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

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. Ninetytwo men and women with at least one pathologyconfirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D 3 versus placebo over 6 months. Overall expression and distributions of p21 waf1/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 6 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. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2933-41)

Markers of the APC/β-Catenin Signaling Pathway as Potential Treatable, Preneoplastic Biomarkers of Risk for Colorectal Neoplasms

“…Also, our results suggest that these biomarkers may be associated with dietary and lifestyle risk factors for colorectal neoplasms, suggesting that these biomarkers may be modifiable. These findings, which support previous findings suggesting that molecular phenotypic differences in the normal-appearing colorectal mucosa may be associated with increased risk of colorectal neoplasms (9-11) and are modifiable (16,(22)(23)(24)(25), are relevant because there are currently no validated treatable, preneoplastic biomarkers of risk for colorectal neoplasms.…”

Vitamin D and colon cancer

“…In a series of recent papers, Fedirko et al reported that 800 IU/day vitamin D 3 and/or 2 g/day calcium (in 92 patients with at least one adenoma, 6 months treatment) increased BAX and p21 CIP1 expression in colorectal crypts (Fedirko et al 2009a,b). These authors also observed a decreased labelling of the DNA oxidation marker 8-OH-dG (only by vitamin D 3 or calcium alone, but not by the combination) and a reduced expression of the marker of long-term proliferation hTERT in the upper part of the crypt (only in the vitamin D 3 plus calcium group) (Fedirko et al 2009b(Fedirko et al , 2010. In addition, the group treated with vitamin D 3 alone showed a reduction in the expression of the proinflammatory cytokines TNF-a, IL6, IL1b and IL8, and the proinflammatory marker C-reactive protein (Hopkins et al 2011).…”

Meta-Analyses of Vitamin D Intake, 25-Hydroxyvitamin D Status, Vitamin D Receptor Polymorphisms, and Colorectal Cancer Risk

“…Vitamin D status modulates various genes in the colorectal mucosa that may influence the cancer risk (71,80). In humans, vitamin D may induce the differentiation and apoptosis (81,82), both in colorectal adenoma or cancer cells (83) and in the normal colorectal epithelium (84)(85)(86).…”