The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (NMSC)

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.

Efficacy of ingenol mebutate gel for actinic keratosis in patients treated by thiazide diuretics

“…Many investigations have indicated that vitamin D 3 action reduces risk of nonmelanoma skin cancers, maybe modulating p53 response to DNA damage in SCC 17,18. The association between plasma 25-hydroxy-vitamin D (25(OH)D) levels and the incident risk of SCC has been recognized, and could be, together with photoprotection, one of the parameters based on which patients having major risk factors for the development of SCC can be treated.…”

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…Upon binding of Shh protein or a mutation in the SSD of Ptch, the pump is turned off, which allows oxysterols to accumulate around Smo. This accumulation of sterols renders Smo to become active or stay on the membrane for a longer period of time (Reichrath and Reichrath, 2013). In contrast to Drosophila , vertebrates possess another level of hedgehog regulation through ligand-dependent antagonism mediated by Hh-interacting protein 1 (Hhip1).…”

Association between genetic variation within vitamin D receptor‐DNA binding sites and risk of basal cell carcinoma

“…Vitamin D levels have been reported to be associated with incidence and outcomes of certain types of cancer, including NMSC . In addition, some studies have shown relationships between VDR gene polymorphisms and the risk of BCC .…”

“…In addition, some studies have shown relationships between VDR gene polymorphisms and the risk of BCC . In addition, vitamin D‐binding protein (VDBP) single‐nucleotide polymorphisms (SNPs) affect 25(OH)D levels, thereby influencing skin carcinogenesis . Recently, genetic variations within VDR binding sites have emerged as important contributors to transcription factor affinity, and therefore, their impact on the function of VDES has begun to be considered .…”