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Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)

Vitamin D

Overview

General Information and History

Vitamin D, also called calciferol, cholecalciferol (D3), or ergocalciferol (D2), is a fat-soluble vitamin found in fortified dairy products, fatty fish, fish liver oil, and eggs. Vitamin D is made naturally by the body when exposed to sunlight.

In 1922, researchers discovered that heated, oxidized cod-liver oil, called "fat-soluble factor A" and later known as vitamin D, played an important role in curing rickets in rats.[1]

Vitamin D performs many roles in the body, including the following:

Vitamin D is needed for bone growth and protects against osteoporosis in adults.[2] Vitamin D status is usually checked by measuring the level of 25-hydroxyvitamin D in the blood.

Preclinical/Animal Studies

In vitro studies

To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of bone marrow. The study reported that 1,25-alpha-dihydroxyvitamin D3 (1,25-D3) suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,25-D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation.[3]

Vitamin D–binding protein (DBP) transports vitamin D in the bloodstream. Studies have shown that one of its products, DBP-macrophage activating factor (DBP-maf), may have antiangiogenic and antitumor activities. One study examined the effects of DBP-maf on prostate cancer cells. Treating prostate cancer cells with DBP-maf resulted in inhibited cellular migration, proliferation, and reduced levels of urokinase plasminogen activator receptor (uPAR; activity of this receptor correlates with tumor metastasis). These findings suggest that DBP-maf has a direct effect on prostate cancer cells.[4]

Studies have reported that 1,25-D3 may play an important role in prostate cancer biology. Studies have suggested that a newly discovered protein, protein disulfide isomerase family A, member 3 (PDIA3), may function as a membrane receptor binding to 1,25-D3. According to one study, PDIA3 is expressed in normal prostate cells as well as in LNCaP and PC-3 prostate cancer cell lines. In addition, their findings suggest that 1,25-D3 may act on prostate cancer cells via multiple signaling pathways, indicating there may be a number of potential therapeutic targets.[5]

In vivo studies

Tumor progression was compared in two murine models of prostate cancer. In vitamin D receptor- knockout animals, rate of tumor progression and cellular proliferation were greater than in wild type animals. However, in mice that were supplemented with testosterone, these differences did not occur, suggesting that there may be significant interaction between androgen signaling and vitamin D signaling.[6]

In a 2011 study, nude mice were fed a control diet or a diet deficient in vitamin D and were then injected with prostate cancer cells into bone marrow or into soft tissues. Osteolytic lesions were larger and progressed at a faster rate in vitamin D–deficient mice that had bone marrow injected with cancer cells than in mice that had adequate levels of vitamin D. However, there was no difference in soft tissue tumors among mice with different vitamin D levels. Results of this study show that vitamin D deficiency is associated with growth of prostate cancer cells in bone but not in soft tissue.[7]

A 2014 study evaluated calcitriol and a less-calcemic vitamin D analog in an aggressive transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Neither vitamin D analog impacted the rate of development of castration -resistant prostate cancer in mice, whether they were treated before or after castration. However, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant organ metastases after prolonged treatment. In sum, intervention with potent vitamin D compounds in TRAMP mice slowed androgen-stimulated tumor progression but, over time, may have led to more aggressive disease as indicated by increased distant metastases (P = .0823).[8] This preclinical data supports findings of the 2008 retrospective study [9] of an association between serum vitamin D levels and aggressive prostate cancer (refer to the Human Studies section in the Vitamin D section of this summary for more information about this study).

Vitamin D as adjuvant therapy

Cryotherapy may be used for treating prostate cancer. Studies have been conducted to identify potential agents that may help improve efficacy of the freezing procedure. In a 2010 study, mice were injected with prostate cancer cells and treated with calcitriol, cryoablation, or both. The combination treatment group experienced larger necrotic areas, more apoptosis, and less cell proliferation than did the other experimental groups.[10] A subsequent study corroborated these findings, showing that combining calcitriol and cryoablation resulted in more cell death than cryotherapy alone.[11]

Vitamin D may help enhance other types of cancer treatments, such as radiation. In another study, prostate cancer cells were treated with valproic acid (VPA) and/or 1,25-D3, followed by radiation. Cells that were treated with VPA and/or 1,25-D3 and radiation had greater decreases in cell proliferation than did cells treated solely with radiation. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,25-D3, and radiation.[12]

Human Studies

Epidemiological studies

The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies. Vitamin D levels were analyzed annually for 5 years in patients with nonmetastatic prostate cancer. Results showed that throughout the course of the study, vitamin D insufficiency was prevalent among these cancer patients.[13] Levels of vitamin D metabolites in prostate cancer patients were examined in a 2011 study. Analysis revealed that patients with the lowest concentrations of prediagnostic plasma 25-hydroxy vitamin D [25(OH)D] levels had a higher risk of developing metastatic prostate cancer than did patients with higher levels of 25(OH)D. However, there was no association between metastatic prostate cancer and circulating levels of 1,25(OH)D.[14] In another study, serum levels of 25(OH)D in prostate cancer patients were assessed. Results suggest that medium or high levels of serum 25(OH)D may be associated with better prognoses than lower levels of serum 25(OH)D. These findings indicate that 25(OH)D may play a role in disease progression and may be a marker of prognosis in prostate cancer patients.[15] Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study who had been diagnosed with prostate cancer and control participants were selected for analysis and monitored for up to 20 years. Results suggested that men with a higher vitamin D status (assessed via serum 25(OH)D concentrations) had a greater risk of developing prostate cancer than did men with lower vitamin D status.[16] A 2008 retrospective study of 749 men with prostate cancer diagnosed 1 to 8 years after blood draw and 781 matched controls found higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.[9] Both of these studies [9,16] were included in a meta-analysis of 21 studies, involving 11,941 cases and 13,870 controls, that found a 17% elevated risk of prostate cancer in men with higher levels of 25(OH)D.[17] One explanation offered for this finding may be a potential detection bias with men from higher socio-economic groups who have higher vitamin D levels and who are more likely to undergo prostate-specific antigen (PSA) testing, resulting in higher reported incidence rates.

Serum 25(OH)D levels were obtained from 667 men in Chicago undergoing first prostate biopsy for an elevated PSA or an abnormal digital rectal exam.[18] Severe vitamin D deficiency (<12 ng/mL) was associated with increased risk of a prostate cancer diagnosis on biopsy among African American men. Severe deficiency was positively associated with higher Gleason score (≥4+4), higher clinical stage (>cT2b), and overall risk category in both white American and African American men. In contrast, baseline serum 25(OH)D levels obtained in a case (n = 1,731)–cohort (n = 3,203) analysis from the Selenium and Vitamin E Cancer Prevention Trial found significantly reduced risks among men who had moderate concentrations (45–70 nmol/L) compared with men who had lower or higher values.[19] This U-shaped association was most pronounced for cancers with Gleason scores of 7 to 10.

An important means of obtaining vitamin D is via sunlight. Studies have investigated the potential link between sunlight exposure and prostate cancer. According to a 2006 study, PSA levels rise at a slower rate during spring and summer than at other times of the year; this may be related to higher vitamin D levels obtained during those months.[20] Another study found that while men with low levels of sun exposure had increased risk of all prostate cancers, among men with prostate cancer, less sun exposure was associated with lower risk of advanced disease. Results of a meta-analysis, published in the same report, showed that men with low sun exposure had an increased risk of incident and advanced prostate cancer.[21] Analysis of mortality rate data from 1950 to 1994 revealed that the geographic distribution of prostate cancer mortality in the United States is inversely related to UV radiation. In addition, this relationship is more evident in areas north of 40 degrees N latitude.[22] Likewise, a study in France reported that UV radiation may be associated with reductions in cancer risk and mortality.[23]

A number of studies have explored a possible connection between the vitamin D receptor (VDR) and risk of prostate cancer. A 2011 prospective study examined VDR expression in prostate tumors. Patients with high levels of VDR expression had lower PSA at diagnosis, less advanced tumor stage, and reduced risk of lethal prostate cancer compared with patients with lower levels of VDR expression in tumors.[24] In a 2009 study, genetic variants in VDR were analyzed in prostate cancer patients participating in the Prostate Testing for Cancer and Treatment (ProtecT) trial. Five polymorphisms of VDR were identified in the participants. A meta-analysis, published in the same report, revealed no association between specific variants and prostate cancer stage (TNM staging system), but found that three genotypes (BSML, APAL, and TAQL) may be associated with cancer grade (Gleason score), suggesting there may be a link between specific VDR polymorphisms and advanced prostate cancer at diagnosis.[25] Polymorphisms in the VDR receptor, the vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) were examined in a 2010 study. Variations in the three genes investigated were associated with changes in risk of recurrence and progression of prostate cancer as well as prostate cancer mortality.[26]

A 2008 meta-analysis of 45 observational studies found no association between intake of vitamin D and prostate cancer risk.[27] A meta-analysis published in 2011 reviewed 25 studies examining the link between prostate cancer incidence and indicators of vitamin D. Analysis of those studies found no association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.[28]

Intervention studies

Calcitriol, the hormonally active form of vitamin D, has been the focus of some studies in prostate cancer patients. In an open-label, phase II study, patients with recurrent prostate cancer were treated with calcitriol and naproxen for 1 year. The combination of calcitriol and naproxen was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression.[29] In a 2010 study, patients with castration-resistant prostate cancer were treated with calcitriol and dexamethasone. The results indicated that while the treatments were well tolerated, they did not have an effect on participants' PSA levels.[30]

In a 2009 study, patients with locally advanced or metastatic prostate cancer and asymptomatic progression of their PSA levels were treated with vitamin D2 (ergocalciferol) at either 10 μg or 25 μg daily. The investigators reported that about 20% of these patients had at least a 25% drop in PSA level 3 months after initiating the vitamin D2.[31]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for CAM clinical trials on vitamin D that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

References

  1. Wolf G: The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr 134 (6): 1299-302, 2004. [PUBMED Abstract]
  2. National Institutes of Health. Office of Dietary Supplements: Dietary Supplement Fact Sheet: Vitamin D. Bethesda, MD: National Institutes of Health, 2011. Available online. Last accessed October 9, 2014.
  3. Hsu JW, Yasmin-Karim S, King MR, et al.: Suppression of prostate cancer cell rolling and adhesion to endothelium by 1α,25-dihydroxyvitamin D3. Am J Pathol 178 (2): 872-80, 2011. [PUBMED Abstract]
  4. Gregory KJ, Zhao B, Bielenberg DR, et al.: Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. PLoS One 5 (10): e13428, 2010. [PUBMED Abstract]
  5. Karlsson S, Olausson J, Lundh D, et al.: Vitamin D and prostate cancer: the role of membrane initiated signaling pathways in prostate cancer progression. J Steroid Biochem Mol Biol 121 (1-2): 413-6, 2010. [PUBMED Abstract]
  6. Mordan-McCombs S, Brown T, Wang WL, et al.: Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status. J Steroid Biochem Mol Biol 121 (1-2): 368-71, 2010. [PUBMED Abstract]
  7. Zheng Y, Zhou H, Ooi LL, et al.: Vitamin D deficiency promotes prostate cancer growth in bone. Prostate 71 (9): 1012-21, 2011. [PUBMED Abstract]
  8. Ajibade AA, Kirk JS, Karasik E, et al.: Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol) treatment in the TRAMP model of prostate cancer. PLoS One 9 (2): e89555, 2014. [PUBMED Abstract]
  9. Ahn J, Peters U, Albanes D, et al.: Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 100 (11): 796-804, 2008. [PUBMED Abstract]
  10. Kimura M, Rabbani Z, Mouraviev V, et al.: Role of vitamin D(3) as a sensitizer to cryoablation in a murine prostate cancer model: preliminary in vivo study. Urology 76 (3): 764.e14-20, 2010. [PUBMED Abstract]
  11. Santucci KL, Snyder KK, Baust JM, et al.: Use of 1,25α dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model. Prostate Cancer Prostatic Dis 14 (2): 97-104, 2011. [PUBMED Abstract]
  12. Gavrilov V, Leibovich Y, Ariad S, et al.: A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells. J Steroid Biochem Mol Biol 121 (1-2): 391-4, 2010. [PUBMED Abstract]
  13. Choo CS, Mamedov A, Chung M, et al.: Vitamin D insufficiency is common in patients with nonmetastatic prostate cancer. Nutr Res 31 (1): 21-6, 2011. [PUBMED Abstract]
  14. Fang F, Kasperzyk JL, Shui I, et al.: Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 6 (4): e18625, 2011. [PUBMED Abstract]
  15. Tretli S, Hernes E, Berg JP, et al.: Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 100 (3): 450-4, 2009. [PUBMED Abstract]
  16. Albanes D, Mondul AM, Yu K, et al.: Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev 20 (9): 1850-60, 2011. [PUBMED Abstract]
  17. Xu Y, Shao X, Yao Y, et al.: Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin Oncol 140 (9): 1465-77, 2014. [PUBMED Abstract]
  18. Murphy AB, Nyame Y, Martin IK, et al.: Vitamin D deficiency predicts prostate biopsy outcomes. Clin Cancer Res 20 (9): 2289-99, 2014. [PUBMED Abstract]
  19. Kristal AR, Till C, Song X, et al.: Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 23 (8): 1494-504, 2014. [PUBMED Abstract]
  20. Vieth R, Choo R, Deboer L, et al.: Rise in prostate-specific antigen in men with untreated low-grade prostate cancer is slower during spring-summer. Am J Ther 13 (5): 394-9, 2006 Sep-Oct. [PUBMED Abstract]
  21. Gilbert R, Metcalfe C, Oliver SE, et al.: Life course sun exposure and risk of prostate cancer: population-based nested case-control study and meta-analysis. Int J Cancer 125 (6): 1414-23, 2009. [PUBMED Abstract]
  22. Schwartz GG, Hanchette CL: UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control 17 (8): 1091-101, 2006. [PUBMED Abstract]
  23. Grant WB: An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol 2 (2): 62-7, 2010. [PUBMED Abstract]
  24. Hendrickson WK, Flavin R, Kasperzyk JL, et al.: Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol 29 (17): 2378-85, 2011. [PUBMED Abstract]
  25. Chen L, Davey Smith G, Evans DM, et al.: Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review. Cancer Epidemiol Biomarkers Prev 18 (11): 2874-81, 2009. [PUBMED Abstract]
  26. Holt SK, Kwon EM, Koopmeiners JS, et al.: Vitamin D pathway gene variants and prostate cancer prognosis. Prostate 70 (13): 1448-60, 2010. [PUBMED Abstract]
  27. Huncharek M, Muscat J, Kupelnick B: Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60 (4): 421-41, 2008. [PUBMED Abstract]
  28. Gilbert R, Martin RM, Beynon R, et al.: Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 22 (3): 319-40, 2011. [PUBMED Abstract]
  29. Srinivas S, Feldman D: A phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 29 (9): 3605-10, 2009. [PUBMED Abstract]
  30. Chadha MK, Tian L, Mashtare T, et al.: Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. Cancer 116 (9): 2132-9, 2010. [PUBMED Abstract]
  31. Newsom-Davis TE, Kenny LM, Ngan S, et al.: The promiscuous receptor. BJU Int 104 (9): 1204-7, 2009. [PUBMED Abstract]
  • Updated: December 12, 2014