Date of Award
Doctor of Philosophy
Ecology and Evolutionary Biology
Michael B. Zemel
Jay Whelan, Michael F. McEntee, Jung Han Kim
Excess adipose tissue is a risk factor for developing colorectal cancer. However, the present studies demonstrate that lack of adipose-derived factor(s), such as adiponectin, due to the substantial loss of body fat on high dairy calcium diet could increase susceptibility to intestinal tumorigenesis. These studies suggest that a minimum amount or threshold level of adipose tissue may be required to significantly attenuate tumorigenesis.
In ApcMin/+ mice, consumption of high dairy calcium diet exhibited markedly reduced adipose tissue and increased tumor number. Our results showed that the high calcium diet reduced fat pad mass by 65%-82% in ApcMin/+ (p<0.03) in comparison with low calcium diet. ApcMin/+ mice on the high calcium diet exhibited an increase in tumor number (76 vs. 29, p=0.009). Moreover, β-catenin gene and cyclin D1 gene expression were significantly induced in intestinal tumor tissue of ApcMin/+ mice on high calcium diet. These effects were not directly resulted from high dietary calcium feeding, but rather associated with loss of body fat mass. Tumor load was not affected by the calcium diet on obese A/yApcMin/+mice despite the fact that high dairy calcium diet produced a substantial loss of body fat, as there was still substantial residual adipose tissue remaining. Our results indicate that protective effects of calcium against colorectal cancer may be least apparent among lean individuals, suggesting that future studies of calcium and colorectal cancer should consider stratification of subjects according to adiposity.
In an in vitro environment to determine the adipose-derived factor(s) responsible, we utilized a co-culture system to observe the influence of human adipocytes on the growth of Caco-2, a human colon cancer cell line. We found that human adipocytes substantially suppressed proliferation of Caco-2 by 62.8%. In addition, we reported that human adipocyte conditioned medium inhibited growth of Caco-2 cells by 28.0%-65.6% compare to DMEM. These findings suggest the protective effect of adipocytes on colonic tumorigenesis. To further investigate if adiponecin, a protein hormone secreted from mature adipocytes, is responsible for this inhibitory effect, anti-human adiponectin-neutralizing antibody was added into the human adipocyte conditioned medium (HACM) and to the co-culture system. The antibody blocked the growth-inhibiting effects in both human adipocytes (HA) and HACM. Consistent with this, siRNA-mediated decrease in adiponectin protein in human adipocytes prevented the inhibitory effect of human adipocytes on Caco-2 proliferation. These data demonstrated that human adipocytes inhibit Caco-2 proliferation and that adiponectin is responsible for this effect.
Ding, Shengli, "Adiposity Related Protection of Intestinal Tumorigenesis: Interaction With Dietary Calcium. " PhD diss., University of Tennessee, 2007.