Advertisement

Physiologic serum 1,25 dihydroxyvitamin D is inversely associated with prostatic Ki67 staining in a diverse sample of radical prostatectomy patients

  • Adrian Rosenberg
  • Oluwarotimi S. Nettey
  • Pooja Gogana
  • Ujalla Sheikh
  • Virgilia Macias
  • Andre Kajdacsy-Balla
  • Roohollah Sharifi
  • Rick A. Kittles
  • Adam B. MurphyEmail author
Original Paper
First Online:
  • 2 Downloads

Abstract

Purpose

To investigate the correlation between serum 25 hydroxyvitamin D, prostatic 25 hydroxyvitamin D, and serum 1,25 dihydroxyvitamin D, and their respective associations with prostatic tumor proliferation at the time of radical prostatectomy.

Methods

In this cross-sectional analysis of 119 men undergoing radical prostatectomy, serum from whole blood and expressed prostatic fluid was collected on the day of surgery. Tumor proliferation was measured in the dominant tumor on formalin-fixed prostatectomy tissues by immunohistochemical staining for Ki67 and quantified by Aperio imaging analysis.

Results

The sample included 88 African Americans (74%) and 31 (26%) European Americans. Serum and prostatic levels of 25 hydroxyvitamin D were correlated with each other (Spearman’s rho (ρ) = 0.27, p = 0.004), and there was also a correlation between serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D (ρ = 0.34, p < 0.001).

Serum and prostatic 25 hydroxyvitamin D levels were not correlated with Ki67 staining in tumor cells. Serum 1,25 dihydroxyvitamin D was inversely correlated with Ki67 staining in tumor cells (ρ = − 0.30, p = 0.002). On linear regression, serum 1,25 dihydroxyvitamin D was negatively associated with Ki67 staining in tumor cells (β − 0.46, 95% CI − 0.75, − 0.04, p = 0.04).

Conclusion

The correlation between physiologic serum levels of 25 hydroxyvitamin D with both prostatic 25 hydroxyvitamin D and serum 1,25 dihydroxyvitamin D suggests that serum levels are reasonable biomarkers of vitamin D status. Furthermore, serum 1,25 dihydroxyvitamin D has an inverse association with Ki67 staining in tumor cells at physiologic levels and may protect against tumor progression.

Keywords

Prostate cancer Vitamin D deficiency Proliferation African American 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors thank the patients, urologists, pathologists and staff at Jesse Brown VA Medical Center for facilitating patient recruitment and specimen acquisition. We thank the Research Histology and Tissue Imaging core at the University of Illinois at Chicago for assistance with staining, image processing, and analysis.

Funding

Funding was provided by U.S. Department of Veterans Affairs (Grant No. IK2CX000926-01).

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest for the listed authors.

References

  1. 1.
    Hollis BW, Marshall DT, Savage SJ, Garrett-Mayer E, Kindy MS, Gattoni-Celli S (2013) Vitamin D3 supplementation, low-risk prostate cancer, and health disparities. J Steroid Biochem Mol Biol 136:233CrossRefGoogle Scholar
  2. 2.
    Ginde AA, Liu MC, Camargo CA Jr (2009) Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch Intern Med 169(6):626CrossRefGoogle Scholar
  3. 3.
    Li H, Stampfer MJ, Hollis JBW, Mucci LA, Gaziano JM, Hunter D, Giovannucci EL, Ma J (2007) A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer (VD, VDR variation, and prostate cancer). PLoS Med 4(3):e103CrossRefGoogle Scholar
  4. 4.
    Holick M (2007) Vitamin D deficiency. N Engl J Med 357(3):266CrossRefGoogle Scholar
  5. 5.
    Nyame YA, Murphy AB, Bowen DK, Jordan G, Batai K, Dixon M, Hollowell CMP, Kielb S, Meeks JJ, Gann PH et al (2016) Associations between serum vitamin D and adverse pathology in men undergoing radical prostatectomy. J Clin Oncol 34(12):1345CrossRefGoogle Scholar
  6. 6.
    Murphy AB, Kelley B, Nyame YA, Martin IK, Smith DJ, Castaneda L, Zagaja GJ, Hollowell CMP, Kittles RA (2012) Predictors of serum vitamin D levels in African American and European American men in Chicago. Am J Men Health 6(5):420CrossRefGoogle Scholar
  7. 7.
    Gilbert R, Martin RM, Beynon R, Harris R, Savovic J, Zuccolo L, Bekkering GE, Fraser WD, Sterne JA, Metcalfe C (2011) Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 22(3):319–340CrossRefGoogle Scholar
  8. 8.
    Shakira MN, Ken B, Chiledum A, Tanya A-C, Rick AK (2016) Association between serum 25-hydroxy-vitamin D and aggressive prostate cancer in African American men. Nutrients 9(1):12CrossRefGoogle Scholar
  9. 9.
    Holick MF: High prevalence of vitamin D inadequacy and implications for health. Mayo Clinic Proc 2006, 81(3):353CrossRefGoogle Scholar
  10. 10.
    Swami S, Krishnan AV, Wang JY, Jensen K, Horst R, Albertelli MA, Feldman D (2012) Dietary vitamin D3 and 1,25-dihydroxyvitamin D3 (calcitriol) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer. Endocrinology 153(6):2576CrossRefGoogle Scholar
  11. 11.
    Woo TCS, Choo R, Jamieson M, Chander S, Vieth R (2005) Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer 51(1):32CrossRefGoogle Scholar
  12. 12.
    Wagner D, Trudel D, Van Der Kwast T, Nonn L, Giangreco AA, Li D, Dias A, Cardoza M, Laszlo S, Hersey K et al (2013) Randomized clinical trial of Vitamin D 3 doses on prostatic Vitamin D metabolite levels and Ki67 labeling in prostate cancer patients. J Clin Endocrinol Metab 98(4):1498CrossRefGoogle Scholar
  13. 13.
    Barreto AM, Schwartz GG, Woodruff R, Cramer SD (2000) 25-Hydroxyvitamin D3, the prohormone of 1,25-dihydroxyvitamin D3, inhibits the proliferation of primary prostatic epithelial cells. Cancer Epidemiol Biomarker Prev 9(3):265. A publication of the American Association for Cancer Research, cosponsored by The American Society of Preventive OncologyGoogle Scholar
  14. 14.
    Marshall D, Savage SJ, Garrett-Mayer E, Keane T, Hollis B, Horst R, Ambrose LH, Kindy MS, Gattoni-Celli S (2012) Vitamin D-3 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(7):2315Google Scholar
  15. 15.
    Peehl DM, Skowronski RJ, Leung GK, Wong ST, Stamey TA, Feldman D (1994) Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Can Res 54(3):805Google Scholar
  16. 16.
    Zhao XY, Peehl DM, Navone NM, Feldman D (2000) 1α,25-dihydroxyvitamin d 3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms. Endocrinology 141(7):2548CrossRefGoogle Scholar
  17. 17.
    Liu G, Oettel K, Ripple G, Staab MJ, Horvath D, Alberti D, Arzoomanian R, Marnocha R, Bruskewitz R, Mazess R et al (2002) Phase I trial of 1α-hydroxyvitamin D 2 in patients with hormone refractory prostate cancer. Clin Cancer Res 8(9):2820PubMedGoogle Scholar
  18. 18.
    Gross C, Stamey T, Hancock S, Feldman D (1998) Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol). J Urol 159(6):2035CrossRefGoogle Scholar
  19. 19.
    Beer TM, Lemmon D, Lowe BA, Henner WD (2003) High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer 97(5):1217CrossRefGoogle Scholar
  20. 20.
    Trump DL, Potter DM, Muindi J, Brufsky A, Johnson CS (2006) Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer 106(10):2136CrossRefGoogle Scholar
  21. 21.
    Krishnan A, Feldman D (2010) Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment. Endocr Relat Cancer 17(1):R19CrossRefGoogle Scholar
  22. 22.
    Beer TM, Myrthue A, Garzotto M, Hara MF, Chin R, Lowe BA, Montalto MA, Corless CL, Henner WD (2004) Randomized study of high-dose pulse calcitriol or placebo prior to radical prostatectomy. Cancer Epidemiology Biomarkers & Prevention 13(12):2225 A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive OncologyGoogle Scholar
  23. 23.
    Moreno J, Krishnan AV, Feldman D (2005) Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer. J Steroid Biochem Mol Biol 97(1):31CrossRefGoogle Scholar
  24. 24.
    Plum L, De Luca H (2009) The functional metabolism and molecular biology of vitamin D action. Clin Rev Bone Min Metab 7(1):20CrossRefGoogle Scholar
  25. 25.
    Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF (1998) Human prostate cells synthesize 1,25-dihydroxyvitamin D 3 from 25-hydroxyvitamin D 3. Cancer Epidemiol Biomarkers Prev 7(5):391PubMedGoogle Scholar
  26. 26.
    Block G, Hartman AM, Dresser CM, Carroll MD, Gannon J, Gardner L (1986) A data-based approach to diet questionnaire design and testing. Am J Epidemiol 124(3):453CrossRefGoogle Scholar
  27. 27.
    Block G, Hartman AM, Naughton D (1990) A reduced dietary questionnaire: development and validation. Epidemiology 1(1):58CrossRefGoogle Scholar
  28. 28.
    Epstein J, Egevad L, Amin MB, Delahunt B, Srigley, Jr, Humphrey PA: The 2014 International Society of Urological Pathology (ISUP) consensus conference on gleason grading of prostatic carcinoma definition of grading patterns and proposal for a new grading system. Am J Surg Pathol 2016, 40(2):244PubMedGoogle Scholar
  29. 29.
    Epstein JI, Zelefsky MJ, Sjoberg DD, Nelson JB, Egevad L, Magi-Galluzzi C, Vickers AJ, Parwani AV, Reuter VE, Fine SW et al (2016) A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 69(3):428CrossRefGoogle Scholar
  30. 30.
    Bubendorf L, Sauter G, Moch H, Schmid HP, Gasser TC, Jordan P, Mihatsch MJ (1996) Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. J Pathol 178(4):437CrossRefGoogle Scholar
  31. 31.
    Verma R, Gupta V, Singh J, Verma M, Gupta G, Gupta S, Sen R, Ralli M (2015) Significance of p53 and ki-67 expression in prostate cancer (original article) (clinical report). Urol Ann 7(4):488CrossRefGoogle Scholar
  32. 32.
    Pascale M, Aversa C, Barbazza R, Marongiu B, Siracusano S, Stoffel F, Sulfaro S, Roggero E, Bonin S, Stanta G: The proliferation marker Ki67, but not neuroendocrine expression, is an independent factor in the prediction of prognosis of primary prostate cancer patients. Radiol Oncol. 50; 2016: 313CrossRefGoogle Scholar
  33. 33.
    Fisher G, Yang ZH, Kudahetti S, Møller H, Scardino P, Cuzick J, Berney DM (2013) Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort. Br J Cancer 108(2):271CrossRefGoogle Scholar
  34. 34.
    Zellweger T, Günther S, Zlobec I, Savic S, Sauter G, Moch H, Mattarelli G, Eichenberger T, Curschellas E, Rüfenacht H et al (2009) Tumour growth fraction measured by immunohistochemical staining of Ki67 is an independent prognostic factor in preoperative prostate biopsies with small-volume or low-grade prostate cancer. Int J Cancer 124(9):2116CrossRefGoogle Scholar
  35. 35.
    Richards Z, Batai K, Farhat R, Shah E, Makowski A, Gann PH, Kittles R, Nonn L (2017) Prostatic compensation of the vitamin D axis in African American men. JCI Insight 2(2):e91054CrossRefGoogle Scholar
  36. 36.
    Medioni J, Deplanque G, Ferrero J-M, Maurina T, Rodier J-MP, Raymond E, Allyon J, Maruani G, Houillier P, Mackenzie S et al (2014) Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients. Clin Cancer Res 20(17):4471CrossRefGoogle Scholar
  37. 37.
    Chan JS, Beer TM, Quinn DI, Pinski JK, Garzotto M, Sokoloff M, Dehaze DR, Ryan CW (2008) A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer. BJU Int 102(11):1601CrossRefGoogle Scholar
  38. 38.
    Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Redfern CH, Fehrenbacher L, Saleh MN, Waterhouse DM et al (2007) Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 25(6):669CrossRefGoogle Scholar
  39. 39.
    Chan JM, Stampfer MJ, Ma J, Gann PH, Gaziano JM, Giovannucci EL (2001) Dairy products, calcium, and prostate cancer risk in the physician’s; health study. Am J Clin Nutr 74(4):549CrossRefGoogle Scholar
  40. 40.
    Batai K, Murphy AB, Ruden M, Newsome J, Shah E, Dixon MA, Jacobs ET, Hollowell CMP, Ahaghotu C, Kittles RA (2017) Race and BMI modify associations of calcium and vitamin D intake with prostate cancer. BMC Cancer 17(1)Google Scholar
  41. 41.
    Malhotra S, Lapointe J, Salari K, Higgins JP, Ferrari M, Montgomery K, van de Rijn M, Brooks JD, Pollack JR (2011) A tri-marker proliferation index predicts biochemical recurrence after surgery for prostate cancer (prostate cancer proliferation index). PLoS ONE 6(5):e20293CrossRefGoogle Scholar
  42. 42.
    Krishnan AV, Feldman D (2011) Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 51:311CrossRefGoogle Scholar
  43. 43.
    Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ (2014) The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 14:342CrossRefGoogle Scholar
  44. 44.
    Robsahm TE, Schwartz GG, Tretli S (2013) The Inverse relationship between 25-hydroxyvitamin D and cancer survival: discussion of causation. Cancers 5(4):1439CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Adrian Rosenberg
    • 1
  • Oluwarotimi S. Nettey
    • 1
  • Pooja Gogana
    • 1
  • Ujalla Sheikh
    • 2
  • Virgilia Macias
    • 2
  • Andre Kajdacsy-Balla
    • 2
  • Roohollah Sharifi
    • 3
    • 4
  • Rick A. Kittles
    • 5
  • Adam B. Murphy
    • 1
    • 3
    • 6
    Email author
  1. 1.Department of UrologyNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Department of PathologyUniversity of Illinois at Chicago School of MedicineChicagoUSA
  3. 3.Section of UrologyJesse Brown VA Medical CenterChicagoUSA
  4. 4.Department of UrologyUniversity of Illinois at Chicago School of MedicineChicagoUSA
  5. 5.Division of Health Equities, Department of Population SciencesCity of Hope Cancer CenterDuarteUSA
  6. 6.ChicagoUSA

Personalised recommendations

Cite article

Buy options