IGF-1 and the initiation of non-melanoma skin cancer

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DESCRIPTION (provided by applicant): The primary goal of these clinical research studies is to define the role of insulin-like growth factor-1 (IGF-1) in the initiation of non-melanoma skin cancer (NMSC). Conclusive evidence has demonstrated that the major environmental risk factor for developing actinic neoplasia (NMSC and pre-cancerous actinic keratoses) is exposure to the ultraviolet wavelengths. The incidence of NMSC increases dramatically with increasing age, becoming most common in individuals over 60 years old. Ongoing studies by our group and others have discovered the involvement of dermal fibroblasts in the increased actinic neoplasia associated with aging. Fibroblast production of the IGF-1 protein appears to dictate how keratinocytes respond to UVB. If sufficient IGF-1 is present (as in young skin), keratinocytes damaged by UVB to the point where their DNA cannot be fully repaired become senescent. If IGF-1 levels are not adequate (as in "aged" skin), then these keratinocytes with damaged DNA fail to become senescent and are thus allowed to replicate. This abnormal response to UVB results in the formation of keratino-cytes proliferating with DNA damage. (primarily UVB) found in sunlight. Our hypothesis is that this represents the mechanism responsible for the population of keratinocytes This new paradigm of how UVB induces actinic neoplasia is supported by data presented in this application, and help explains why skin cancers are predominantly found in older individuals. Moreover, this new paradigm also explains results of previous studies indicating that sunscreen/sun protection decreases the numbers of actinic neoplasia. Our ongoing studies demonstrate that dermal wounding with fractionated laser resurfacing or non-ablative laser can reverse the effects of aging by increasing the amounts of fibroblast IGF-1, resulting in a "normal" UVB response. The three specific aims proposed are designed to provide a direct link between IGF-1R signaling and UVB-mediated production of initiated carcinogenic keratinocytes. The first aim consists of studies testing the ability of an IGF-1R inhibitor to augment the abilityof chronic UVB treatments to induce initiated keratinocytes and actinic neoplasia using human skin transplanted onto immunodeficient mice. The second aim will test the relative effectiveness of multiple UVB treatments on localized areas of young versus that eventuate in skin cancers in geriatric patients. geriatric volar forearm skin to create the earliest actinic neoplastic moleculr changes including p53 mutations. Localized injections of IGF-1 will be used to inhibit this process in geriatric subjects. The third aim will test the ability of fractionated laser resurfacin or non-ablative laser treatments to protect geriatric volar forearm skin against these chronic UVB-mediated actinic neoplastic changes. These studies will not only confirm the critical role that IGF-1R signaling plays in the development of actinic neoplasia, they provide the impetus for novel interventions involving laser-mediated dermal wounding to protect against UVB-mediated keratinocyte initiation. Since actinic neoplasia is the most common skin disorder of veterans, these studies have tremendous significance for veteran's health care.