Role of gut barrier dysfunction and endotoxemia in development of colon cancer cachexia
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Cachexia, accounts for ~30% of all cancerrelated deaths, and up to 50% of deaths in patients with gastrointestinal cancers. ApcMin/+ mice have been used as a model of colorectal cancer that become cachetic at 45 months of age. Gut barrier dysfunction (GBD) is an increase in the permeability of intestinal epithelium which can allow bacteria to breach the gut barrier and induce an inflammatory response. The purpose of this study was to determine if GBD is associated with cachexia in the ApcMin/+ mouse. Mice were administered FITCdextran, FD4, (MW 4000 Da) by gavage and blood sampled 1h later via retraorbital stick. Plasma endotoxin was measured with the limulus assay at 12wk and 19wk of age. There was a 27% decrease in body weight of the ApcMin/+ mice at 20 wks compared to the C57/BL6 wild type. Plasma FD4 was increased in the ApcMin/+ mice at 20wk compared to 14wks (6.92.4 g/ml, n=10 vs 0.5.5g/ml, n=7). Endotoxin was greater at 19wks than 12wk ApcMin/+ mice (10.53EU/ml, n=9 vs 2.02.8EU/ml, n=4). Mesentaric lymphs were taken at the 20wks were significantly larger in the ApcMin/+ mice compared with wild type mice (382.4mg, n=6 vs 24.41.7mg, n=9). Tumor number between 12 and 20 weeks was not different but, 20wk ApcMin/+ mice had an 8 fold greater number of large tumors. From these results, we hypothesize that GBD and resultant endotoxemia induce the proinflammatory state that leads to development of cachexia in ApcMin/+ mice.
