Trp53 Deletion Promotes Exacerbated Colitis, Facilitates Lgr5+ Cancer Stem Cell Expansion, and Fuels Tumorigenesis in AOM/DSS-Induced Colorectal Cancer

Colorectal cancer CRC remains one of the leading causes of cancer-related deaths worldwide, with chronic intestinal inflammation identified as a major risk factor. Notably, the tumor suppressor <i>TP53</i> undergoes mutation at higher rates and earlier stages during human inflammation-driven colon tumorigenesis than in sporadic cases. We investigated whether deleting <i>Trp53</i> affects inflammation-induced tumor growth and the expression of Lgr5+ cancer stem cells in mice. We examined azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis in wild-type <i>Trp53 (+/+)</i>, heterozygous <i>(+/-)</i>, and knockout <i>(-/-)</i> mice. <i>Trp53-/-</i> mice showed increased sensitivity to DSS colitis and earlier accelerated tumorigenesis with 100% incidence. All groups could develop invasive tumors, but knockouts displayed the most aggressive features. Unlike wild-type CRC, knockouts selectively showed increased populations of Lgr5+ colon cancer stem-like cells. <i>Trp53</i> loss also boosted laminin, possibly facilitating the disruption of the tumor border. This study highlights how <i>Trp53</i> deletion promotes the perfect storm of inflammation and stemness, driving colon cancer progression. <i>Trp53</i> deletion dramatically shortened AOM/DSS latency and improved tumor induction efficiency, offering an excellent inflammation-driven CRC model.