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Cancer Control Research

Abstract

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to better understand how calcium and vitamin D influence colorectal carcinogenesis. Epidemiological studies have generally supported an inverse association between calcium, vitamin D and risk of colorectal cancer, although findings have been inconsistent. Of dietary factors tested in intervention studies of adenomatous polyp recurrence, calcium has most consistently reduced risk. Recent evidence further supports either an interactive or additive role of calcium and vitamin D. Two intriguing mechanistic hypotheses concern vitamin D autocrine/paracrine activity and tissue-specific calcium sensing receptors (CaSR). Calcium and vitamin D exhibit anti-proliferative and pro-differentiation effects in vitro and in vivo. The active form of vitamin D, 1,25(OH)2D, is the natural ligand for the vitamin D receptor (VDR), which regulates expression of numerous genes involved in cell cycle control. Classically 1,25(OH)2D synthesis has been thought to be solely regulated by the action of 1,alpha(OH)ase (CYP27B1) on 25(OH)D (storage form of vitamin D) in the kidney. However, 1,25(OH)2D is now also known to be directly synthesized and degraded in colon tissue, independent of usual triggers of renal 1,25(OH)2D synthesis. Remarkably little is known about the factors that initiate tissue-specific 1,25(OH)2D synthesis (by CYP27B1) and catabolism (by CYP24). The calcium sensing receptor (CaSR) is upregulated by 1,25(OH)2D and is also thought to regulate epithelial differentiation. VDR expression, which is influenced by multiple factors, may modify the preventive efficacy of calcium and vitamin D. Whether expression of vitamin D metabolizing enzymes or CaSR in colon tissue responds to plasma vitamin D concentrations, diet, or non-dietary factors, and whether the effects of vitamin D or calcium on the colon is modified by VDR expression, is of current interest. This study uses data and biological samples (blood and biopsies of normal-appearing colorectal tissue) collected in an ongoing, randomized, double-blind, placebo-controlled 2x2 factorial pilot trial (n=88) of calcium and vitamin D in the modulation of biomarkers of risk for colorectal cancer in sporadic colorectal adenoma patients. Using automated quantitative immunohistochemistry with image analysis, we will measure the expression of CYP27B1 and CYP24 hydroxylases (as measures of tissue-specific 1,25(OH)2D synthesis and degradation, respectively), the CaSR, and the VDR in the normal-appearing colorectal epithelium to investigate whether calcium or vitamin D supplementation, vitamin D metabolites in the blood, or other diet and lifestyle factors influence their expression. This pilot study will provide the estimates of variability required for power calculations to apply these research questions to a larger, ongoing, intervention trial. The results of this study are needed for further progress in developing vitamin D, calcium and related agents in preventing colorectal cancer, the second leading cause of cancer deaths in the US.