Consideration of possible effects of vitamin D on established cancer, with reference to malignant melanoma

Epidemiological studies indicate that Vitamin D has a beneficial, inhibitory effect on cancer development and subsequent progression, including melanoma (MM), and favourable MM outcome has been reported as directly related to vitamin D₃ status, assessed by serum 25-hydroxyvitamin D₃ (25[OH]D₃) levels taken at diagnosis. It has been recommended that MM patients with deficient levels of 25(OH)D₃ be given vitamin D₃. We examine possible beneficial or detrimental effects of treating established cancer with vitamin D₃. We consider the likely biological determinants of cancer outcome, the reported effects of vitamin D₃ on these in both cancerous and non-cancerous settings, and how the effect of vitamin D₃ might change depending on the integrity of tumour vitamin D receptor (VDR) signalling. We would argue that the effect of defective tumour VDR signalling could result in loss of suppression of growth, reduction of anti-tumour immunity, with potential antagonism of the elimination phase and enhancement of the escape phase of tumour immunoediting, possibly increased angiogenesis but continued suppression of inflammation. In animal models, having defective VDR signalling, vitamin D₃ administration decreased survival and increased metastases. Comparable studies in man are lacking but in advanced disease, a likely marker of defective VDR signalling, studies have shown modest or no improvement in outcome with some evidence of worsening. Work is needed in assessing the integrity of tumour VDR signalling and the safety of vitamin D₃ supplementation when defective.