Skip to main content

Advertisement

Log in

Vitamin D, cancer, and dysregulated phosphate metabolism

  • Mini Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Recently reported findings from major clinical trials show no cancer protection from vitamin D supplementation, and results from observational studies of vitamin D in cancer prevention are inconsistent. There is a need for new hypotheses to guide investigations of the controversies surrounding vitamin D supplementation and cancer. Bioactive vitamin D, 1,25(OH)2D, is an endocrine factor that regulates phosphate homeostasis by increasing dietary phosphate intestinal absorption. When phosphorus serum levels are high, as in hyperphosphatemia, an endocrine feedback mechanism lowers bioactive vitamin D which reduces intestinal phosphate absorption. Low vitamin D levels have been associated with cancer incidence, and tumorigenesis is associated with high levels of dysregulated phosphate in the body. In this mini-review, the author hypothesizes that hyperphosphatemia may be an intermediating factor in the association of lowered vitamin D levels and increased risk for tumorigenesis. Furthermore, this article challenges the UVB–vitamin D-cancer hypothesis which proposes that reduced cancer incidence at lower geographic latitudes is related to high levels of vitamin D from UVB exposure. The author proposes that reduced phosphorus content and availability in tropical and subtropical soil, and lower dietary phosphate intake from consumption of tropical and subtropical crops (as in the Mediterranean diet), may mediate the association of reduced cancer risk with lower latitudes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. D.D. Bikle, Vitamin D and cancer: the promise not yet fulfilled. Endocrine 46(1), 29–38 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. J.E. Manson, N.R. Cook, I.-M. Lee, W. Christen, S.S. Bassuk, S. Mora, H. Gibson, D. Gordon, T. Copeland, D. D’Agostino, Vitamin D supplements and prevention of cancer and cardiovascular disease. New Engl. J. Med. 380(1), 33–44 (2019)

    Article  CAS  PubMed  Google Scholar 

  3. R. Scragg, K.-T. Khaw, L. Toop, J. Sluyter, C.M. Lawes, D. Waayer, E. Giovannucci, C.A. Camargo, Monthly high-dose vitamin D supplementation and cancer risk: a post hoc analysis of the vitamin D assessment randomized clinical trial. JAMA Oncol. 4(11), e182178–e182178 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  4. N. Keum, D. Lee, D. Greenwood, J. Manson, E. Giovannucci, Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. Ann. Oncol 30, 733–743 (2019)

  5. Z.-H. Hu, J.E. Connett, J.-M. Yuan, K.E. Anderson, Role of survivor bias in pancreatic cancer case-control studies. Ann. Epidemiol. 26(1), 50–56 (2016)

    Article  PubMed  Google Scholar 

  6. J. Lappe, P. Watson, D. Travers-Gustafson, R. Recker, C. Garland, E. Gorham, K. Baggerly, S.L. McDonnell, Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. Jama 317(12), 1234–1243 (2017)

    Article  CAS  PubMed  Google Scholar 

  7. X. Wu, W. Hu, L. Lu, Y. Zhao, Y. Zhou, Z. Xiao, L. Zhang, H. Zhang, X. Li, W. Li, Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment. Acta. Pharma. Sinica. B. 9, 203–219 (2018)

  8. Y. Omura, D. Lu, M.K. Jones, A. Nihrane, H. Duvvi, D. Yapor, Y. Shimotsuura, M. Ohki, Optimal dose of vitamin D3 400 IU for Average adults has a significant anti-cancer effect, while widely used 2000 IU or higher promotes cancer: marked reduction of taurine & 1α, 25 (OH) 2D3 was found in various cancer tissues and oral intake of optimal dose of taurine 175 mg for average adults, rather than 500 mg, was found to be a new potentially safe and more effective method of cancer treatment. Acupunct. electro-Ther. Res. 41(1), 39–60 (2016)

    Article  Google Scholar 

  9. M. Haznadar, K.W. Krausz, E. Margono, C.M. Diehl, E.D. Bowman, S.K. Manna, A.I. Robles, B.M. Ryan, F.J. Gonzalez, C.C. Harris, Inverse association of vitamin D3 levels with lung cancer mediated by genetic variation. Cancer Med. 7(6), 2764–2775 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. T.L. Gomes, R.C. Fernandes, L.L. Vieira, R.M. Schincaglia, J.F. Mota, M.S. Nóbrega, C. Pichard, G.D. Pimentel, Low vitamin D at ICU admission is associated with cancer, infections, acute respiratory insufficiency, and liver failure. Nutrition 60, 235–240 (2019)

    Article  CAS  PubMed  Google Scholar 

  11. S. Hossain, M.A. Beydoun, H.A. Beydoun, X. Chen, A.B. Zonderman, R.J. Wood, Vitamin D and breast cancer: a systematic review and meta-analysis of observational studies. Clin. Nutr. ESPEN. 30, 170–184 (2019)

  12. D. Muller, A. Hodge, A. Fanidi, D. Albanes, X. Mai, X. Shu, S. Weinstein, T. Larose, X. Zhang, J. Han, No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3). Ann. Oncol. 29(6), 1468–1475 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. X. Jiang, N.L. Dimou, K. Al-Dabhani, S.J. Lewis, R.M. Martin, P.C. Haycock, M.J. Gunter, T.J. Key, R.A. Eeles, K. Muir, Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study. Int. J. Epidemiol. (2018). https://doi.org/10.1093/ije/dyy284

  14. P. Chandler, D. Tobias, L. Wang, S. Smith-Warner, D. Chasman, L. Rose, E. Giovannucci, J. Buring, P. Ridker, N. Cook, Association between vitamin D genetic risk score and cancer risk in a large cohort of US women. Nutrients 10(1), 55 (2018)

    Article  CAS  PubMed Central  Google Scholar 

  15. F. Alshahrani, N. Aljohani, Vitamin D: deficiency, sufficiency and toxicity. Nutrients 5(9), 3605–3616 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. D.J. Owens, R. Allison, G.L. Close, Vitamin D and the athlete: current perspectives and new challenges. Sports Med. 48(1), 3–16 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  17. M.R.I. Young, Y. Xiong, Influence of vitamin D on cancer risk and treatment: why the variability? Trends cancer Res. 13, 43 (2018)

    PubMed  PubMed Central  Google Scholar 

  18. S.-M. Jeon, E.-A. Shin, Exploring vitamin D metabolism and function in cancer. Exp. Mol. Med. 50(4), 20 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. S. Minisola, F. Ferrone, V. Danese, V. Cecchetti, J. Pepe, C. Cipriani, L. Colangelo, Controversies surrounding vitamin D: focus on supplementation and cancer. Int. J. Environ. Res. public health 16(2), 189 (2019)

    Article  CAS  PubMed Central  Google Scholar 

  20. R.B. Brown, A. Haq, C.F. Stanford, M.S. Razzaque, Vitamin D, Phosphate and Vasculotoxicity. Can. J. Physiol. Pharmacol. 93, 1077–1082 (2015)

  21. R.B. Brown, F. Al Anouti, M.S. Razzaque, Vitamin D supplements: Magic pill or overkill? South East Asia. J. Public Health 5(2), 1–3 (2015)

    Google Scholar 

  22. R.B. Brown, M.S. Razzaque: Chapter 31 - Endocrine Regulation of Phosphate Homeostasis. In: A.K. Singh, G.H. Williams (eds.) Textbook of Nephro-Endocrinology (Second Edition). pp. 539–548. Academic Press, (2018)

  23. M. Waterhouse, B. Hope, L. Krause, M. Morrison, M.M. Protani, M. Zakrzewski, R.E. Neale, Vitamin D and the gut microbiome: a systematic review of in vivo studies. Eur. J. Nutr. 1–16 (2018). https://doi.org/10.1007/s00394-018-1842-7

  24. P. Lips, Relative value of 25 (OH) D and 1, 25 (OH) 2D measurements. J. Bone Miner. Res. 22(11), 1668–1671 (2007)

    Article  CAS  PubMed  Google Scholar 

  25. A. Webb, B. DeCosta, M. Holick, Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation. J. Clin. Endocrinol. Metab. 68(5), 882–887 (1989)

    Article  CAS  PubMed  Google Scholar 

  26. R.B. Brown, M.S. Razzaque, Phosphate toxicity and tumorigenesis. Biochim. Biophys. Acta. Rev. Cancer 1869(2), 303–309 (2018)

    Article  CAS  PubMed  Google Scholar 

  27. R.B. Brown, M.S. Razzaque, Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity. Bonekey reports 4, 705 (2015)

  28. Y. Kuang, J.D. Nagy, J.J. Elser, Biological stoichiometry of tumor dynamics: mathematical models and analysis. Discret. Contin. Dyn. Syst. Ser. B 4(1), 221–240 (2004)

    Google Scholar 

  29. C.D. Papaloucas, M.D. Papaloucas, V. Kouloulias, K. Neanidis, K. Pistevou-Gompaki, J. Kouvaris, A. Zygogianni, K. Mystakidou, A.C. Papaloucas, Measurement of blood phosphorus: a quick and inexpensive method for detection of the existence of cancer in the body. Too good be true, or. Forgot. Knowl. ? Med Hypotheses 82(1), 24–25 (2014). https://doi.org/10.1016/j.mehy.2013.10.028

    Article  CAS  Google Scholar 

  30. J.J. Elser, M.M. Kyle, M.S. Smith, J.D. Nagy, Biological stoichiometry in human cancer. PLoS ONE. 2(10), e1028 (2007)

  31. M. D’Arcangelo, O. Brustugun, Y. Xiao, Y. Choi, C. Behrens, L. Solis, Y. Wang, R. Firestein, T. Boyle, M. Lund-Iversen, 194 Prevalence and prognostic significance of sodium-dependent phosphate transporter 2B (NaPi2B) protein expression in non-small cell lung cancer (NSCLC). Ann. Oncol. 25(suppl 4), iv66–iv67 (2014)

    Article  Google Scholar 

  32. D. Ward, A. Griffin, Phosphorus incorporation into nucleic acids and proteins of liver nuclei of normal and azo dye-fed rats. Cancer Res. 15, 456–461 (1955)

    CAS  PubMed  Google Scholar 

  33. H. Jin, C.-X. Xu, H.-T. Lim, S.-J. Park, J.-Y. Shin, Y.-S. Chung, S.-C. Park, S.-H. Chang, H.-J. Youn, K.-H. Lee, High dietary inorganic phosphate increases lung tumorigenesis and alters Akt signaling. Am. J. Respir. Crit. care Med. 179(1), 59–68 (2009)

    Article  CAS  PubMed  Google Scholar 

  34. C.E. Camalier, M.R. Young, G. Bobe, C.M. Perella, N.H. Colburn, G.R. Beck, Elevated phosphate activates N-ras and promotes cell transformation and skin tumorigenesis. Cancer Prev. Res. 3(3), 359–370 (2010)

    Article  CAS  Google Scholar 

  35. K.M. Wilson, I.M. Shui, L.A. Mucci, E. Giovannucci, Calcium and phosphorus intake and prostate cancer risk: a 24-y follow-up study. Am. J. Clin. Nutr. 101, 173–183 (2015)

  36. P. Liu, H. Cheng, T.M. Roberts, J.J. Zhao, Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer. Nat. Rev. Drug Discov. 8(8), 627 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Y. Lin, K.E. McKinnon, S.W. Ha, G.R. Beck, Inorganic phosphate induces cancer cell mediated angiogenesis dependent on forkhead box protein C2 (FOXC2) regulated osteopontin expression. Mol. Carcinog. 54(9), 926–934 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. A.A. Bobko, T.D. Eubank, B. Driesschaert, I. Dhimitruka, J. Evans, R. Mohammad, E.E. Tchekneva, M.M. Dikov, V.V. Khramtsov, Interstitial inorganic phosphate as a tumor microenvironment marker for tumor progression. Sci. Rep. 7, 41233 (2017). https://doi.org/10.1038/srep41233

  39. J. Chudek, A. Nagy, F. Kokot, A. Podwinski, A. Wiecek, E. Ritz, G. Kovacs, Phosphatemia is related to chromosomal aberrations of parathyroid glands in patients with hyperparathyroidism. J. Nephrol. 20(2), 164–172 (2007)

    CAS  PubMed  Google Scholar 

  40. S. Yamada, M. Tokumoto, N. Tatsumoto, M. Taniguchi, H. Noguchi, T. Nakano, K. Masutani, H. Ooboshi, K. Tsuruya, T. Kitazono, Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. Am. J. Physiol.-Ren. Physiol. 306(12), F1418–F1428 (2014)

    Article  CAS  Google Scholar 

  41. R.J. Klement, The emerging role of ketogenic diets in cancer treatment. Curr. Opin. Clin. Nutr. Metab. Care 22(2), 129–134 (2019)

    Article  PubMed  Google Scholar 

  42. F. Bozzetti, B. Zupec-Kania, Toward a cancer-specific diet. Clin. Nutr. 35(5), 1188–1195 (2016)

    Article  CAS  PubMed  Google Scholar 

  43. C.F. Garland, F.C. Garland, Do sunlight and vitamin D reduce the likelihood of colon cancer? Int. J. Epidemiol. 9(3), 227–231 (1980)

    Article  CAS  PubMed  Google Scholar 

  44. I. Savoye, C.M. Olsen, D.C. Whiteman, A. Bijon, L. Wald, L. Dartois, F. Clavel-Chapelon, M.-C. Boutron-Ruault, M. Kvaskoff, Patterns of ultraviolet radiation exposure and skin cancer risk: the E3N-SunExp study. J. Epidemiol. 28, 27–33 (2017)

  45. R. Krause, B. Matulla-Nolte, M. Essers, A. Brown, W. Hopfenmüller, UV radiation and cancer prevention: what is the evidence? Anticancer Res. 26(4A), 2723–2727 (2006)

    CAS  PubMed  Google Scholar 

  46. W.B. Grant, Ecological studies of the UVB–vitamin D–cancer hypothesis. Anticancer Res. 32(1), 223–236 (2012)

    CAS  PubMed  Google Scholar 

  47. B. Lindelöf, B. Krynitz, S. Ayoubi, C. Martschin, D. Wiegleb-Edström, K. Wiklund, Previous extensive sun exposure and subsequent vitamin D production in patients with basal cell carcinoma of the skin, has no protective effect on internal cancers. Eur. J. Cancer 48(8), 1154–1158 (2012)

    Article  CAS  PubMed  Google Scholar 

  48. F. Turati, M. Rossi, C. Pelucchi, F. Levi, C. La Vecchia, Fruit and vegetables and cancer risk: a review of southern European studies. Br. J. Nutr. 113(S2), S102–S110 (2015)

    Article  CAS  PubMed  Google Scholar 

  49. F.L. Meyskens, E. Szabo, Diet and cancer: the disconnect between epidemiology and randomized clinical trials. Cancer Epidemiology and Prevention. Biomarkers 14(6), 1366–1369 (2005)

    CAS  Google Scholar 

  50. T.M. Gibson, L.M. Ferrucci, J.A. Tangrea, A. Schatzkin, Epidemiological and clinical studies of nutrition. In: Seminars in oncology 2010, vol. 3, pp. 282–296. Elsevier

  51. USDA: National Nutrient Database for Standard Reference, Legacy. (2018). https://ndb.nal.usda.gov/ndb/ Accessed March 4 2019

  52. S. McClure, A. Chang, E. Selvin, C. Rebholz, L. Appel, Dietary sources of phosphorus among adults in the United States: Results from NHANES 2001–2014. Nutrients 9(2), 95 (2017)

    Article  PubMed Central  Google Scholar 

  53. U. Fresán, J. Sabaté, M.A. Martínez-Gonzalez, G. Segovia-Siapco, C. de la Fuente-Arrillaga, M. Bes-Rastrollo, Adherence to the 2015 Dietary Guidelines for Americans and mortality risk in a Mediterranean cohort: The SUN project. Prev. Med. 118, 317–324 (2019)

    Article  PubMed  Google Scholar 

  54. M. Schulpen, P.H. Peeters, P.A. van den Brandt, Mediterranean diet adherence and risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study. Gastric Cancer 22, 663–674 (2019)

  55. W.J. Witlox, F.H. van Osch, M. Brinkman, S. Jochems, M.E. Goossens, E. Weiderpass, E. White, P.A. van den Brandt, G.G. Giles, R.L. Milne, An inverse association between the Mediterranean diet and bladder cancer risk: a pooled analysis of 13 cohort studies. Eur. J. Nutr. (2019). https://doi.org/10.1007/s00394-019-01907-8

  56. A. Castelló, P. Amiano, N.F. de Larrea, V. Martín, M.H. Alonso, G. Castaño-Vinyals, B. Pérez-Gómez, R. Olmedo-Requena, M. Guevara, G. Fernandez-Tardon, Low adherence to the western and high adherence to the mediterranean dietary patterns could prevent colorectal cancer. Eur. J. Nutr. 58(4), 1495–1505 (2019). https://doi.org/10.1007/s00394-018-1674-5

  57. L. Schneider, L.J. Su, L. Arab, J.T. Bensen, L. Farnan, E.T. Fontham, L. Song, J. Hussey, A.T. Merchant, J.L. Mohler, Dietary patterns based on the Mediterranean diet and DASH diet are inversely associated with high aggressive prostate cancer in PCaP. Ann. Epidemiol. 29, 16–22. e11 (2019)

    Article  PubMed  Google Scholar 

  58. F. Turati, G. Carioli, F. Bravi, M. Ferraroni, D. Serraino, M. Montella, A. Giacosa, F. Toffolutti, E. Negri, F. Levi, Mediterranean diet and breast cancer risk. Nutrients 10(3), 326 (2018)

    Article  CAS  PubMed Central  Google Scholar 

  59. A. Hodge, J. Bassett, N. Shivappa, J. Hébert, D. English, G. Giles, G. Severi, Dietary inflammatory index, Mediterranean diet score, and lung cancer: a prospective study. Cancer Causes Control 27(7), 907–917 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Y. Mahamat-Saleh, I. Cervenka, I. Savoye, M.-C. Boutron-Ruault, M. Kvaskoff, Mediterranean dietary pattern and skin cancer risk: a prospective cohort study in French women. Rev. d.'Épidémiologie et. de. St.é Publique 66, S272 (2018)

    Google Scholar 

  61. L. Schwingshackl, C. Schwedhelm, C. Galbete, G. Hoffmann, Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis. Nutrients 9(10), 1063 (2017)

    Article  CAS  PubMed Central  Google Scholar 

  62. C. Zhang, H. Tian, J. Liu, S. Wang, M. Liu, S. Pan, X. Shi, Pools and distributions of soil phosphorus in China. Global Biogeochem. Cycles 19(1), 1–8 (2005)

    Article  CAS  Google Scholar 

  63. X. Liu, W. Meng, G. Liang, K. Li, W. Xu, L. Huang, J. Yan, Available phosphorus in forest soil increases with soil nitrogen but not total phosphorus: evidence from subtropical forests and a pot experiment. PloS ONE 9(2), e88070 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brazil nut. (2009). http://www.newworldencyclopedia.org/p/index.php?title=Brazil_nut&oldid=905997

  65. J. Parry, Pacific islanders pay heavy price for abandoning traditional diet. World Health Organization. Bull. World Health Organ. 88(7), 484 (2010)

    Article  Google Scholar 

  66. M.A. Moore, F. Baumann, S. Foliaki, M.T. Goodman, R. Haddock, R. Maraka, J. Koroivueta, D. Roder, T. Vinit, H.J. Whippy, Cancer epidemiology in the pacific islands-past, present and future. Asian Pac. J. cancer Prev.: APJCP 11(0 2), 99 (2010)

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ronald B. Brown.

Ethics declarations

Conflict of interest

The author declares that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brown, R.B. Vitamin D, cancer, and dysregulated phosphate metabolism. Endocrine 65, 238–243 (2019). https://doi.org/10.1007/s12020-019-01985-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-019-01985-y

Keywords

Navigation