Prostaglandin E2 and Akt promote stemness in Apc mutant Dclk1+ cells to give rise to colitis-associated cancer

Loss of the tumor suppressor gene Apc in Lgr5+ intestinal stem cells results in aberrant Wnt signaling and colonic tumorigenesis. In the setting of injury, however, we and others have also shown that non-stem cells can also give rise to colonic tumors. The mechanism by which inflammation leads to cellular plasticity and cancer, however, remains largely unknown. RNA expression analysis of Wnt, COX and Akt signaling was assessed in patients with quiescent or active UC and patients with UC-associated neoplasia using available datasets. The role of COX signaling in colonic tumorigenesis was examined using epithelial and Dclk1+ cell specific conditional COX-1 knockout mice and pharmacologic treatment with different NSAIDs. In this study, we show that prostaglandins and phospho-Akt are key inflammatory mediators that promote stemness in Apc mutant Dclk1+ cells that give rise to colorectal cancer. Moreover, prostaglandin E2 (PGE2) and Akt are increased in colitis in both mice and humans, leading to inflammation-associated dysplasia upon activation of Wnt signaling. Importantly, inhibition of epithelial derived COX-1 by Aspirin or conditional knockout in Dclk1+ cells reduced PGE2 levels and prevented the development of inflammation-associated colorectal cancer. Our data shows that epithelial and Dclk1+ cell derived COX-1 plays an important role in inflammation-associated tumorigenesis. Importantly, low dose Aspirin was effective in chemo-prevention through inhibition of COX-1 that reduced colitis-associated cancer.