Trace element supplementation to enhance calcium-mediated suppression of human colon adenoma growth

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ABSTRACT Epidemiological and interventional studies have demonstrated an inverse relationship between calcium intake and colon polyp formation. Recent meta-analysis of the calcium chemoprevention literature indicates that the protective effects of calcium extend to colorectal cancer, itself. However, the effects are modest. It has been estimated that a reduction in tumor formation of approximately 8% might be achieved for each 300 mg per day increase in calcium intake (over a baseline of 1000 mg per day). The proposed studies will test the hypothesis that a combination of calcium and a mix of cationic trace elements will be more effective than calcium alone at suppressing the growth of human colonic adenomas (colon polyps). For the proposed studies, we will utilize human colon polyp tissue maintained in enteroid culture. We have developed a culture system to grow the premalignant human colon tissue using a minimally supplemented culture medium containing only epidermal growth factor and pituitary extract as growth promoters. Adenoma tissue in enteroid culture from 21 different cultures (representing 17 subjects) is now “banked away” as frozen stocks. DNA sequencing and bioinformatic data identifying the presence of mutations thought to influence colon polyp growth are available for each established culture. Phenotypic information (immuno-histochemical marker data) is also available for each of the premalignant tumors. In the proposed studies, enteroid cultures will be maintained under control conditions or exposed to increasing concentrations of calcium – either alone or in conjunction with additional trace elements. The effects of each intervention will be evaluated over time by assessing phenotypic markers of growth and differentiation. RNA sequencing and proteomic display differences will be used to identify global changes induced by each intervention. The use of colon enteroid cultures provides a way to determine directly if human colon polyp growth can be more effectively modulated by calcium in conjunction with additional trace elements than by calcium alone. By using cultures established from tumors of several different subjects, we are in position to determine the variability in responsiveness to each intervention as a first step toward understanding the basis for variation in response among individuals.