Effects of Vitamin D and Calcium on Proliferation and Differentiation in Normal Colon Mucosa: A Randomized Clinical Trial

• Authors: Veronika Fedirko, Emory University; Roberd M Bostick, Emory University; W Dana Flanders, Emory University; Qi Long, Emory University; Eduard Sidelnikov, Emory University; Aasma Shaukat, University of Minnesota; Carrie R. Daniel, National Institutes of Health; Robin E Rutherford, Emory University; Jill Joelle Woodard, Emory University
• Journal Title: Cancer Epidemiology, Biomarkers and Prevention
• Volume: Volume 18, Number 11
• Publisher: American Association for Cancer Research | 2009-11, Pages 2933-2941
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/1055-9965.EPI-09-0239
• Subjects: Health Sciences, Oncology; Health Sciences, Epidemiology
• Keywords: vitamin D; calcium; colonic neoplasms; cell differentiation; cell proliferation; clinical trial; normal colorectal mucosa; biomarkers

Abstract

To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop ‘treatable’ phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2×2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with calcium 2 g/day and/or vitamin D3 800 IU/day vs. placebo over six months. Overall expression and distributions of p21waf1/cip1 (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P=0.03), 242% (P=0.005), and 25% (P=0.47), respectively, along the full lengths of colorectal crypts after six months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P=0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may “normalize” the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms.