Immuno-oncology

Oral

Aberrant Form of muc1 Promotes an Inflammatory Microenvironment Aggravating Colitis-associated Tumorigenesis

Thursday, June 15
5:45 PM - 7:00 PM

MUC1 mucin, a transmembrane glycoprotein is overexpressed and hypoglycosylated in human adenocarcinoma and chronic inflammatory conditions compared to healthy tissues. Using azoxymethane/dextran sulfate sodium (AOM/DSS) murine model of inflammation driven colon carcinogenesis, we explored the consequence of this abnormal expression of MUC1 in colitis-associated colon cancer (CAC). MUC1.Tg mice showed higher tumor incidence, decreased survival and greater body weight loss. High expression levels of pro-inflammatory cytokines, including TNF-α and IL-6, were found in MUC1+ inflamed colon tissues and exogenous TNF-α promoted the transcriptional activity of MUC1 as well as over-expression of its hypoglycosylated form. We also discovered that MUC1/p65 complex up-regulated IL-6 and TNF-α gene expression in the intestinal epithelial cells (IECs). Therefore, the presence of human MUC1 established a positive feedback circuit of inflammatory cytokines in CAC. To understand the significance of MUC1/p65-modulated cytokines in progressive colitis that gives rise to colon cancer, we analyzed infiltration of inflammatory cells into the inflamed colon tissues. Immunofluorescence assay indicated increased presence of CD206+ type 2 macrophages (M2) in colon tissues of AOM/DSS-treated MUC1.Tg mice compared to WT mice. We are currently analyzing the abundance of M1- and M2- macrophages in colon tissues from inflammatory bowel disease patients. Preliminary data showed expression of hypoglycosylated MUC1 on the inflamed tissues and the presence of macrophages expressing CD163+ a human M2 marker. We are currently exploring in vitro the direct role of MUC1 in the recruitment and polarization of macrophages. Thus our findings suggest a novel pro-inflammatory role for MUC1 in CAC.

Jana Al Hashash

University of Pittsburgh Medical Center

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    Douglas Hartman

    University of Pittsburgh Medical Center

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      Raahul Sriram

      University of Pittsburgh

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        Michael Kvorjak

        University of Pittsburgh

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          Sarangarajan Ranganathan

          Children Hospital of Pittsburgh of UPMC

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            Olivera Finn

            University of Pittsburgh

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              Sandra Cascio

              Research Assistant Professor
              University of Pittsburgh

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