Inhibition of UVB-induced inflammation and carcinogenesis by black raspberry extr

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DESCRIPTION (provided by applicant): Compared to the general population, transplant recipients are at greater risk for developing non-melanoma skin cancers, especially aggressive, life-threatening squamous cell carcinomas. In addition to ultraviolet light (UV) exposure, immunosuppression from multiple anti-rejection medications is implicated in the increased risk of skin cancer There is a clear need for treatments to prevent and treat skin cancer in transplant recipients. Ideally, such treatments could be administered after the damage of sun exposure has occurred, would not be administered as a pill or tablet and would have limited systemic effects. We hypothesize that topical application of black raspberry extracts (BRE) fulfill these criteria and should be explored as a treat- ment/preventive for non-melanoma skin cancer. Our preliminary data indicate that topical BRE applied after UVB exposure reduce DVB-induced inflammation and inhibit tumor development. This proposal will seek to determine the mechanisms by which inflammation is reduced. This proposal uses a murine model to test the novel hypothesis that BRE inhibit UV-induced skin inflammation and inhibit tumor formation through anti- oxidant properties, resulting in reduced keratinocyte activation, proliferation and DNA damage, reduced neutrophil infiltration and activity, and increased CD4+ T cell infiltration (Specific Aim 1). Further, we hypothesize that BRE will slow tumor progression to aggressive SCC when administered after tumors have formed (Specific Aim 2). Our team of investigators is uniquely able to test the hypothesis and perform these experiments due to complementary expertise in transplant and cellular immunology (VanBuskirk), photo- carcinogenesis and pathology (Kusewitt), skin inflammation and carcinogenesis (Oberyszyn), and the use of black raspberry extracts to prevent and treat cancer (Stoner and Hecht). The data obtained from our studies in this pre-clinical model will provide insights into the mechanisms by which BRE inhibit inflammation and tumor formation and will provide preliminary data for a more complete mechanism dissection and utilization in an R01 application. These studies are directly relevant to the RFA and the mission of NCCAM in that they begin dissection of the mechanisms by which topical application of a natural product, BRE, reduce inflammation after sun exposure and thereby inhibit skin tumor formation. These studies will also determine if BRE slow tumor progression, which will be important for future clinical applications