Melanoma and vitamin D

Abstract

Vitamin D is a fat-soluble steroid hormone, which is essential to health and for which epidemiological studies suggest a role in autoimmune disease, infections, cardiovascular disease and cancer. It is ingested in foods such as oily fish and supplements, so that average levels vary between countries, but most individuals worldwide make most of their vitamin D as a result of the effects of sun exposure on the skin. Many studies in different populations around the world have in recent years shown that sub-optimal levels of vitamin D (<70 nmol/L) are common. A series of epidemiological studies have suggested that low vitamin D levels increase the risk of cancers, particularly of the breast and gastrointestinal tracts, so that there has been much interest in understanding the effects of vitamin D on cancer cells. Vitamin D binds to the vitamin D receptor (VDR) resulting in transcription of a number of genes playing a role in inhibition of MAPK signalling, induction of apoptosis and cell-cycle inhibition, and therefore vitamin D has anti-proliferative and pro-apoptotic effects in cells of many lineages. It also has suppressive effects on adaptive immunity and is reported to promote innate immunity. Here we review data on vitamin D and melanoma. There are in vitro data, which suggest that vitamin D has the same anti-proliferative effects on melanoma cells as have been demonstrated in other cells. We have reported data to suggest that vitamin D levels at diagnosis have a role in determining outcome for melanoma patients. There is a curious relationship between melanoma risk and sun exposure where sunburn is causal but occupational sun exposure is not (at least in temperate climes). Seeking to understand this, we discuss data, which suggest (but by no means prove) that vitamin D might also have a role in susceptibility to melanoma. In conclusion, much remains unknown about vitamin D in general and certainly about vitamin D and melanoma. However, the effects of avoidance of suboptimal vitamin D levels on cancer cell proliferation are likely to be beneficial to the melanoma patient. The possible results of high vitamin D levels on the immune system remain unclear however and a source of some concern, but the data support the view that serum levels in the range 70-100 nmol/L might be a reasonable target for melanoma patients as much as for other members of the population.

Figure 1

Vitamin D Metabolism and Biological effects. Sun exposure (UVB) results in photoactivation of 7‐dehydrocholesterol to pro‐D3(cholecalciferol), then heat results in production of Vit D3. Endogenous and dietary Vit D3 along with dietary D2 (ergocalciferol) are metabolized by the liver and kidney to 1,25(OH)2D3 (1,25 dihydrocholecalciferol) via the enzymes 25‐OHase (25‐hydroxylase) and 1αOHase (1α‐hydroxylase) encoded by the genes CYP27A1 and CYP27B1 respectively. 1,25(OH)2D3 has a negative feedback on PTH secretion and it's classical effects are on intestinal absorption and bone mineralization. Many cells have the ability to synthesis 1,25 dihydrocholecalciferol locally, resulting in possible apocrine and paracrine non‐classical effects on a variety of tissue and immune cells. Vitamin D forms a heterodimer with retinoid X receptor and binds to the nuclear vitamin D receptor (VDR) resulting in effects on gene expression.

Figure 2

Variation in serum vitamin D levels by season of venepuncture in the Leeds Melanoma Cohort. A level of 78 nmol/L indicated by red line is the level that PTH stabilisation is expected and <50 nmol/L below the blue line is used by some studies to define vitamin D insufficient which illustrates how many melanoma patients have sub‐optimal levels at diagnosis.

Figure 3

Up to date (Sept 2010) Kaplan‐Meier curves for relapse free survival probabilities for serum vitamin D levels (nmol/L) at interview (categorized based on tertile cutoff) in the Leeds Melanoma Cohort. The text box shows the overall proportion of relapsers by vitamin D category.