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/+;Apc^Min/+) 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 Apc^Min/+ 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 Apc^Min/+ mice were crossed with obesity prone lethal yellow agouti (A ^y /a) mice to generate obese A^y/Apc^Min/+ mice. Low (0.2%), normal (0.5%), and high (1.2%) calcium diets were fed to both A^y/Apc ^Min/+ mice and Apc^Min/+ 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 /Apc^Min/+(P < 0.004) and by 65–82% in Apc^Min/+(P < 0.03).Apc^Min/+ 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 A^y/Apc^Min/+ mice.β-Catenin and cyclin D1 gene expression were significantly induced with high calcium diet in intestinal tumor tissue of Apc^Min/+ mice but not in A^y/Apc^Min/+ mice. We conclude that the differential effect of dietary calcium on intestinal tumorigenesis in lean vs. obese Apc^Min/+ may result from the loss of adipose-derived protective factor(s) due to the substantial loss of body fat in Apc^Min/+ mice fed a high calcium dairy diet, increasingβ-catenin and cyclin D1 in tumors.

Acknowledgments and Notes

This research was supported, in part, by a research grant from The American Institute for Cancer Research.

Notes

^a Data expressed as mean ± SE.

^a Data expressed as mean ± SE. ∗P < 0.01 vs. low calcium diet group in A ^y /Apc ^Min/+mice.

^a Data expressed as mean ± SE.

^b Values in each row with different symbols(∗,†) are significantly different by 1-way analysis of variance (ANOVA), P < 0.05.

^‡ Value is significantly different from § value by 1-way ANOVA, P < 0.05.

^a None observed.

^b Number of tumors.

^c Data expressed as mean ± SE.

^d Values in row with different symbols (∗, †) are significantly different by 1-way analysis of variance, P < 0.05.