Linking Inflammation To Tumorigenesis In A Mouse Model of High Fat Diet-Enhanced Colon Cancer: Does Fat Type Matter?

摘要

Many observational epidemiologic studies suggest an association between high-fat diet (HFD) and colon cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in colon cancer progression and HFD has been reported to increase inflammation; however, the inflammatory effects of HFD in colon cancer have yet to be established. We sought to examine the relationship between HFD (different ratios of saturated and unsaturated fat) and inflammation in relation to colon cancer progression in ApcMin/+ mice. Male ApcMin/+ mice (7-8/group) were assigned to one of four treatment groups as follows: 1) AIN-76A (5% fat) Control (Con), 2) Higher Saturated Fat Diet (24% saturated & 16% unsaturated) (HFD-24%), 3) American Standard Diet (12% saturated & 28% unsaturated) (HFD-12%), or 4) Lower Saturated Fat Diet (6% saturated & 34% unsaturated) (HFD-6%). A C57BL/6 group (wild-type) (n=11), fed the Con diet, was also included as a comparison. Mice were fed their respective treatments from 4-12 weeks of age. At 12 weeks of age mice were sacrificed and body composition, markers of obesity, adipose tissue inflammation, and polyp burden were examined. In general, all HFD groups increased fat mass and markers of obesity; however this was most significant in the HFD-12% group and not the HFD-24% group as expected. We found that HFD-24% significantly increased overall polyp burden, total polyp number in intestinal section 1, and increased the incidence of medium polyps, while all HFD groups increased percent large polyps. With regard to adipose tissue inflammation, overall expression of macrophages was significantly increased in the HFD-12% group, and HFD-12% and 6% increased the M1 macrophage sub-population. This suggests that a high-fat diet can promote infiltration of macrophages in the adipose tissue, specifically activating pro-inflammatory M1 macrophages. We also examined gene expression of macrophage markers and inflammatory mediators in the intestinal polyps. Interestingly, we found that expression of macrophages (EMR-1) as well as certain markers of M1 (IL-12) and M2 (CD206 and CCL17) macrophages were significantly increased in the HFD-6% group but not the HFD-12% or HFD-24%. As expected, all HFD treatments increased inflammatory mediators but this effect was greatest with the HFD-12% and HFD-24% groups. We report that a high-fat diet can lead to obesity, which can be associated with increased tumorigenesis, adipose tissue inflammation, and alterations in immune regulation and inflammation in the tumor microenvironment. However, these responses are dependent on the saturated versus unsaturated fat content of the diet. A greater understanding of the effects of high fat diet on promotion of colon cancer is necessary, especially with regards to different fat compositions.