A protective role for the Polymeric Immunoglobulin Receptor in Colitis-Associated Cancer

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The intestinal epithelium acts as a protective interface between the vast gut microbiota and the immune cells in the underlying lamina propria. Secretory IgA (SlgA) antibodies are the most abundant immunoglobulins in gut secretions, where they neutralize potentially hazardous microbes and environmental substances. Transport of IgA across intestinal epithelial cells (lEC) into external secretions is mediated by the polymeric immunoglobulin receptor (plgR). Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), result from a dysregulated mucosal immune response to the gut microbiota in genetically susceptible individuals. Colitis-associated cancer (CAC) is the most serious complication of IBD and the leading cause of death in these patients. The risk is particularly high in UC and is directly correlated with the extent and duration of disease; after 30 years of disease, approximately 18% of UC patients develop CAC. Several lines of evidence support a role for plgR in regulation of intestinal inflammation in human IBD and in experimental models of colitis. Decreased expression of plgR and diminished transport of SlgA have been observed in regenerating and dysplastic epithelium in IBD patients. We recently reported that plgR expression was Significantly down-regulated in the colonic mucosa of CD and UC patients, and in a mouse model of chronic colitis. Mice genetically deficient in plgR have been shown to be more susceptible than wild-type mice to acute chemically-induced colitis induced by oral administration of DSS. Significantly, we and others have shown that expression of plgR is diminished in human colon adenocarcinomas. We hypothesize that decreased plgR expression in the colonic mucosa may be a risk factor for both colitis and CAC. To test the hypothesis that plgR-deficient mice are more susceptible than wild-type mice to chronic inflammation and CAC development, CAC will be induced by systemic administration of the carcinogen azoxymethane (AOM) followed by oral administration of the colitis-inducing agent dextran sulfate sodium (D55). At specific time points, mice will be assessed for the severity of inflammation, and the extent of dysplasia and tumor load. IECs and lamina propria immune cells will be purified and analyzed for expression of several genes known to be dysregulated in CAC. These include pro-inflammatory factors IL-6, TNF, 1L1-I3, MIP-1, KC and MCP-1, antiirl'Hammatory factors IL-10 and TGF-I3, and factors involved in cell survival, angiogenesis and tumor invasion, such as Cox-2, MMP-9, MMP-2, VEGF and HIF-a.
Effective start/end date7/1/106/30/11


  • American Cancer Society


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