BACKGROUND & 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 ulcerative colitis (UC) and patients with UC-associated neoplasia using available datasets. The role of COX signaling in colonic tumorigenesis was examined using epithelial and doublecortin-like kinase 1 (Dclk1)+ cell-specific conditional COX-1 knockout mice and pharmacologic treatment with different nonsteroidal anti-inflammatory drugs. 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 E 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.