The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (NMSC): Present concepts and future perspectives.

Solar UV (UV)-B-radiation exerts both beneficial and adverse effects on human health. On the one hand, it is the most important environmental risk factor for the development of non-melanoma skin cancer [NMSC; most importantly basal (BCC) and squamous (SCC) cell carcinomas], that represent the most common malignancies in Caucasian populations. On the other hand, the human body's requirements of vitamin D are mainly achieved by UV-B-induced cutaneous photosynthesis. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer has been convincingly demonstrated. In line with these findings, epidemiologic and laboratory investigations now indicate that vitamin D and its metabolites have a risk reducing effect for NMSC. Potential mechanisms of action include inhibition of the hedgehog signaling pathway (BCC) and modulation of p53-mediated DNA damage response (SCC). As a consequence of these new findings it can be concluded that UV-B-radiation exerts both beneficial and adverse effects on risk and prognosis of NMSC. It can be assumed that many independent factors, including frequency and dose of UV-B exposure, skin area exposed, and individual factors (such as skin type and genetic determinants of the skin`s vitamin D status and of signaling pathways that are involved in the tumorigenesis of NMSC) determine whether UV-B exposure promotes or inhibits tumorigenesis of NMSC. Moreover, these findings may help to explain many of the differential effects of UV-B radiation on risk of NMSC, including variation in the dose-dependent risk for development of SCC in situ (actinic keratosis, AK), invasive SCC, and BCC. In this review, we analyze the relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of NMSC and give an overview of present concepts and future perspectives.