Chronic Ethanol Feeding Promotes Azoxymethane (AOM) and Dextran Sodium Sulfate (DSS)‐Induced Colonic Tumorigenesis by Enhancing Mucosal Inflammation

Abstract

Alcohol consumption is a major risk factor for colorectal cancer, but the mechanism involved in this is unknown. We evaluated the effect of ethanol (EtOH) on AOM‐DSS‐induced colonic tumorigenesis in mice. Adult female mice were treated with AOM (10 mg/kg BW) and colitis was induced after 5 days (d) by 3% DSS in drinking water for 5 d. DSS colitis was repeated twice with 15‐d intervals. Tumorigenesis was observed at 30 d after the 3rd DSS cycle. During the 15‐d intervals and 30 d after 3rd DSS cycle animals were fed Lieber‐DeCarli liquid diet with or without 4% EtOH; non‐EtOH group were pair fed with isocaloric diet. Colon was examined for tumors, cryosections stained for p‐Smad, VEGF and HIF1α. At a precancerous stage, colon was analyzed by microarray analysis and RT‐PCR. Cryosections of colon were examined for inflammatory markers, myeloperoxidase (MPO), GR1 (neutrophil) and CD68 (macrophage) by confocal microscopy. EtOH feeding dramatically elevated colonic tumors; both the number and size of tumors were greater. AOM+DSS‐induced elevation of p‐Smad, VEGF and HIF1α in the colon was greater in EtOH‐fed mice. At the precancerous stage, EtOH feeding significantly reduced (46‐94% decline) the AOM+DSS‐induced expression of defensin genes (Defcr1,3,5,6,20,21,26); colons in untreated and EtOH alone controls showed no defensin expression. EtOH feeding increased the expression of proinflammatory cytokines/chemokines (IL‐6 & CCL5) and the elevation of inflammatory markers MPO, GR1 & CD68 in AOM+DSS treated mice. This study suggests that chronic EtOH feeding promotes colonic tumorigenesis by delaying the post colitis recovery by suppressing defensins leading to sustained inflammation.