Effects of Calcium and Vitamin D Supplementation on Toll-Like Receptor 4 (TLR4) Expression in the Normal-Appearing Colorectal Mucosa of Individuals at High Risk for Colorectal Neoplasms Restricted; Files Only

Hodge, Rebecca (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/sb397914f?locale=en
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Abstract

Inflammation plays an important role in colorectal carcinogenesis. Toll-like receptor 4 (TLR4)-mediated pro-inflammatory signaling in response to bacterial lipopolysaccharide (LPS) and other substrates has also been found to involved in colon carcinogenesis. Calcium and vitamin D, known to be promising chemopreventive agents for colorectal cancer, have been shown in cell culture and animal models to affect TLR4 regulation and expression, and it is possible their protective effects against carcinogenesis are at least in part mediated through inhibition of this pathway. Therefore, to test the effects of vitamin D and calcium supplementation on the TLR4 signaling pathway, we conducted a biomarker adjunct study nested within a larger randomized, double-blind, placebo-controlled, partial 2x2 factorial chemoprevention clinical trial of supplemental calcium (1,200 mg daily) and vitamin D (1000 IU daily), alone and in combination versus placebo. We assessed TLR4 expression in the normal-appearing colorectal mucosa of 105 patients at high risk of developing colorectal cancer at baseline and 1-yr follow up using standardized, automated immunohistochemistry and quantitative image analysis. Vitamin D3 and calcium did not affect TLR4 expression in colorectal crypts. However, a combined treatment with both agents decreased the proportion of TLR4 expression in the upper portion of the crypt (differentiation zone) relative to the whole crypt (12% increase, p-value 0.039). At baseline, regular NSAID use, cigarette smoking, vitamin D deficiency status, intakes of fruits and vegetables, and dietary fiber, and having advanced or serrated adenomas were found to be associated with TLR4 expression. The results from our pilot biomarker study suggest that a combined treatment with vitamin D and calcium may modify the distribution of TLR4 within the colon crypts by reducing TLR4 expression in the differentiation zone relative to the whole crypt; and that several known risk factors for colorectal cancer risk might be associated with TLR4 expression. Future studies are needed to understand a combined effect of vitamin D and calcium supplementation, and a role of environmental and lifestyle modifiable factors on TLR4 signaling pathway.

Table of Contents

INTRODUCTION

Colorectal Cancer

The Role of Inflammation and TLR4 in Colorectal Cancer Development

Vitamin D

Calcium

MATERIALS AND METHODS

Clinical Trial Protocol

Rectal Biopsy Tissue Collection and Biomarker Quantification

Statistical Analyses

RESULTS

Baseline Characteristics of Study Participants

Vitamin D and/or Calcium Effects on TLR4 Expression

Stratified Analyses

Predictors of Baseline TLR4

DISCUSSION

Predictors of TLR4

Strengths and Limitations

CONCLUSION AND RECOMMENDATIONS

REFERENCES

LIST OF TABLES

APPENDICES: SUPPLEMENATARY TABLES

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