Active surveillance (AS) is an attractive alternative to immediate treatment for men with low-risk prostate cancer. Thus, the identification of environmental factors that promote the progression of indolent disease towards aggressive stages is critical to optimize clinical management. Epidemiological studies suggest that calcium-rich diets contribute to an increased risk of developing prostate cancer and that vitamin D reduces this risk. However, the potential effect of these nutrients on the progression of early-stage prostate tumours is uncertain, as studies in this setting are scarce and have not provided unambiguous conclusions. By contrast, the results of a preclinical study from our own group demonstrate that a diet high in calcium dose-dependently accelerated the progression of early-stage prostate tumours and that dietary vitamin D prevented this effect. The extent to which the conclusions of preclinical and epidemiological studies support a role for calcium and vitamin D and the relevance of monitoring and adjustment of calcium and/or vitamin D intake in patients on AS require further investigation.
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Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 67, 7–30 (2017).
Potosky, A. L., Miller, B. A., Albertsen, P. C. & Kramer, B. S. The role of increasing detection in the rising incidence of prostate cancer. JAMA 273, 548–552 (1995).
Skinner, H. G. & Schwartz, G. G. The relation of serum parathyroid hormone and serum calcium to serum levels of prostate-specific antigen: a population-based study. Cancer Epidemiol. Biomarkers Prev. 18, 2869–2873 (2009).
Aune, D. et al. Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies. Am. J. Clin. Nutr. 101, 87–117 (2015).
Yang, E. S., Maiorino, C. A., Roos, B. A., Knight, S. R. & Burnstein, K. L. Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. Mol. Cell Endocrinol. 186, 69–79 (2002).
Moreno, J., Krishnan, A. V. & Feldman, D. Molecular mechanisms mediating the anti-proliferative effects of vitamin D in prostate cancer. J. Steroid Biochem. Mol. Biol. 97, 31–36 (2005).
Bao, B. Y., Yeh, S. D. & Lee, Y. F. 1alpha, 25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases. Carcinogenesis 27, 32–42 (2006).
Sung, V. & Feldman, D. 1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration. Mol. Cell. Endocrinol. 164, 133–143 (2000).
Bao, B. Y., Yao, J. & Lee, Y. F. 1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis 27, 1883–1893 (2006).
Giovannucci, E. Dietary influences of 1,25(OH)2 vitamin D in relation to prostate cancer: a hypothesis. Cancer Causes Control 9, 567–582 (1998).
Dell’Atti, L., Galosi, A. B. & Ippolito, C. Prostatic calculi detected in peripheral zone of the gland during a transrectal ultrasound biopsy can be significant predictors of prostate cancer. Arch. Ital. Urol. Androl. 88, 304–307 (2016).
Smolski, M., Turo, R., Whiteside, S., Bromage, S. & Collins, G. N. Prevalence of prostatic calcification subtypes and association with prostate cancer. Urology 85, 178–181 (2015).
Bernichtein, S. et al. Vitamin D3 prevents calcium-induced progression of early-stage prostate tumors by counteracting TRPC6 and calcium sensing receptor upregulation. Cancer Res. 77, 355–365 (2017).
Giovannucci, E., Liu, Y., Stampfer, M. J. & Willett, W. C. A prospective study of calcium intake and incident and fatal prostate cancer. Cancer Epidemiol. Biomarkers Prev. 15, 203–210 (2006).
Park, Y. et al. Calcium, dairy foods, and risk of incident and fatal prostate cancer: the NIH-AARP Diet and Health Study. Am. J. Epidemiol. 166, 1270–1279 (2007).
Bristow, S. M. et al. Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials. Br. J. Nutr. 110, 1384–1393 (2013).
Rowland, G. W., Schwartz, G. G., John, E. M. & Ingles, S. A. Calcium intake and prostate cancer among African Americans: effect modification by vitamin D receptor calcium absorption genotype. J. Bone Miner. Res. 27, 187–194 (2012).
Giovannucci, E. et al. Calcium and fructose intake in relation to risk of prostate cancer. Cancer Res. 58, 442–447 (1998).
Wright, M. E., Bowen, P., Virtamo, J., Albanes, D. & Gann, P. H. Estimated phytanic acid intake and prostate cancer risk: a prospective cohort study. Int. J. Cancer 131, 1396–1406 (2012).
Ahn, J. et al. Dairy products, calcium intake, and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol. Biomarkers Prev. 16, 2623–2630 (2007).
Allen, N. E. et al. Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition. Br. J. Cancer 98, 1574–1581 (2008).
Keum, N., Aune, D., Greenwood, D. C., Ju, W. & Giovannucci, E. L. Calcium intake and colorectal cancer risk: dose-response meta-analysis of prospective observational studies. Int. J. Cancer 135, 1940–1948 (2014).
Tantamango-Bartley, Y. et al. Independent associations of dairy and calcium intakes with colorectal cancers in the Adventist Health Study-2 cohort. Public Health Nutr. 20, 2577–2586 (2017).
Margolis, K. L. & Manson, J. E. Calcium supplements and cardiovascular disease risk: what do clinicians and patients need to know? Ann. Intern. Med. 165, 884–885 (2016).
Pettersson, A. et al. Milk and dairy consumption among men with prostate cancer and risk of metastases and prostate cancer death. Cancer Epidemiol. Biomarkers Prev. 21, 428–436 (2012).
Gilbert, 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, 319–340 (2011).
Xu, 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, 1465–1477 (2014).
Jackson, M. D. et al. Both serum 25-hydroxyvitamin D and calcium levels may increase the risk of incident prostate cancer in Caribbean men of African ancestry. Cancer Med. 4, 925–935 (2015).
Wong, Y. Y. et al. In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of prostate, but not colorectal or lung cancer. PLoS ONE 9, e99954 (2014).
Sawada, N. et al. Plasma 25-hydroxy vitamin D and subsequent prostate cancer risk in a nested Case-Control study in Japan: the JPHC study. Eur. J. Clin. Nutr. 71, 132–136 (2017).
Skaaby, T. et al. Prospective population-based study of the association between serum 25-hydroxyvitamin-D levels and the incidence of specific types of cancer. Cancer Epidemiol. Biomarkers Prev. 23, 1220–1229 (2014).
Layne, T. M. et al. Serum 25-hydroxyvitamin D, vitamin D binding protein, and prostate cancer risk in black men. Cancer 123, 2698–2704 (2017).
Deschasaux, M. et al. A prospective study of plasma 25-hydroxyvitamin D concentration and prostate cancer risk. Br. J. Nutr. 115, 305–314 (2016).
Paller, C. J. et al. Risk of prostate cancer in African-American men: evidence of mixed effects of dietary quercetin by serum vitamin D status. Prostate 75, 1376–1383 (2015).
Kristal, A. R. et al. Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol. Biomarkers Prev. 23, 1494–1504 (2014).
Tuohimaa, P. et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int. J. Cancer 108, 104–108 (2004).
Schenk, J. M. et al. Serum 25-hydroxyvitamin D concentrations and risk of prostate cancer: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol. Biomarkers Prev. 23, 1484–1493 (2014).
Ross, A. C. et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab. 96, 53–58 (2011).
Garland, C. F. & Gorham, E. D. Dose-response of serum 25-hydroxyvitamin D in association with risk of colorectal cancer: a meta-analysis. J. Steroid Biochem. Mol. Biol. 168, 1–8 (2017).
Vaughan-Shaw, P. G. et al. The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis. Br. J. Cancer 116, 1092–1110 (2017).
Brandstedt, J., Almquist, M., Manjer, J. & Malm, J. Vitamin D, PTH, and calcium in relation to survival following prostate cancer. Cancer Causes Control 27, 669–677 (2016).
Mondul, A. M., Weinstein, S. J., Moy, K. A., Mannisto, S. & Albanes, D. Circulating 25-hydroxyvitamin D and prostate cancer survival. Cancer Epidemiol. Biomarkers Prev. 25, 665–669 (2016).
Marshall, D. T. et al. Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. J. Clin. Endocrinol. Metab. 97, 2315–2324 (2012).
Beer, T. M. & Myrthue, A. Calcitriol in cancer treatment: from the lab to the clinic. Mol. Cancer Ther. 3, 373–381 (2004).
Trump, D. L. et al. Anti-tumor activity of calcitriol: pre-clinical and clinical studies. J. Steroid Biochem. Mol. Biol. 89–90, 519–526 (2004).
Medioni, J. et al. Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients. Clin. Cancer Res. 20, 4471–4477 (2014).
Ray, R. et al. Effect of dietary vitamin D and calcium on the growth of androgen-insensitive human prostate tumor in a murine model. Anticancer Res. 32, 727–731 (2012).
Swami, S., Krishnan, A. V. & Feldman, D. Vitamin D metabolism and action in the prostate: implications for health and disease. Mol. Cell. Endocrinol. 347, 61–69 (2011).
Ittmann, M. et al. Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res. 73, 2718–2736 (2013).
Kovalenko, P. L. et al. Dietary vitamin D and vitamin D receptor level modulate epithelial cell proliferation and apoptosis in the prostate. Cancer Prev. Res. 4, 1617–1625 (2011).
Mordan-McCombs, S. 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, 368–371 (2010).
Banach-Petrosky, W. et al. Vitamin D inhibits the formation of prostatic intraepithelial neoplasia in Nkx3.1;Pten mutant mice. Clin. Cancer Res. 12, 5895–5901 (2006).
Bernichtein, S. et al. High milk consumption does not affect prostate tumor progression in two mouse models of benign and neoplastic lesions. PLoS ONE 10, e0125423 (2015).
Capiod, T. The need for calcium channels in cell proliferation. Recent Patents Anti-Cancer Drug Discov. 8, 4–17 (2013).
Whitfield, J. F. Calcium signals and cancer. Crit. Rev. Oncog. 3, 55–90 (1992).
Capiod, T. Extracellular calcium has multiple targets to control cell proliferation. Adv. Exp. Med. Biol. 898, 133–156 (2016).
Brown, E. M. et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366, 575–580 (1993).
Riccardi, D. & Kemp, P. J. The calcium-sensing receptor beyond extracellular calcium homeostasis: conception, development, adult physiology, and disease. Annu. Rev. Physiol. 74, 271–297 (2012).
Sheinin, Y. et al. Immunocytochemical localization of the extracellular calcium-sensing receptor in normal and malignant human large intestinal mucosa. J. Histochem. Cytochem. 48, 595–602 (2000).
Haven, C. J., van Puijenbroek, M., Karperien, M., Fleuren, G. J. & Morreau, H. Differential expression of the calcium sensing receptor and combined loss of chromosomes 1q and 11q in parathyroid carcinoma. J. Pathol. 202, 86–94 (2004).
Mateo-Lozano, S., Garcia, M., Rodriguez-Hernandez, C. J. & de Torres, C. Regulation of differentiation by calcium-sensing receptor in normal and tumoral developing nervous system. Front. Physiol. 7, 169 (2016).
Joeckel, E. et al. High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor. Mol. Cancer 13, 42 (2014).
Mihai, R., Stevens, J., McKinney, C. & Ibrahim, N. B. Expression of the calcium receptor in human breast cancer — a potential new marker predicting the risk of bone metastases. Eur. J. Surg. Oncol. 32, 511–515 (2006).
Ahearn, T. U. et al. Calcium sensing receptor tumor expression and lethal prostate cancer progression. J. Clin. Endocrinol. Metab. 101, 2520–2527 (2016).
Colella, M., Gerbino, A., Hofer, A. M. & Curci, S. Recent advances in understanding the extracellular calcium-sensing receptor. F1000Res 5, 2535 (2016).
Mamillapalli, R., VanHouten, J., Zawalich, W. & Wysolmerski, J. Switching of G-protein usage by the calcium-sensing receptor reverses its effect on parathyroid hormone-related protein secretion in normal versus malignant breast cells. J. Biol. Chem. 283, 24435–24447 (2008).
Fiorio Pla, A. & Gkika, D. Emerging role of TRP channels in cell migration: from tumor vascularization to metastasis. Front. Physiol. 4, 311 (2013).
Thebault, S. et al. Differential role of transient receptor potential channels in Ca2+ entry and proliferation of prostate cancer epithelial cells. Cancer Res. 66, 2038–2047 (2006).
Yue, D., Wang, Y., Xiao, J. Y., Wang, P. & Ren, C. S. Expression of TRPC6 in benign and malignant human prostate tissues. Asian J. Androl 11, 541–547 (2009).
Olszak, I. T. et al. Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo. J. Clin. Invest. 105, 1299–1305 (2000).
Hendy, G. N. & Canaff, L. Calcium-sensing receptor, proinflammatory cytokines and calcium homeostasis. Semin. Cell Dev. Biol. 49, 37–43 (2016).
Bornefalk, E. et al. Regulation of interleukin-6 secretion from mononuclear blood cells by extracellular calcium. J. Bone Miner. Res. 12, 228–233 (1997).
Canaff, L., Zhou, X. & Hendy, G. N. The proinflammatory cytokine, interleukin-6, up-regulates calcium-sensing receptor gene transcription via Stat1/3 and Sp1/3. J. Biol. Chem. 283, 13586–13600 (2008).
Cifuentes, M. et al. Calcium sensing receptor activation elevates proinflammatory factor expression in human adipose cells and adipose tissue. Mol. Cell. Endocrinol. 361, 24–30 (2012).
Giangreco, A. A. et al. Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model. J. Steroid Biochem. Mol. Biol. 148, 156–165 (2015).
Zhang, Y. et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J. Immunol. 188, 2127–2135 (2012).
De Marzo, A. M. et al. Inflammation in prostate carcinogenesis. Nat. Rev. Cancer 7, 256–269 (2007).
Xie, D. D. et al. Low vitamin D status is associated with inflammation in patients with prostate cancer. Oncotarget 8, 22076–22085 (2017).
Tennakoon, S., Aggarwal, A. & Kallay, E. The calcium-sensing receptor and the hallmarks of cancer. Biochim. Biophys. Acta 1863, 1398–1407 (2016).
Hagenau, T. et al. Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. Osteoporos Int. 20, 133–140 (2009).
Palacios, C. & Gonzalez, L. Is vitamin D deficiency a major global public health problem? J. Steroid Biochem. Mol. Biol. 144, 138–145 (2014).
Hilger, J. et al. A systematic review of vitamin D status in populations worldwide. Br. J. Nutr. 111, 23–45 (2014).
Lassemillante, A. C., Doi, S. A., Hooper, J. D., Prins, J. B. & Wright, O. R. Prevalence of osteoporosis in prostate cancer survivors II: a meta-analysis of men not on androgen deprivation therapy. Endocrine 50, 344–354 (2015).
Lassemillante, A. C., Doi, S. A., Hooper, J. D., Prins, J. B. & Wright, O. R. Prevalence of osteoporosis in prostate cancer survivors: a meta-analysis. Endocrine 45, 370–381 (2014).
Wang, A. et al. Risk of fracture in men with prostate cancer on androgen deprivation therapy: a population-based cohort study in New Zealand. BMC Cancer 15, 837 (2015).
Holick, M. F. et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 1911–1930 (2011).
United States Department of Agriculture. USDA national nutrient database for standard reference release 28. USDA Food Composition Databases http://ndb.nal.usda.gov/ndb/foods (2015).
Singhal, S., Baker, R. D. & Baker, S. S. A. Comparison of the nutritional value of cow’s milk and nondairy beverages. J. Pediatr. Gastroenterol. Nutr. 64, 799–805 (2017).
Brown, E. M. & MacLeod, R. J. Extracellular calcium sensing and extracellular calcium signaling. Physiol. Rev. 81, 239–297 (2001).
Nemeth, E. F. Calcimimetic and calcilytic drugs: just for parathyroid cells? Cell Calcium 35, 283–289 (2004).
Conigrave, A. D. & Hampson, D. R. Broad-spectrum L-amino acid sensing by class 3 G-protein-coupled receptors. Trends Endocrinol. Metab. 17, 398–407 (2006).
Conigrave, A. D., Mun, H. C. & Lok, H. C. Aromatic L-amino acids activate the calcium-sensing receptor. J. Nutr. 137, (Suppl. 1), 1524S–1527S (2007).
Brennan, S. C. et al. Receptor expression modulates calcium-sensing receptor mediated intracellular Ca2+ mobilization. Endocrinology 156, 1330–1342 (2015).
The authors are grateful to the Association pour la Recherche sur les Tumeurs de la Prostate (ARTP), the Institut Européen d’Expertise en Physiologie (IEEP), INSERM, the Centre National de la Recherche Scientifique (CNRS), and the University Paris Descartes for funding support of this project. They also thank the numerous colleagues who participated in the preclinical study described herein and L. Sackmann Sala for critical reading of the manuscript. T.C., N.B.D., N.P., and V.G. are members of the French Network for Nutrition and Cancer Research (NACRe network, team 63).
The authors declare no competing interests.
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Capiod, T., Barry Delongchamps, N., Pigat, N. et al. Do dietary calcium and vitamin D matter in men with prostate cancer?. Nat Rev Urol 15, 453–461 (2018). https://doi.org/10.1038/s41585-018-0015-z
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