Vitamin D and systemic cancer: is this relevant to malignant melanoma?

Summary 1,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] is a well‐known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH) 2 D 3 involves 25‐ and 1α‐hydroxylation of vitamin D 3 , in the liver and kidney, respectively, of absorbed or skin‐synthesized vitamin D 3 . There is recent focus on the importance in growth control of local metabolism of 1,25(OH) 2 D 3 , which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24‐hydroxylase. The classical signalling pathway of 1,25(OH) 2 D 3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH) 2 D 3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH) 2 D 3 has a major inhibitory effect on the G 1 /S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor‐β and downregulation of the epidermal growth factor receptor. 1,25(OH) 2 D 3 may induce apoptosis either indirectly through effects on the insulin‐like growth receptor and tumour necrosis factor‐α or more directly via the Bcl‐2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress‐activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D 3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D 3 /1,25(OH) 2 D 3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D 3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D 3 /1,25(OH) 2 D 3 /VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH) 2 D 3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH) 2 D 3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D 3 in MM, but ultraviolet radiation, which is a principal source of vitamin D 3 , is mutagenic. Further work is necessary on the influence of serum vitamin D 3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D 3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D 3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM.