19 - NOTCH1 MEDIATES PROTECTION IN COLITIS ASSOCIATED CANCER
(Room Pinyon 1/2)
20 Jan 18
8:28 AM
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8:35 AM
Introduction: Ulcerative colitis patients have an increased risk of colitis associated cancer (CAC). It is driven by continuous exposure to inflammation and it is different than sporadic colon cancer (CRC). CAC advances through “dysplasia-carcinoma axis” while CRC through “adenoma-carcinoma axis”. In CAC, chronic inflammation exposes the epithelial mucosal defensive lining to inflammatory mediators (cytokines, anti-microbial peptides) causing alteration of microbiota population and immune response. The intercellular receptor Notch1, is critical for stem cell differentiation, lineage commitment, and contributes significantly in carcinogenesis. However, its function is highly tissue specific and can be oncogenic or tumor suppressive. We have previously shown that mice treated with γ-secretase inhibitor, to inhibit Notch1, were more susceptible to CAC vs the vehicle group. Aim: Aim of this study is to determine the protective role of Notch1 in CAC. Methods: We used Notchflox/flox mice (control group, NWT) and crossed them with villin-cre mice to generate Ncre mice, which cannot express Notch1 in villi. CAC was induced by one injection of azoxymethane and two cycles of dextran sodium sulfate. Results: Our WB analysis showed absence of Notch1 expression in colon, spleen, and small intestine among Ncre mice. Organoids from Ncre mice displayed delayed differentiation. In CAC, Ncre mice had more weight loss, polyps, and dysplasia compared to NWT mice. In vivo permeability assay showed dysregulated barrier function and ROS assay showed increased ROS levels among Ncre mice in CAC. QPCR indicated decreased microbiota and altered levels of Bacteroidetes, A. muciniphila and Firmicutes among Ncre mice in CAC. Conclusion: Our study has two clinically relevant outcomes. 1) Notch1 promotes the beneficial microbiota population and controls the ROS production, therefore acts as a tumor suppressor. 2) The use of targeted Nocth1 inhibitors, specifically in CAC treatment, can worsen it.