UV and skin: Photocarcinogenesis

Abstract

Because the annual incidence of nonmelanoma skin cancers (NMSCs), both basal cell carcinomas and squamous cell carcinomas, exceeds that of all other cancers combined, there is a need to understand the mechanisms by which these neoplasms occur in order to develop more effective methods for their prevention and therapy. Most are caused by overexposure to ultraviolet (UV) radiation; the discipline of photocarcinogenesis seeks to understand the pathogenesis of UV-induced skin cancers. The sequence of events in which molecular and biochemical changes accumulate in keratinocytes over long periods of time has been divided into three distinct stages: initiation, promotion, and progression. During initiation, UV-induced DNA damage, primarily cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone 6-4 photoproducts (6-4PPs), form in keratinocytes. These photochemical changes cause mutations in TP53, Ptch, and other genes that control cell death, proliferation, and differentiation. During the promotion stage, repeated doses of UV cause chronic inflammation and encourage clonal expansion of initiated keratinocytes. The end results of promotion are premalignant actinic keratoses (AKs). In the progression stage, additional biochemical changes occur, such as epithelial-mesenchymal transition, which allows premalignant AKs to become invasive squamous cell carcinomas. In addition to these stages of photocarcinogenesis, UV radiation impairs host immune responses that have evolved to identify and neutralize mutant, premalignant, and malignant cells. Recent advances in our understanding of photocarcinogenesis have resulted in new treatments, such as small molecule inhibitors of the hedgehog pathway. There are also many promising chemopreventive and chemotherapeutic agents under investigation.