CONICET | Buscador de Institutos y Recursos Humanos

Inflammatory Bowel Diseases (IBD), which include two forms of intestinalinflammation, Crohn?s disease and Ulcerative Colitis, are a group of chronic, relapsing and remitting intestinal inflammatory pathologies. Although traditional therapies such as general immunosuppressive agents and tumor necrosis factor inhibitors are established as conventional treatments, they present serious drawbacks, such as high costs, lack of specificity or eventual loss of response. Besides the severe symptoms affecting the digestive system, IBD has been also subject of interest for its association with an increased risk of colorectal cancer (CRC) development, although the underlying molecular mechanisms are not yet completely understood. Colorectal cancer is a high incident and lethal neoplastic disease, from which 1.5 million people are diagnosed every year and accounts for more than 700,000 yearly deaths worldwide. Although the detailed causes of CRC development and progression are still unclear, CRC is a multifactorial pathology where genetic mutations, diet, inflammation, gut microbiota and intestinal inflammation are crucial factors that modulate the disease outcome. During the last decades, aberrant cell surface glycosylation has been considered an important hallmark of inflammation and tumor progression. Glycosylation changes trigger different biological processes via interaction with glycan-binding proteins such as galectins. We aimed to study the effect of the inflammatory microenvironment over the galectin-glycan interactions and colitis-associated CRC progression. We focused our research on the association between intestinal inflammation and neoplastic development with special emphasis in the glycome and its interaction with Galectin-1, as it exerts important roles in CRC progression and its metastatic potential. With this purpose, we have established a mouse model of colitis-associated colorectal cancer based on the administration of azoxymethane (AOM) and dextran sulfate sodium (DSS). Wild-type and Galectin-1 KO mice were injected with AOM and then exposed to DSS-containing drinking water. Weight loss, stool consistency and rectal blood were monitored and, after sacrifice, we analyzed number of tumors and tumor size, studied the cellular immune infiltrate and performed immunohistochemical analyses for selected molecules. We found that Galectin-1-lacking mice develop an improved immune response against the tumors, with an increase in activated CD4 + and CD8 + T cells. We also carried out a meta-analysis of transcriptomic data for mouse models of sporadic CRC (sCRC) and CACRC. Metadata analysis showed differential glycogene expression profiles between sCRC and CACRC, indicating a potential influence of intestinal inflammation in aberrant glycosylation profiles. Keywords: Colorectal cancer, colitis, IBD, galectin, glycans.