| First Author | Good HJ | Year | 2025 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 19 |
| Issue | 6 | Pages | 101469 |
| PubMed ID | 39884575 | Mgi Jnum | J:376593 |
| Mgi Id | MGI:8271074 | Doi | 10.1016/j.jcmgh.2025.101469 |
| Citation | Good HJ, et al. (2025) Prostaglandin E(2) and Akt Promote Stemness in Apc Mutant Dclk1+ Cells to Give Rise to Colitis-associated Cancer. Cell Mol Gastroenterol Hepatol 19(6):101469 |
| abstractText | 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 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(2) (PGE(2)) 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 PGE(2) 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. |
