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Thursday, August 23, 2012

Ethanol-Induced Mast Cell-Mediated Inflammation Leads to Increased Susceptibility of Intestinal Tumorigenesis in the APCΔ468 Min Mouse Model of Colon

Chronic and frequent alcohol (ethanol [EtOH]) intake has been associated with an increased incidence of several types of cancers including breast, mouth, throat, esophageal, stomach, and colorectal (CRC). The underlying mechanism of this deleterious carcinogenic effect of alcohol has not been clearly established but inflammation may be 1 unifying feature of these cancers. We have recently shown that intestinal mast cells play a central role in intestinal carcinogenesis. In this study, we tested our hypothesis that mast cell-mediated inflammation is 1 underlying mechanism by which chronic alcohol promotes intestinal tumorigenesis.

APCΔ468 mice were fed either an alcohol-containing Nanji liquid diet or isocaloric dextrose-containing Nanji diet for 10 weeks and then sacrificed to collect small and large intestine samples. Assessments of tumor number and size as well as mast cell number and mast cell activity and histology score for invasion were compared between Control (dextrose-fed) and alcohol-fed APC∆468 mice. The effect of alcohol on mast cell-mediated tumor migration was also assessed using an in vitro migration assay.

Alcohol feeding increased both polyp number and size within both the small and the large intestines of APC∆468 mice. Only alcohol-fed mice showed evidence of tumor invasion. Chronic alcohol feeding also resulted in an increased mast cell number and activity in tumor stroma and invading borders. In vitro migration assay showed that alcohol significantly increases mast cell-mediated tumor migration in vitro.

Our data show that chronic alcohol intake promotes: (i) intestinal tumorigenesis and tumor invasion in genetically susceptible mice; (ii) increases in polyp-associated mast cells; and (iii) mast cell-mediated tumor migration in vitro. Both our in vivo and in vitro studies suggest that mast cell-mediated inflammation could be 1 mechanism by which alcohol promotes carcinogenesis.

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