; IRS2, insulin receptor substrate1; PI3K, phosphoinositide-3-kinase; SHC, SRC-homology and collagen-like. Experiments that assessed the role of various growth factors on the response of keratinocytes to UVB irradiation identified that the activation status of the IGF-1R was a critical component affecting UVB-induced apoptosis in vitro (Figure 1; Kuhn et al., 1999Kuhn C. Kumar M. Hurwitz S.A. Cotton J. Spandau D.F. Activation of the insulin-like growth factor-1 receptor promotes the survival of human keratinocytes following ultraviolet B irradiation.Int J Cancer. 1999; 80: 431-438Crossref PubMed Scopus (102) Google Scholar). Inhibition of the IGF-1R, by ligand withdrawal, treatment with neutralizing antibodies, or treatment with IGF-1R-specific small molecule inhibitors before irradiation increased the sensitivity of keratinocytes to UVB-induced apoptosis (Kuhn et al., 1999Kuhn C. Kumar M. Hurwitz S.A. Cotton J. Spandau D.F. Activation of the insulin-like growth factor-1 receptor promotes the survival of human keratinocytes following ultraviolet B irradiation.Int J Cancer. 1999; 80: 431-438Crossref PubMed Scopus (102) Google Scholar; Lewis et al., 2006Lewis D.A. Hengeltraub S. Gao F. Leivant M.A. Spandau D.F. Aberrant NF-κB activity in HaCaT cells alters their response to UVB signaling.J Invest Dermatol. 2006; 126: 1885-1892Crossref PubMed Scopus (45) Google Scholar, Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar; Lewis and Spandau, 2007Lewis D.A. Spandau D.F. UVB activation of NF-κB in normal human keratinocytes occurs via a unique mechanism.Arch Dermatol Res. 2007; 299: 93-101Crossref PubMed Scopus (28) Google Scholar, Lewis and Spandau, 2008Lewis D.A. Spandau D.F. UVB-induced activation of NF kappa B is regulated by the IGF-1R and dependent on p38 MAPK.J Invest Dermatol. 2008; 128: 1022-1029Crossref PubMed Scopus (30) Google Scholar). For simplicity in this review, keratinocytes grown in conditions that permit the functional activation of the IGF-1R will be called (+)IGF-1R keratinocytes whereas cells containing functionally inactive IGF-1Rs will be referred to as (-)IGF-1R keratinocytes (Lewis and Spandau, 2008Lewis D.A. Spandau D.F. UVB-induced activation of NF kappa B is regulated by the IGF-1R and dependent on p38 MAPK.J Invest Dermatol. 2008; 128: 1022-1029Crossref PubMed Scopus (30) Google Scholar, Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar). It is important to note that the expression of the IGF-1R protein is equal in both (+)IGF-1R and (-)IGF-1R keratinocytes; they only differ in the activation status of the IGF-1R. These studies identified that the functional activation of the IGF-1R provided protection to human keratinocytes from UVB-induced apoptosis. However, an equally important observation was that these surviving keratinocytes cannot replicate and become senescent (Figure 1; Kuhn et al., 1999Kuhn C. Kumar M. Hurwitz S.A. Cotton J. Spandau D.F. Activation of the insulin-like growth factor-1 receptor promotes the survival of human keratinocytes following ultraviolet B irradiation.Int J Cancer. 1999; 80: 431-438Crossref PubMed Scopus (102) Google Scholar; Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar). We propose this UVB response occurs in the epidermis where the induction of senescence in response to UVB irradiation is a tumor evasion mechanism that maintains the important barrier function of the epidermis while ensuring keratinocytes cannot proliferate in the presence of irreparable UVB-induced DNA damaged. If the IGF-1R is functionally inactive at the time of UVB irradiation, a portion of the keratinocytes will undergo apoptosis; however, keratinocytes that survive do not become senescent, do not repair UVB-damaged DNA, and they can continue to proliferate with the potential of converting the damaged DNA into initiating carcinogenic mutations (Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar). Data generated from our lab (Cotton and Spandau, 1997Cotton J. Spandau D.F. Ultraviolet B dose influences the induction of apoptosis and p53 in human keratinocytes.Radiat Res. 1997; 147: 148-155Crossref PubMed Scopus (81) Google Scholar; Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar) and many others (Qin et al., 2002Qin J.Z. Chaturvedi V. Denning M.F. Bacon P. Panella J. Choubey D. et al.Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes.Oncogene. 2002; 21: 2991-3002Crossref PubMed Scopus (87) Google Scholar; Chaturvedi et al., 2004Chaturvedi V. Qin J.Z. Stennett L. Choubey D. Nickoloff B.J. Resistance of UV-induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53.J Cell Physio. 2004; 198: 100-109Crossref PubMed Scopus (46) Google Scholar; Chaturvedi et al., 2005Chaturvedi V. Sitailo L.A. Qin J.Z. Bodner B. Denning M.F. Curry J. et al.Knockdown of p53 levles in human keratinocytes accelerated Mcl-1 and Bcl-x(L) reduction thereby enhancing UV-light induced apoptosis.Oncogene. 2005; 24: 5299-5312Crossref PubMed Scopus (41) Google Scholar) have demonstrated that UVB irradiation of keratinocytes initiates a DNA damage response involving the phosphorylation of the tumor suppressor p53. Recently, we have shown that UVB activation of p53 is also dependent on the status of the IGF-1R (Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar). Activation of the IGF-1R resulted in higher levels of UVB-induced total p53 protein and increased phosphorylation at serine 15 (p53S15) and serine 46 (p53S46) (Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar). Intriguingly, the phosphorylation of p53S46 was only observed in (+)IGF-1R keratinocytes and was not influenced by UVB irradiation (Lewis et al., 2008Lewis D.A. Yi Q. Travers J.B. Spandau D.F. UVB-induced senescence in human keratinocytes requires a functional IGF-1R and p53.Mol Biol Cell. 2008; 19: 1349-1353Crossref Scopus (78) Google Scholar). The UVB response of keratinocytes expressing a p53 gene where serine 46 is replaced by glutamic acid (p53S46D; which structurally and functionally mimics a phosphorylated serine residue) was found to be independent of the activation status of the IGF-1R. These data indicate that the UVB response of keratinocytes (senescence and apoptosis) requires a functional IGF-1R and the subsequent downstream phosphorylation of p53S46. Our in vitro data showing IGF-1R activation status was an important factor in the response of epidermal keratinocytes to UVB led us to hypothesize that the reduced activation of the IGF-1R may be correlated with an increased susceptibility to skin cancer in vivo. In a retrospective epidemiological study, we found that type 2 diabetic patients using insulin to treat their disease had a 2.5-fold decreased risk of developing NMSC over the control group and type 2 diabetic patients using non-insulin medicines to treat their disease (Chuang et al., 2005Chuang T.-Y. Lewis D.A. Spandau D.F. Decreased incidence of non-melanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study.Br J Derm. 2005; 153: 552-557Crossref PubMed Scopus (28) Google Scholar). Intriguingly, the protective effect of insulin use increased with age, implying that insulin was somehow protecting against the age-associated increase in NMSC (Chuang et al., 2005Chuang T.-Y. Lewis D.A. Spandau D.F. Decreased incidence of non-melanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study.Br J Derm. 2005; 153: 552-557Crossref PubMed Scopus (28) Google Scholar). These important data suggested the clinical relevance for the involvement of the IGF-1R signaling pathway in NMSC in vivo. Recently, we have started to examine the age-related changes in the IGF-1/IGF-1R signal transduction pathway in vivo. Our lab and others have shown that production of IGF-1 diminishes as fibroblasts become senescent (Ferber et al., 1993Ferber 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: 17883-17888PubMed Google Scholar; unpublished data). Given the critical role of dermal fibroblasts in supplying IGF-1 to epidermal keratinocytes, an age-related decrease in fibroblast IGF-1 may result in keratinocytes in aged epidermis having functionally deficient activation of IGF-1R and subsequently respond inappropriately to UVB irradiation. We examined the expression of IGF-1 in skin samples obtained from sun-protected anatomical locations representing young adults (20–28years old) or geriatric individuals (>65years old). Immunohistochemical and quantitative RT-PCR analysis of IGF-1 in samples of geriatric individuals showed a significant reduction in IGF-1 levels when compared to young adults (unpublished data). Accordingly, keratinocyte activated IGF-1R levels were high in young adult compared to virtual absence in geriatric individuals (unpublished data). It has been reported that the difference between UVB-induced DNA damage repair in young and aged human skin is the rate at which DNA damaged is cleared (Yamada et al., 2006Yamada M. Udono M. Hori M. Hirose R. Sato S. Mori T. et al.Aged human skin removes UVB-induced pyrimidine dimmers from the epidermis more slowly than younger adult skin in vivo.Arch Dermatol Res. 2006; 297: 294-302Crossref PubMed Scopus (41) Google Scholar). However, we propose that any DNA damage existing while cell proliferation continues (such as we have found in aged skin) leaves the possibility for the propagation of mutations. We believe that the age-related decrease in IGF-1 expression, IGF-1R inactivation, and proliferation with DNA damage are major components in the development of NMSC seen in geriatric patients (Figure 2). We believe that cellular senescence affects the UVB response of keratinocytes in the epidermis through two distinct and opposite mechanisms; one mechanism suppresses UVB-induced transformation of keratinocytes and the other mechanism promotes keratinocyte carcinogenesis. On the positive side, we hypothesize that keratinocytes use stress-induced senescence as a tumor evasion mechanism. The advantage to cellular senescence versus UVB-induced apoptosis is that senescence maintains the cellularity of the epidermis, thus preserving the barrier function. In other words, widespread UVB-induced keratinocyte apoptosis in the epidermis will severely compromise the epidermal barrier function whereas UVB-induced keratinocyte senescence will not. In this manner, the induction of senescence in UVB-irradiated keratinocytes suppresses carcinogenesis. On the negative side, cellular senescence in dermal fibroblasts may promote UVB-induced carcinogenesis in aging skin. We hypothesize that IGF-1 expression by dermal fibroblasts is critical for the appropriate response of keratinocytes to UVB irradiation. The silencing of IGF-1 expression by senescent fibroblasts might contribute to an increased initiation of transformed keratinocytes by UVB exposure. Furthermore, the altered inflammatory phenotype of senescent fibroblasts may promote the expansion of clones of initiated keratinocytes. Given the increase in NMSC incidence with its associated morbidity and cost, the prevention of these tumors has significant importance. Present strategies for tumor prevention include avoiding excess UV exposure. For patients with established actinic keratoses precursor lesions, strategies include destruction by physical modalities as well as by topical chemotherapy with 5-fluorouracil or immune-mediated destruction with topical imiquimod (Gold and Nestor, 2006Gold M.H. Nestor M.S. Current treatments of actinic keratosis.J Drugs Dermatol. 2006; 5: 17-25PubMed Google Scholar). Though somewhat effective in treating established pre- or low-grade cancerous lesions, these treatment strategies do not appear to effect the underlying process by which aged skin is more susceptible to neoplasia. If the major deciding feature of keratinocyte response to UVB resides in the senescence status of the dermal fibroblast, then this suggests new treatments. One possible new treatment strategy would be to develop methods to rejuvenate the fibroblasts to allow production of factors such as IGF-1. Though marketed for cosmetic purposes, skin-damaging agents ranging from chemical peels, laser resurfacing, heating of the skin, and other "wounding" procedures could restimulate the expression of IGF-1 in the treated fibroblasts (Meshkinpour et al., 2005Meshkinpour A. Ghasri P. Pope K. Lyubovitsky J.G. Risteli J. Krasieva T.B. et al.Treatment of hypertrophic scars and keloids with a radiofrequency device: a study of collagen effects.Lasers Surg Med. 2005; 37: 343-349Crossref PubMed Scopus (37) Google Scholar; DeHoratius and Dover, 2007DeHoratius D.M. Dover J.S. Nonablative tissue remodeling and photorejuvenation.Clin Dermatol. 2007; 25: 474-479Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Since there appears to be a protective effect of exogenous insulin in skin cancer development (Chuang et al., 2005Chuang T.-Y. Lewis D.A. Spandau D.F. Decreased incidence of non-melanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study.Br J Derm. 2005; 153: 552-557Crossref PubMed Scopus (28) Google Scholar), systemic treatment with IGF-1 (currently used for short-stature syndromes) could also be studied (Collett-Solberg et al., 2008Collett-Solberg P.F. 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 Endocrin Metabol. 2008; 93: 10-18Crossref PubMed Scopus (42) Google Scholar). Thus, this new paradigm of the role of aging in the development of skin cancer could have significant clinical implications. In summary, we propose that the reduced expression of IGF-1 that characterizes geriatric skin could be an important component in the development of aging-related non-melanoma skin cancer. Furthermore, dermal fibroblasts are critical in maintaining appropriate activation of the keratinocyte IGF-1R that can be ameliorated in aged dermis by the presence of senescent fibroblasts. Finally, this paradigm suggests a role for the IGF-1R in suppressing UVB-induced carcinogenesis by induction of stress-induced keratinocyte senescence. Further study of this model not only could allow a better understanding of carcinogenesis, it could provide the impetus for new prevention strategies. The authors state no conflict of interest. We are grateful to Tsu-Yi Chuang, Jenny Cotton, Steven Hurwitz, Raymond Konger, Christine Kuhn, Manish Kumar, Michael Southall, Mohammed Al-Hassani, Yongxue Yao, Qiaofang Yi, and Qiwei Zhang for their contributions to the development of this work. This work was supported by grants from the National Institutes of Health (R01ES11155 to DFS; R01HL062996 to JBT) and VA Merit Award (JBT). Figure S1. IGF-1R signal transduction cascade.