Role of Myd88-mediated signaling in the prevention of colon adenocarcinomas (95.10)

Abstract Signaling through the adaptor protein MyD88 promotes carcinogenesis in several chemically induced cancer models. In contrast, in the AOM/DSS model of chronic colitis induced cancer, we observed a protective role for MyD88 in the development of colitis-associated cancer (CAC). The inability of Myd88-/- mice to heal ulcers generated upon DSS treatment creates an altered inflammatory environment that induces profound early alterations in expression of genes encoding pro-inflammatory factors as well as pathways regulating cell proliferation and apoptosis. Additionally, AOM/DSS treatment induced alterations in DNA repair in MyD88 deficient mice, resulting in increased frequency of mutations and a dramatic increase in adenoma formation and progression to invasive phenotype. Others have reported that Tlr4 deficient mice share similar susceptibility to colitis as Myd88 deficient mice but, unlike the latter, are resistant to CAC. We observed that mice deficient for Tlr2 or IL-1R do not show a differential susceptibility to colitis or CAC. In contrast, AOM/DSS treatment resulted in increased susceptibility to colitis development and enhanced polyp formation in Il-18-/- mice. This indicates that the phenotype of Myd88 -/- mice is in part due to their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that differentially impact tissue homeostasis and carcinogenesis.