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The role of vitamin D in reducing cancer risk and progression

Key Points

  • Vitamin D3 is the precursor to the potent steroid hormone calcitriol (1,25 dihydroxyvitamin D3 (1,25(OH)2D3)) that regulates the expression of many genes in most tissues of the body.

  • Dietary vitamin D3 is converted into 25 hydroxyvitamin D3 (25(OH)D3) in the liver; this is the circulating form of vitamin D, which is subsequently hydroxylated to form calcitriol by the cytochrome P450 enzyme CYP27B1 in the kidneys. Calcitriol is also synthesized locally by CYP27B1 present in most extrarenal tissues, including many cancer cells, where it acts in a paracrine manner. Levels of calcitriol are additionally regulated by the cytochrome P450 enzyme CYP24A1, which begins the inactivation of calcitriol through 24-hydroxylation.

  • Calcitriol regulates multiple signalling pathways involved in proliferation, apoptosis, differentiation, inflammation, invasion, angiogenesis and metastasis, and it therefore has the potential to affect cancer development and growth. Recent findings indicate that calcitriol also regulates microRNA expression and may affect cancer stem cell biology.

  • Multiple cell culture and animal models of cancer support a role for dietary vitamin D3 and calcitriol in retarding cancer development and progression; however, data from human clinical trials are thus far inconsistent.

  • Epidemiological studies suggest that vitamin D deficiency is associated with increased incidence of cancer and worse outcomes, although many studies do not demonstrate these associations.

  • Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D3 synthesis and degradation pathways have been implicated in affecting the risk of cancer development.

  • Given the interest in using vitamin D3 to reduce cancer risk, further research is needed, particularly randomized controlled trials (RCTs), to demonstrate in humans whether individuals with low levels of circulating 25(OH)D are at increased risk of developing cancer and whether calcitriol or vitamin D supplements can reduce cancer risk and progression and improve outcomes.

Abstract

Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.

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Figure 1: The renal endocrine pathway and the extrarenal autocrine or paracrine pathway of calcitriol synthesis.
Figure 2: Genomic mechanism of calcitriol action through the VDR and its antineoplastic actions.
Figure 3: Calcitriol regulation of specific signalling pathways that drive breast, colon and prostate cancer growth.

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Acknowledgements

D.F. acknowledges research grant support from California Breast Cancer Research Program, the American Institute for Cancer Research and the Department of Defense Breast and Prostate Cancer Research Programs. B.J.F. is supported by a US National Institutes of Health (NIH) Director's New Innovator Award (DP2OD006740) and the California Breast Cancer Research Program.

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Glossary

Randomized clinical trials

(RCTs). Trials in humans that are the gold standard for proof of efficacy of an intervention in cancer and other diseases.

Hypercalcaemia

Increased levels of blood calcium that can lead to many symptoms, including muscle cramps, drowsiness, bone pain, kidney stones and, in severe cases, cardiac arrest and coma.

Calciotropic hormones

A complex network of hormones that regulates calcium and phosphate metabolism to normalize bone mineralization, including calcitriol, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23).

Prostate-specific antigen

(PSA). A useful biomarker for prostate growth, especially to monitor the recurrence of prostate cancer.

Naproxen

An anti-inflammatory drug that inhibits cyclooxygenase 2 (COX2), which is the rate-limiting enzyme that catalyses prostaglandin synthesis.

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Feldman, D., Krishnan, A., Swami, S. et al. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 14, 342–357 (2014). https://doi.org/10.1038/nrc3691

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