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

Abstract

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.

Keywords: and treatment of non-melanoma skin cancer (NMSC); basal cell carcinoma; prevention; skin cancer; solar UV radiation; squamous cell carcinoma; tumorigenesis; vitamin D; vitamin D endocrine system (VDES).

Figure 1. Immunohistochemical analysis of vitamin D receptor (VDR) expression in a basal cell carcinoma (BCC). Please note strong nuclear staining that is increased in tumor cells (↓) as compared with unaffected overlying epidermis (↑) of human skin (labeled streptavidin-biotin technique using mAb 9A7γ).

Figure 2. Schematic illustration of the theory suggesting that Ptch regulates Smo by removing oxysterols. Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the crucial molecular defect that causes the formation of BCCs in human skin. Ptch1 possesses a sterol sensing domain (SSD), which is important for suppression of the activity of Smoothened (Smo), the signal transduction partner of Ptch. A current theory suggests that Ptch regulates Smo by removing oxysterols from Smo. Ptch acts like a sterol pump and removes oxysterols that have been created by 7-dehydrocholesterol reductase. Upon binding of a Hh protein or a mutation in the SSD of Ptch the pump is turned off allowing oxysterols to accumulate around Smo. This accumulation of sterols allows Smo to become active via GLI signaling or to remain on the cell membrane for a longer period of time.