Abstract 3337: The G protein-coupled P2Y6 pyrimidoceptor increases tumorigenesis potential of epithelial cell in colorectal cancer associated to colitis
Authors: Morgane Placet, Caroline M. Molle, Djordje M. Grbic Grbic, Guillaume Arguin, Sameh Geha, Fernand-Pierre Gendron
Journal: Cancer Research (2017)

Abstract BACKGROUND: Carcinogenesis is a complex process induced by various genetic mutations, which is characterized by 3 phases. The initiation phase, inflammation is predominant, as in colitis-associated carcinogenesis, and involves the active recruitment of immune cells like macrophages, dendritic cells and T cells. The promotion and progression phases are respectively tied to dysplasia and carcinoma and metastasis. Inflammatory bowels disease (IBD), including colitis, induces an unbalance in pro- and anti-inflammatory cytokines, a breakage in the epithelial barrier, pathogens infiltration and leucocytes recruitment and activation. During inflammation, nucleotides are released in a large amount in the extracellular environment. The P2Y6 receptor was associated with IBD where its expression was increased in T cells infiltrating inflamed colonic tissue and on the epithelial cells of the inflamed tissue. In this context, activation of the P2Y6 receptor may contribute to the formation of a tumor-promoting environment by modulating the immune response and establishment of tumors. METHODS: Colorectal cancer associated to colitis was induced in P2ry6 gene knockout mice (P2Y -/- 6 ) using azoxymethane, as a carcinogen, and dextran sulfate sodium challenges as a promoting agent. Mice were euthanatized and the number and size of tumor measured. Tissues were fixed and stained prior to histological characterization. The impact of P2Y6R activation on apoptosis and NFκB pathway was determined by western blotting, and the impact on inflammatory cytokines balance and mucus layer were analyzed by histology and qPCR of different markers. RESULTS: Invalidation of the P2ry6 gene in mice lead to a reduction in the number of colorectal tumors in our AOM-DSS model. We have linked this observation to the protective role of P2Y6R toward TNFα-induced apoptosis of cancerous epithelial cells. Furthermore, P2Y6R regulates the balance between pro- and anti-inflammatory cytokines in inflammatory conditions, and maintain the integrity of the epithelial barrier by modulating the density of the mucus layer. CONCLUSION: In this study, we have shown that P2Y6R could contribute to colorectal cancer colitis associated by blocking the apoptotic process, modulating the cytokine network, and regulating the integrity of the mucus layer. These results suggest that P2Y6R can be a prime target to reduce colorectal cancer colitis associated. Citation Format: Morgane Placet, Caroline M. Molle, Djordje M. Grbic Grbic, Guillaume Arguin, Sameh Geha, Fernand-Pierre Gendron. The G protein-coupled P2Y6 pyrimidoceptor increases tumorigenesis potential of epithelial cell in colorectal cancer associated to colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3337. doi:10.1158/1538-7445.AM2017-3337