Adiposity-related protection of intestinal tumorigenesis: interaction with dietary calcium.
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. beta-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, increasing beta-catenin and cyclin D1 in tumors.
Ding
S
S
Department of Nutrition, University of Tennessee, Knoxville, TN 37996-1920, USA.
McEntee
M F
MF
Whelan
J
J
Zemel
M
M
D050154:Adiposity / Q000502:physiology*; D000818:Animals; D002136:Calcium, Dietary / Q000008:administration & dosage* / Q000009:adverse effects*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018095:Germ-Line Mutation; D007414:Intestinal Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D011897:Random Allocation; D015430:Weight Gain; D051176:beta Catenin / Q000378:metabolism*
D002136:Calcium, Dietary; D051176:beta Catenin; D019938:Cyclin D1