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WCRF/AICR
Global Network

AICR ScienceNow
Volume 19
Winter 2007

Vitamin D's Role in Cancer

As a growing number of studies adds to the evidence that high doses and/or levels of vitamin D may reduce risk of cancer, researchers are investigating how this occurs. Recent studies by AICR-supported researchers provide clues to the mechanisms by which vitamin D plays a role in prostate and skin cancers.

Over the past three decades, numerous epidemiologic and laboratory studies have shown an association between increased vitamin D - measured via blood levels and/or dietary intake - and reduced cancer risk. Recent studies offer new clues to the mechanisms by which vitamin D may influence cancer risk. These findings may point the way to uses for vitamin D to help prevent and treat cancer.

People can obtain vitamin D from foods, supplements and sun exposure. Ultraviolet rays from the sun trigger the production of vitamin D in keratinocytes, which are the major type of cell in the upper layer of skin. This inactive vitamin D is then converted in the liver and then kidney into its active hormone form, known as calcitriol. Scientists have discovered that keratinocytes also have the unique ability to form active vitamin D (calcitriol) for use within the cells.

Laboratory studies in the 1980s showed that vitamin D inhibited the growth of malignant melanoma cells, leukemic cells and squamous carcinoma cells (malignant keratinocytes). Since that time, researchers have found that vitamin D - once considered important only for its role in boosting calcium absorption - regulates numerous genes that influence cellular processes crucial to cancer development, including proliferation, blood-vessel formation (angiogenesis), and apoptosis. This suggests that vitamin D may play a role in the therapy of many types of cancer, says David Feldman, M.D., Professor of Medicine at Stanford University School of Medicine.

Mechanisms in Prostate Cancer

Dr. Feldman and his colleagues have recently demonstrated that calcitriol targets genes that inhibit the synthesis and activity of prostaglandins, hormone-like substances that stimulate cancer growth and progression in cell cultures. In studies aimed at developing treatments, the researchers found that calcitriol acts to inhibit prostaglandins in prostate cancer cells by three separate mechanisms, including decreasing the expression of the COX-2 gene, which synthesizes prostaglandins

Dr. Feldman's research, partially funded by AICR, focuses on the role of vitamin D in prostate cancer. Other studies from his lab suggest that vitamin D elevates levels of insulin-like growth factor binding protein 3 (IGFBP-3) in prostate cancer cells. Higher levels of IGFBP-3 have been shown to reduce the risk of prostate cancer development and metastasis. Another research group, at the University of Rochester, has recently shown that vitamin D inhibits the invasive ability of human prostate cancer cell lines and blocks two critical steps in tumor angiogenesis.

A Role in Skin Cancer

In order to better understand the role of vitamin D and its derivatives in skin cancers, Daniel D. Bikle, M.D., Ph.D., Professor in Medicine, and his colleagues at the University of California, San Francisco, are investigating the differentiation of epithelial keratinocyte cells. These cells convert vitamin D to calcitriol, which stimulates the differentiation of keratinocytes. Abnormal keratinocyte differentiation can develop into squamous cell carcinoma, the most common form of skin cancer.

Dr. Bikle, who has received previous AICR grants relating to vitamin D's role in gene regulation, published a review of his work in late 2005. His cell experiments have revealed several mechanisms by which calcitriol regulates cells' differentiation, and how it fails to induce differentiation in squamous carcinoma cells.

One finding was that squamous carcinoma cells over-express a vitamin D receptor protein complex (DRIP) that promotes the proliferation of the keratinocyte. In normal differentiating cells, the role of this protein complex is taken over by a different vitamin D receptor protein complex (SRC), which binds to the vitamin D receptor and appears to promote the differentiation of these cells. In the cancerous, undifferentiated cells the DRIP complex may prevent the SRC complex from binding to the vitamin D receptor.

"Although we are focused on the skin, I could easily believe the mechanisms would be comparable in other tissues," says Dr. Bikle, who is beginning to test his vitamin D findings in mouse studies. Along with prostate, other cancers that will likely benefit from mechanistic findings of vitamin D are cancers of the breast and colon - both associated with vitamin D deficiency.

References
Bikle DD, Oda Y, Xie Z. Vitamin D and skin cancer: a problem in gene regulation. J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):83-91. Epub 2005 Jul 21.

Moreno J, Krishnan AV, Peehl DM, Feldman D. Related Articles, Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway. Anticancer Res. 2006 Jul-Aug;26(4A):2525-30.

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