Xu Wu, Wei Hu, Lan Lu, Yueshui Zhao, Yejiang Zhou, Zhangang Xiao, Lin Zhang, Hanyu Zhang, Xiaobing Li, Wanping Li, Shengpeng Wang, Chi Hin Cho, Jing Shen, Mingxing Li. Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 203-219

Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment
Xu Wua, Wei Hub, Lan Luc, Yueshui Zhaoa, Yejiang Zhoud, Zhangang Xiaoa, Lin Zhanga,e, Hanyu Zhanga, Xiaobing Lia, Wanping Lia, Shengpeng Wangf, Chi Hin Choa, Jing Shena, Mingxing Lia
a Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China;
b Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, China;
c Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610106, China;
d Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China;
e Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China;
f State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
Tumor cells along with a small proportion of cancer stem cells exist in a stromal microenvironment consisting of vasculature, cancer-associated fibroblasts, immune cells and extracellular components. Recent epidemiological and clinical studies strongly support that vitamin D supplementation is associated with reduced cancer risk and favorable prognosis. Experimental results suggest that vitamin D not only suppresses cancer cells, but also regulates tumor microenvironment to facilitate tumor repression. In this review, we have outlined the current knowledge on epidemiological studies and clinical trials of vitamin D. Notably, we summarized and discussed the anticancer action of vitamin D in cancer cells, cancer stem cells and stroma cells in tumor microenvironment, providing a better understanding of the role of vitamin D in cancer. We presently re-propose vitamin D to be a novel and economical anticancer agent.
Key words:    Vitamin D    1α,25-Dihydroxyvitamin D3    Tumor microenvironment    Cancer stem cell    Tumor-infiltrating lymphocyte    Tumor-derived endothelial cell    Cancer-associated fibroblast   
Received: 2018-05-11     Revised: 2018-07-04
DOI: 10.1016/j.apsb.2018.09.002
Funds: This work was supported by the National Natural Science Foundation of China (Nos.81770562,81602166 and 81703807) and grants from the Science and Technology Planning Project of Luzhou,Sichuan Province,China (Nos.2016LZXNYD-Z04 and 2017LZXNYD-J02).
Corresponding author: Jing Shen, Mingxing Li;
Author description:
PDF(KB) Free
Xu Wu
Wei Hu
Lan Lu
Yueshui Zhao
Yejiang Zhou
Zhangang Xiao
Lin Zhang
Hanyu Zhang
Xiaobing Li
Wanping Li
Shengpeng Wang
Chi Hin Cho
Jing Shen
Mingxing Li

1. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008;27:5904-12.
2. Mlecnik B, Bindea G, Kirilovsky A, Angell HK, Obenauf AC, Tosolini M, et al. The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med 2016;8:327ra26.
3. Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007;7:139-47.
4. Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, Zitvogel L. Targeting the tumor microenvironment:removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol 2016;27:1482-92.
5. Zhao X, Chen R, Liu M, Feng J, Chen J, Hu K. Remodeling the blood-brain barrier microenvironment by natural products for brain tumor therapy. Acta Pharm Sin B 2017;7:541-53.
6. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80:1678S-688SS.
7. Sun H, Wang C, Hao M, Sun R, Wang Y, Liu T, et al. CYP24A1 is a potential biomarker for the progression and prognosis of human colorectal cancer. Hum Pathol 2016;50:101-8.
8. Shiratsuchi H, Wang Z, Chen G, Ray P, Lin J, Zhang Z, et al. Oncogenic potential of CYP24A1 in lung adenocarcinoma. J Thorac Oncol 2017;12:269-80.
9. Luo W, Yu WD, Ma Y, Chernov M, Trump DL, Johnson CS. Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25-dihydroxyvitamin D3 antitumor activity in human prostate cancer cells. Cancer Res 2013;73:2289-97.
10. Friedrich M, Axt-Fliedner R, Villena-Heinsen C, Tilgen W, Schmidt W, Reichrath J. Analysis of vitamin D-receptor (VDR) and retinoid X-receptor α in breast cancer. Histochem J 2002;34:35-40.
11. Izkhakov E, Somjen D, Sharon O, Knoll E, Aizic A, Fliss DM, et al. Vitamin D receptor expression is linked to potential markers of human thyroid papillary carcinoma. J Steroid Biochem Mol Biol 2016;159:26-30.
12. Khadzkou K, Buchwald P, Westin G, Dralle H, Akerstrom G, Hellman P. 25-hydroxyvitamin D3-1α-hydroxylase and vitamin D receptor expression in papillary thyroid carcinoma. J Histochem Cytochem 2006;54:355-61.
13. Cross HS, Bareis P, Hofer H, Bischof MG, Bajna E, Kriwanek S, et al. 25-Hydroxyvitamin D3-1α-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis. Steroids 2001;66:287-92.
14. Hendrickson WK, Flavin R, Kasperzyk JL, Fiorentino M, Fang F, Lis R, et al. Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol 2011;29:2378-85.
15. Kim SH, Chen G, King AN, Jeon CK, Christensen PJ, Zhao L, et al. Characterization of vitamin D receptor (VDR) in lung adenocarcinoma. Lung Cancer 2012;77:265-71.
16. Wang K, Dong M, Sheng W, Liu Q, Yu D, Dong Q, et al. Expression of vitamin D receptor as a potential prognostic factor and therapeutic target in pancreatic cancer. Histopathology 2015;67:386-97.
17. Momen-Heravi F, Masugi Y, Qian ZR, Nishihara R, Liu L, SmithWarner SA, et al. Tumor expression of calcium sensing receptor and colorectal cancer survival:results from the nurses' health study and health professionals follow-up study. Int J Cancer 2017;141:2471-9.
18. Ferrer-Mayorga G, Gomez-Lopez G, Barbachano A, FernandezBarral A, Pena C, Pisano DG, et al. Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer. Gut 2017;66:1449-62.
19. Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159:80-93.
20. Li M, Li L, Zhang L, Hu W, Shen J, Xiao Z, et al. 1,25-Dihydroxyvitamin D3 suppresses gastric cancer cell growth through VDR-and mutant p53-mediated induction of p21. Life Sci 2017;179:88-97.
21. Zheng Y, Trivedi T, Lin RC, Fong-Yee C, Nolte R, Manibo J, et al. Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/b-catenin signaling. Bone Res 2017;5:17023.
22. Holick MF. Vitamin D deficiency. New Engl J Med 2007;357:266-81.
23. Malabanan A, Veronikis I, Holick M. Redefining vitamin D insufficiency. Lancet 1998;351:805-6.
24. Corder EH, Guess HA, Hulka BS, Friedman GD, Sadler M, Vollmer RT, et al. Vitamin D and prostate cancer:a prediagnostic study with stored sera. Cancer Epidemiol Biomar Prev 1993;2:467-72.
25. Deschasaux M, Souberbielle JC, Latino-Martel P, Sutton A, Charnaux N, Druesne-Pecollo N, et al. A prospective study of plasma 25-hydroxyvitamin D concentration and prostate cancer risk. Br J Nutr 2016;115:305-14.
26. Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med 2007;4:e103.
27. Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, et al. Serum vitamin D concentration and prostate cancer risk:a nested case-control study. J Natl Cancer Inst 2008;100:796-804.
28. Gao J, Wei W, Wang G, Zhou H, Fu Y, Liu N. Circulating vitamin D concentration and risk of prostate cancer:a dose-response meta-analysis of prospective studies. Ther Clin Risk Manag 2018;14:95-104.
29. Ahn J, Park S, Zuniga B, Bera A, Song CS, Chatterjee B. Vitamin D in prostate cancer. Vitam Horm 2016;100:321-55.
30. Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et al. Vitamin D and prevention of breast cancer:pooled analysis. J Steroid Biochem Mol Biol 2007;103:708-11.
31. John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk:the NHANES I Epidemiologic follow-up study, 1971-1975 to 1992. National Health and Nutrition Examination Survey. Cancer Epidemiol Biomar Prev 1999;8:399-406.
32. Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 2008;100:1581-91.
33. Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst 2002;94:1301-11.
34. de Sousa Almeida-Filho B, De Luca Vespoli H, Pessoa EC, Machado M, Nahas-Neto J, Nahas EAP. Vitamin D deficiency is associated with poor breast cancer prognostic features in postmenopausal women. J Steroid Biochem Mol Biol 2017;174:284-9.
35. Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007;167:1050-9.
36. Anderson LN, Cotterchio M, Vieth R, Knight JA. Vitamin D and calcium intakes and breast cancer risk in pre-and postmenopausal women. Am J Clin Nutr 2010;91:1699-707.
37. Yao S, Kwan ML, Ergas IJ, Roh JM, Cheng TD, Hong CC, et al. Association of serum level of vitamin D at diagnosis with breast cancer survival:a case-cohort analysis in the pathways study. JAMA Oncol 2017;3:351-7.
38. Palmer JR, Gerlovin H, Bethea TN, Bertrand KA, Holick MF, RuizNarvaez EN, et al. Predicted 25-hydroxyvitamin D in relation to incidence of breast cancer in a large cohort of African American women. Breast Cancer Res 2016;18:86.
39. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer:a 19-year prospective study in men. Lancet 1985;1:307-9.
40. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer:eightyear prospective study. Lancet 1989;2:1176-8.
41. Lee JE, Li H, Chan AT, Hollis BW, Lee IM, Stampfer MJ, et al. Circulating levels of vitamin D and colon and rectal cancer:the Physicians' Health Study and a meta-analysis of prospective studies. Cancer Prev Res (Phila) 2011;4:735-43.
42. McCullough M, Zoltick E, Weinstein S, Fedirko V, Wang M, Cook N, et al. Circulating vitamin D and colorectal cancer risk:an international pooling project of 17 cohorts. J Natl Cancer Inst 2018. Available from:
43. Hightower JM, Dalessandri KM, Pope K, Hernandez GT. Low 25-Hydroxyvitamin D and myofascial pain:association of cancer, colon polyps, and tendon rupture. J Am Coll Nutr 2017;36:455-61.
44. Mohr SB, Gorham ED, Kim J, Hofflich H, Cuomo RE, Garland CF. Could vitamin D sufficiency improve the survival of colorectal cancer patients?. J Steroid Biochem Mol Biol 2015;148:239-44.
45. Song M, Nishihara R, Wang M, Chan AT, Qian ZR, Inamura K, et al. Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status. Gut 2016;65:296-304.
46. Takeshige N, Yin G, Ohnaka K, Kono S, Ueki T, Tanaka M, et al. Associations between vitamin D receptor (VDR) gene polymorphisms and colorectal cancer risk and effect modifications of dietary calcium and vitamin D in a Japanese population. Asian Pac J Cancer Prev 2015;16:2019-26.
47. Chen W, Dawsey SM, Qiao YL, Mark SD, Dong ZW, Taylor PR, et al. Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers. Br J Cancer 2007;97:123-8.
48. Abnet CC, Chen Y, Chow WH, Gao YT, Helzlsouer KJ, Le Marchand L, et al. Circulating 25-hydroxyvitamin D and risk of esophageal and gastric cancer:Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 2010;172:94-106.
49. Ren C, Qiu MZ, Wang DS, Luo HY, Zhang DS, Wang ZQ, et al. Prognostic effects of 25-hydroxyvitamin D levels in gastric cancer. J Transl Med 2012;10:16.
50. Zhao Y, Chen C, Pan W, Gao M, He W, Mao R, et al. Comparative efficacy of vitamin D status in reducing the risk of bladder cancer:a systematic review and network meta-analysis. Nutrition 2016;32:515-23.
51. Zhang H, Zhang H, Wen X, Zhang Y, Wei X, Liu T. Vitamin D deficiency and increased risk of bladder carcinoma:a meta-analysis. Cell Physiol Biochem 2015;37:1686-92.
52. Ben Fradj MK, Gargouri MM, Hammami MB, Ben Rhouma S, Kallel A, Jemaa R, et al. Bladder cancer is associated with low plasma 25-hydroxyvitamin D concentrations in tunisian population. Nutr Cancer 2016;68:208-13.
53. Dimitrakopoulou VI, Tsilidis KK, Haycock PC, Dimou NL, AlDabhani K, Martin RM, et al. Circulating vitamin D concentration and risk of seven cancers:mendelian randomisation study. BMJ 2017;359:j4761.
54. Gromowski T, Gapska P, Scott RJ, Kaklewski K, Marciniak W, Durda K, et al. Serum 25(OH)D concentration, common variants of the VDR gene and lung cancer occurrence. Int J Cancer 2017;141:336-41.
55. Ong JS, Cuellar-Partida G, Lu Y, Australian Ovarian Cancer S, Fasching PA, Hein A, et al. Association of vitamin D levels and risk of ovarian cancer:a Mendelian randomization study. Int J Epidemiol 2016;45:1619-30.
56. van Duijnhoven FJB, Jenab M, Hveem K, Siersema PD, Fedirko V, Duell EJ, et al. Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations. Int J Cancer 2018;142:1189-201.
57. Yuan C, Qian ZR, Babic A, Morales-Oyarvide V, Rubinson DA, Kraft P, et al. Prediagnostic plasma 25-hydroxyvitamin D and pancreatic cancer survival. J Clin Oncol 2016;34:2899-905.
58. Omura Y, Lu D, Jones MK, Nihrane A, Duvvi H, Yapor D, et al. Optimal dose of vitamin D3 400 I.U. for average adults has a significant anti-cancer effect, while widely used 2000 I.U. or higher promotes cancer:marked reduction of taurine & 1a, 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 Electrother Res 2016;41:39-60.
59. Cheng TY, Lacroix AZ, Beresford SA, Goodman GE, Thornquist MD, Zheng Y, et al. Vitamin D intake and lung cancer risk in the Women's Health Initiative. Am J Clin Nutr 2013;98:1002-11.
60. Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women:a randomized clinical trial. JAMA 2017;317:1234-43.
61. Crockett SD, Barry EL, Mott LA, Ahnen DJ, Robertson DJ, Anderson JC, et al. Calcium and vitamin D supplementation and increased risk of serrated polyps:results from a randomised clinical trial. Gut. 2018. Available from:
62. Beer TM, Garzotto M, Katovic NM. High-dose calcitriol and carboplatin in metastatic androgen-independent prostate cancer. Am J Clin Oncol 2004;27:535-41.
63. Tiffany NM, Ryan CW, Garzotto M, Wersinger EM, Beer TM. High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer:a phase I/Ⅱ study. J Urol 2005;174:888-92.
64. Chan JS, Beer TM, Quinn DI, Pinski JK, Garzotto M, Sokoloff M, et al. A phase Ⅱ study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer. BJU Int 2008;102:1601-6.
65. Beer TM, Javle MM, Ryan CW, Garzotto M, Lam GN, Wong A, et al. Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer. Cancer Chemother Pharmacol 2007;59:581-7.
66. Trump DL, Potter DM, Muindi J, Brufsky A, Johnson CS. Phase Ⅱ trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer 2006;106:2136-42.
67. Blanke CD, Beer TM, Todd K, Mori M, Stone M, Lopez C. Phase Ⅱ study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Invest New Drugs 2009;27:374-8.
68. Chadha MK, Tian L, Mashtare T, Payne V, Silliman C, Levine E, et al. Phase 2 trial of weekly intravenous 1,25-dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castrationresistant prostate cancer. Cancer 2010;116:2132-9.
69. Ramnath N, Daignault-Newton S, Dy GK, Muindi JR, Adjei A, Elingrod VL, et al. A phase I/Ⅱ pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 2013;71:1173-82.
70. Srinivas S, Feldman D. A phase Ⅱ trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 2009;29:3605-10.
71. Scher HI, Jia X, Chi K, de Wit R, Berry WR, Albers P, et al. Randomized, open-label phase Ⅲ trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol 2011;29:2191-8.
72. Lokeshwar BL, Schwartz GG, Selzer MG, Burnstein KL, Zhuang SH, Block NL, et al. Inhibition of prostate cancer metastasis in vivo:a comparison of 1,25-dihydroxyvitamin D (calcitriol) and EB1089. Cancer Epidemiol Biomar Prev 1999;8:241-8.
73. Ghous Z, Akhter J, Pourgholami MH, Morris DL. Inhibition of hepatocellular cancer by EB1089:in vitro and in vivo study. Anticancer Res 2008;28:3757-61.
74. James SY, Mercer E, Brady M, Binderup L, Colston KW. EB1089, a synthetic analogue of vitamin D, induces apoptosis in breast cancer cells in vivo and in vitro. Br J Pharmacol 1998;125:953-62.
75. Blutt SE, Polek TC, Stewart LV, Kattan MW, Weigel NL. A calcitriol analogue, EB1089, inhibits the growth of LNCaP tumors in nude mice. Cancer Res 2000;60:779-82.
76. Wu G, Fan RS, Li W, Ko TC, Brattain MG. Modulation of cell cycle control by vitamin D3 and its analogue, EB1089, in human breast cancer cells. Oncogene 1997;15:1555-63.
77. Diaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A. Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells:possible implications for prevention and therapy. Cancer Res 2000;60:2304-12.
78. Simboli-Campbell M, Narvaez CJ, van Weelden K, Tenniswood M, Welsh J. Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells. Breast Cancer Res Treat 1997;42:31-41.
79. Hoyer-Hansen M, Bastholm L, Mathiasen IS, Elling F, Jaattela M. Vitamin D analog EB1089 triggers dramatic lysosomal changes and beclin 1-mediated autophagic cell death. Cell Death Differ 2005;12:1297-309.
80. Evans TR, Colston KW, Lofts FJ, Cunningham D, Anthoney DA, Gogas H, et al. A phase Ⅱ trial of the vitamin D analogue seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br J Cancer 2002;86:680-5.
81. Dalhoff K, Dancey J, Astrup L, Skovsgaard T, Hamberg KJ, Lofts FJ, et al. A phase Ⅱ study of the vitamin D analogue seocalcitol in patients with inoperable hepatocellular carcinoma. Br J Cancer 2003;89:252-7.
82. Schwartz GG, Hall MC, Stindt D, Patton S, Lovato J, Torti FM. Phase I/Ⅱ study of 19-nor-1a-25-dihydroxyvitamin D2 (paricalcitol) in advanced, androgen-insensitive prostate cancer. Clin Cancer Res 2005;11:8680-5.
83. Lawrence JA, Akman SA, Melin SA, Case LD, Schwartz GG. Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D2) in women receiving chemotherapy for metastatic breast cancer:a feasibility trial. Cancer Biol Ther 2013;14:476-80.
84. Ma Y, Yu WD, Hidalgo AA, Luo W, Delansorne R, Johnson CS, et al. Inecalcitol, an analog of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. Cell Cycle 2013;12:743-52.
85. Okamoto R, Delansorne R, Wakimoto N, Doan NB, Akagi T, Shen M, et al. Inecalcitol, an analog of 1α,25(OH)2D3, induces growth arrest of androgen-dependent prostate cancer cells. Int J Cancer 2012;130:2464-73.
86. Medioni J, Deplanque G, Ferrero JM, Maurina T, Rodier JM, Raymond E, 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 2014;20:4471-7.
87. Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgenindependent prostate cancer:a report from the ASCENT Investigators. J Clin Oncol 2007;25:669-74.
88. Wagner D, Trudel D, Van der Kwast T, Nonn L, Giangreco AA, Li D, et al. Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients. J Clin Endocrinol Metab 2013;98:1498-507.
89. Shamseddine A, Farhat FS, Elias E, Khauli RB, Saleh A, Bulbul MA. High-dose calcitriol, docetaxel and zoledronic acid in patients with castration-resistant prostate cancer:a phase Ⅱ study. Urol Int 2013;90:56-61.
90. Pommergaard HC, Burcharth J, Rosenberg J, Raskov H. Aspirin, calcitriol, and calcium do not prevent adenoma recurrence in a randomized controlled trial. Gastroenterology 2016;150:114-22[e4].
91. Brinkhuizen T, Frencken KJ, Nelemans PJ, Hoff ML, KellenersSmeets NW, Zur Hausen A, et al. The effect of topical diclofenac 3% and calcitriol 3 μg/g on superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC):a phase Ⅱ, randomized controlled trial. J Am Acad Dermatol 2016;75:126-34.
92. Liu S, Barry EL, Baron JA, Rutherford RE, Seabrook ME, Bostick RM. Effects of supplemental calcium and vitamin D on the APC/β-catenin pathway in the normal colorectal mucosa of colorectal adenoma patients. Mol Carcinog 2017;56:412-24.
93. Barry EL, Peacock JL, Rees JR, Bostick RM, Robertson DJ, Bresalier RS, et al. Vitamin D receptor genotype, vitamin D3 supplementation, and risk of colorectal adenomas:a randomized clinical trial. JAMA Oncol 2017;3:628-35.
94. Gong C, Long Z, Yu Y, Zhu L, Tian J, Li S, et al. Dietary factors and polymorphisms in vitamin D metabolism genes:the risk and prognosis of colorectal cancer in northeast China. Sci Rep 2017;7:8827.
95. Vidigal VM, Silva TD, de Oliveira J, Pimenta CAM, Felipe AV, Forones NM. Genetic polymorphisms of vitamin D receptor (VDR), CYP27B1 and CYP24A1 genes and the risk of colorectal cancer. Int J Biol Markers 2017;32:e224-30.
96. Shui IM, Mucci LA, Kraft P, Tamimi RM, Lindstrom S, Penney KL, et al. Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer:a prospective nested case-control study. J Natl Cancer Inst 2012;104:690-9.
97. Garcia-Albeniz X, Rudolph A, Hutter C, White E, Lin Y, Rosse SA, et al. CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk. Br J Cancer 2016;114:221-9.
98. Wu X, Cheng J, Yang K. Vitamin D-related gene polymorphisms, plasma 25-hydroxy-vitamin D, cigarette smoke and non-small cell lung cancer (NSCLC) risk. Int J Mol Sci 2016;17:1597.
99. Yang J, Wang H, Ji A, Ma L, Wang J, Lian C, et al. Vitamin D signaling pathways confer the susceptibility of esophageal squamous cell carcinoma in a northern chinese population. Nutr Cancer 2017;69:593-600.