Aberrant MUC1 glycoforms modulate the interplay between tumor-associated macrophages and intestinal epithelial cells in IBD and CAC
Michael Kvorjak1,Jana Al Hashash2, Raahul Sriram1, Douglas Hartman2,Olivera Finn1 and Sandra Cascio1,3 1Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA, 15261; 2Department of Gastroenterology, University of Pittsburgh Medical Center, PA, USA, 15260; 3Fondazione Ri.Med, via Bandiera 11, Palermo, Italy, 90133
Mucin 1 (MUC1) is a transmembrane glycoprotein over-expressed and hypoglycosylated in human adenocarcinoma and chronic inflammatory conditions compared to healthy tissues. Using dextran sulfate sodium (DSS) and azoxymethane/dextran sulfate sodium (AOM/DSS) murine models, we are exploring the consequence of this abnormal expression of MUC1 in inflammatory bowel disease (IBD) and colitis-associated colon cancer (CAC). We have recently reported that AOM/DSS-treated human MUC1.Tg mice showed higher tumor incidence, decreased survival and greater body weight loss when compared to wild-type (WT) mice. 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. Next, we analyzed infiltration of polarized M1 and M2 macrophages into the inflamed colon tissues. Immunofluorescence assay indicated increased presence of macrophages, and in particular CD206+ (M2), in inflamed colon tissues of MUC1.Tg mice compared to WT mice. In addition, Immunohistochemistry staining of macrophages in colon tissues from IBD patients showed expression of hypoglycosylated MUC1 and the presence of macrophages expressing CD163+, a human M2 marker. In vitro co-culture assay indicated that M1 and M2 polarized macrophages, via secretion of pro-inflammatory cytokines, differently affect the glycosylation state of MUC1 of epithelial cells. We are currently determining the activity of MUC1 in the recruitment and polarization of macrophages in inflamed pre-malignant and tumor microenviroment. Our findings will elucidate a novel role of the hypoglycosylated forms of MUC1 in the crosstalk between macrophages and intestinal epithelial cells. Moreover, aberrant MUC1 glycoforms, such as sT- and sTn-MUC1, might result as novel class of therapeutic targets for IBD treatment and prevention of cancer development.