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A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/?-catenin pathway in the normal mucosa of colorectal adenoma patients.

ABSTRACT: APC/?-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on adenomatous polyposis coli (APC), ?-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months (N = 92; 23/group). Overall APC, ?-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D(3)-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (?h APC) increased 21% (P = 0.01), ?-catenin decreased 12% (P = 0.18), E-cadherin increased 72% (P = 0.03), and the ?h APC/?-catenin ratio (APC/?-catenin score) increased 31% (P = 0.02). In the calcium-supplemented group ?h APC increased 10% (P = 0.12), ?-catenin decreased 15% (P = 0.08), and the APC/?-catenin score increased 41% (P = 0.01). In the calcium/vitamin D(3)-supplemented group, ?-catenin decreased 11% (P = 0.20), E-cadherin increased 51% (P = 0.08), and the APC/?-catenin score increased 16% (P = 0.26). These results support (i) that calcium and vitamin D modify APC, ?-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, (ii) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and (iii) the potential of APC, ?-catenin, and E-cadherin expression as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.

SUBMITTER: Ahearn TU

PROVIDER: S-EPMC3466388 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients.

Ahearn Thomas U TU Shaukat Aasma A Flanders W Dana WD Rutherford Robin E RE Bostick Roberd M RM

Cancer prevention research (Philadelphia, Pa.) 20120910 10

APC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on adenomatous polyposis coli (APC), β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases we ...[more]

PMID: 22964475

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Project description:Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.

Dataset Information

A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/?-catenin pathway in the normal mucosa of colorectal adenoma patients.

Publications

A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients.

Similar Datasets

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