Abstract
Abstract Obesity is a risk factor for a number of chronic diseases including many types of cancer. The chronic, low-grade inflammation that develops as a result of obesity may be a primary mechanistic target underlying obesity-associated carcinogenesis. While the link between obesity and inflammation is not well understood, increases in adipose tissue macrophages may perpetuate and exacerbate a chronic inflammatory environment through production of inflammatory cytokines such as interleukin (IL)-6. In this study we tested the hypothesis that macrophage infiltration underlies our previously observed anticancer effects of calorie restriction (CR) in a mouse model of colon cancer. Six-week-old female C57BL/6 mice (n=30 per diet) were singly housed and randomized to either a control diet consumed ad libitum (which results in an overweight phenotype) or a 30% calorie-restricted diet regimen (CR) for 22 weeks, at which time 15 mice per group were euthanized and adiposity was measured using dual-energy X-ray absorptiometry (DXA). The remaining 15 mice/diet were then injected subcutaneously (flank) with 50,000 syngeneic mouse colon (MC)-38-adenocarcinoma cells and continued on their diet regimens while tumor growth was monitored for an additional 5 weeks. Excised tumors underwent histological analysis of macrophage infiltration (hematoxylin and eosin staining) and real-time RT-PCR analyses of macrophage (F4/80 and S100A9) and IL-6 gene expression. CR mice had lower body weight (20.3g +/− 0.2 vs. 26.0g +/− 0.5 (mean +/− SEM), p<0.05) and body adiposity (22.9% +/− 1.2 vs. 29% +/− 1.7, p<0.05) after 21 weeks on study compared to control mice. Additionally, CR mice had smaller tumors (100.3 mm^3 +/− 13.2 vs. 242.4 mm^3 +/− 28.3, p<0.05) relative to controls. Tumors from CR mice, relative to controls, exhibited a 3-fold decrease in F4/80 and S100A9 gene expression and a 2.5 fold decrease in IL-6 (p<0.05). Furthermore, HandE staining showed reduced macrophage infiltration in CR tumors compared to control tumors. These findings suggest that the inhibitory effects of CR on MC38 colon tumor growth are associated with reduced tumor infiltration of macrophages, which may lead to new targets for the prevention of colon cancer. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B54.
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