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

Abstract

Background and aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.