Adiposity-Related Protection of Intestinal Tumorigenesis: Interaction With Dietary Calcium

Abstract

Although high-calcium diets have been reported to reduce the risk of colorectal cancer, our preliminary data with the adenomatous polyposis coli (Apc) Min mutation (Min/+;ApcMin/+) mouse shows a paradoxical increase in intestinal tumor loads (> 65%) with high calcium diets. Since we previously demonstrated that increasing dietary calcium reduces adiposity, and ApcMin/+ mice on high calcium diets exhibited profound loss of adipose tissue, we hypothesized that loss of an adipose tissue-derived tumor suppressor factor(s) resulted in increased tumor susceptibility in animals on the high calcium diet. Accordingly, tumor prone ApcMin/+ mice were crossed with obesity prone lethal yellow agouti (A y /a) mice to generate obese Ay/ApcMin/+ mice. Low (0.2%), normal (0.5%), and high (1.2%) calcium diets were fed to both Ay/Apc Min/+ mice and ApcMin/+ mice from 35–40 days until 90 days of age (n = 21/strain, n = 7/diet group). The high calcium diet reduced weight gain in both strains (P < 0.01) and reduced fat pad mass by 46–57% in A y /ApcMin/+(P < 0.004) and by 65–82% in ApcMin/+(P < 0.03).ApcMin/+ mice on the high calcium diet exhibited an increase in tumor number (76 vs. 29, P = 0.009), but this effect was not seen in the Ay/ApcMin/+ mice.β-Catenin and cyclin D1 gene expression were significantly induced with high calcium diet in intestinal tumor tissue of ApcMin/+ mice but not in Ay/ApcMin/+ mice. We conclude that the differential effect of dietary calcium on intestinal tumorigenesis in lean vs. obese ApcMin/+ may result from the loss of adipose-derived protective factor(s) due to the substantial loss of body fat in ApcMin/+ mice fed a high calcium dairy diet, increasingβ-catenin and cyclin D1 in tumors.