Hypovitaminosis D and malignancies
One of the many pleiotropic actions of vitamin D involves effects that are important to prevent the initiation and progression of malignant cell proliferation, including the regulation of cell growth and the cell cycle, cellular differentiation, and apoptosis.35,36
A number of ecological studies have described higher rates of various types of cancers in individuals living at higher latitudes,37-42 fueling speculation that the lower 25(OH)D levels resulting from less UV radiation exposure in these individuals may be responsible for this. A significant limitation of these studies was a lack of measured 25(OH)D levels; hence the described associations could have been the result of some other relevant factor associated with geographical location.
Interestingly, studies examining associations of actual 25(OH)D levels with overall cancer-related mortality have yielded less unanimous results: some,43,44 but not all28,45 have shown an association between lower 25(OH)D levels and increased cancer-related mortality. This discrepancy may be related to the heterogeneous nature of malignancies, as some studies that could not detect an association between 25(OH)D and overall cancer-related mortality were able to discern significant associations between lower 25(OH)D levels and mortality from certain types of cancers (mostly colorectal).45 Based on this possibility, it is important to consider the effect of 25(OH)D deficiency on the incidence of various types of malignancies separately. Such studies showed fairly robust associations between hypovitaminosis D and colorectal cancer incidence.46
More controversial were the associations with pancreatic cancer, for which some,47 but not all48,49 studies were able to detect a link with lower 25(OH)D levels. Most of the studies examining associations between 25(OH)D and prostate cancer were also negative.50-56 Interestingly, the link between 25(OH)D and prostate cancer may not relate to its overall incidence, but rather to its clinical course, as one study detected a significant association between hypovitaminosis D and a more aggressive histological variant of prostate cancer.57
Furthermore, in this study the presence of a less functional allele of the vitamin D receptor appeared to impart a significantly higher risk of aggressive prostate cancer in patients with lower 25(OH)D levels, suggesting that genetic variants of the vitamin D receptor can result in different biological activity and may explain the negative findings of some epidemiologic studies. The importance of genetic variants of the vitamin D receptor were further highlighted by studies examining these in association with prostate cancer58-60 and with breast cancer,61 and finding significant associations for certain types of polymorphisms.
Besides the issue of genetic polymorphism, the results of epidemiologic studies examining the association of 25(OH)D levels with various types of cancers could also have been influenced by the loss of ability to convert 25(OH)D into 1,25(OH)2D in some cancer cells or the difficulty of ascertaining relevant vitamin D status in the case of cancers that have long latency periods (such as prostate cancer).62-64
The uncertainties caused by these considerations can be overcome by randomized controlled trials testing the effect of vitamin D supplementation on cancer incidence and/or cancer-related mortality. This has been done in the Women’s’ Health Initiative, which randomized patients to 1000 mg of calcium + 400 units of vitamin D vs. placebo, and detected no difference in the incidence of colorectal cancers between these two groups.65 While the results of this study seems to cast doubt over the direct effect of vitamin D on cancer incidence, the amount of vita- min D that was administered to individuals in this study may have been too low to have a significant impact.
In summary, the association between 25(OH)D level with cancer-related mortality and with the incidence of various types of cancers is not clear, with various studies often showing contradictory results. This and the negative results of the Women’s Health Initiative suggest that, in spite of several plausible biological mechanisms, the role of vitamin D in the development and clinical outcome of malignancies has not yet been fully understood.