Wounding Therapy and Photocarcinogenesis - ABSTRACT Non-melanoma skin cancer (NMSC) is a disease primarily afflicting geriatric patients as evidenced by the fact that 80% of all non-melanoma skin cancers are diagnosed in patients over the age of 60 years. As such, geriatric skin responds to cancer-inducing ultraviolet B (UVB) irradiation in a manner that allows the establishment of tumor cells. While the correlation between aged epidermis and skin cancer is obvious, the mechanism responsible for this relationship remains obscure. Recent in vitro evidence as well as epidemiological data suggests one possible mechanism may involve alterations in the insulin-like growth factor-1 receptor (IGF-1R) signaling network. Using normal human keratinocytes grown in vitro, activated IGF- 1Rs protect keratinocytes from UVB-induced apoptosis; however, while UVB-irradiated keratinocytes with activated IGF-1Rs survive, they are incapable of further cellular replication, in fact they are senescent. The critically important observation was that in the absence of IGF-1R activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate. In the skin, keratinocytes express the IGF-1R but they do not synthesize IGF-1. Dermal fibroblasts support the proliferation of keratinocytes in the epidermis by secreting IGF-1. Interestingly, as dermal fibroblasts age, their capacity to produce IGF-1 is severely diminished; therefore, in aged skin keratinocytes are provided with a reduced supply of IGF-1 and a concomitant reduction in IGF-1R activation. We have demonstrated that geriatric skin responds to UVB irradiation in a manner that could lead to initiated carcinogenic keratinocytes. This inappropriate UVB response can be corrected by treatment with exogenous IGF-1. Furthermore, we have shown that treatment of geriatric skin with non-ablative dermal rejuvenation therapies can re-establish youthful IGF-1 levels and subsequently reinstate the appropriate UVB response on geriatric skin. Moreover, we have demonstrated this protection to acute UVB exposure is durable for up to two years. In this proposal, we will continue and expand our ongoing clinical trials on the prophylactic effect of non-ablative wounding therapies to both treat and prevent UVB-induced skin cancer. In particular, we will recruit post-menopausal females for these studies as this is an underserved population for skin cancer studies. A novel non-invasive mesoscopic imaging platform will be used to monitor actinic neoplasia progression. In addition, we will examine the mechanisms responsible for the ability of non-ablative wounding therapies to increase fibroblast-associated IGF-1 expression. These studies will have a major impact on the treatment of NMSC by establishing a novel anti-carcinogenic role for dermal wounding. Furthermore, the data from these studies will confirm a new paradigm defining the mechanism of age-associated skin cancer. Outcomes for these studies include novel therapeutic strategies as well as non-invasive imaging platforms to monitor field carcinogenesis in at risk-populations.
