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

• Published in: International journal of molecular sciences Vol. 25; no. 20; p. 10953
• Main Authors: Cunha, Anderson F, Delou, João M, Barbosa, Pedro S, Conceição, Julia S M, Souza, Karen C S, Chagas, Vera, Soletti, Rossana C, de Souza, Heitor S P, Borges, Helena L
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.10.2024; MDPI
• Subjects: Animals; Azoxymethane - toxicity; Cancer therapies; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Colitis; Colitis - chemically induced; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Colonoscopy; Colorectal cancer; Colorectal Neoplasms - chemically induced; Colorectal Neoplasms - etiology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Development and progression; Dextran; Dextran Sulfate; Diarrhea; Disease Models, Animal; Gene Deletion; Health aspects; Inflammation; Inflammatory bowel disease; Laminin; Lymphoma; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Proteins; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Risk factors; Stem cells; Sulfates; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; Brazil; Lgr5; colorectal cancer; inflammatory bowel disease; p53
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms252010953

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 undergoes mutation at higher rates and earlier stages during human inflammation-driven colon tumorigenesis than in sporadic cases. We investigated whether deleting 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 , heterozygous , and knockout mice. 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. loss also boosted laminin, possibly facilitating the disruption of the tumor border. This study highlights how deletion promotes the perfect storm of inflammation and stemness, driving colon cancer progression. deletion dramatically shortened AOM/DSS latency and improved tumor induction efficiency, offering an excellent inflammation-driven CRC model.