Knock down of BMSC-derived Wnt3a or its antagonist analogs attenuate colorectal carcinogenesis induced by chronic Fusobacterium nucleatum infection.

By establishing the Fusobacterium nucleatum (F. nucleatum) infected-bone mesenchymal stem cells (BMSCs) transplantation model in APCMin/+ mice, we investigated the role of BMSCs in the development of intestinal tumors induced by F. nucleatum. ApcMin/++F. nucleatum + BMSCs mice showed increased susceptibility to intestinal tumors and accelerated tumor growth. BMSCs could also enhance tumor-initiating capability, invasive traits after F. nucleatum infection in vitro, and tumorigenicity in a nude murine model. Mechanistically, BMSCs were recruited to the submucosa, migrated to the mucosal layer, and might activate the canonical Wnt/ß-catenin/TGIF axis signaling. Further mechanistic results illustrated increased production of the Wnt3a protein was found in ApcMin/++F. nucleatum + BMSCs mice, and BMSCs were likely the major source of Wnt3a. Intriguingly, a deletion of Wnt3a via BMSC interference or antagonist analogs led to a significantly attenuated capacity of ApcMin/++F. nucleatum mice to generate intestinal tumors. The findings suggest that BMSCs have the potential to migrate and accelerate F. nucleatum-induced colorectal tumorigenesis by modulating Wnt3a secretion; knockdown of BMSC-derived Wnt3a or antagonist analogs could attenuate carcinogenesis. Thus, Wnt3a might be a potential pharmaceutical target for the prevention and treatment of F. nucleatum-related colorectal cancer.