title: Targeted Deletion of p53 in Lgr5-Expressing Intestinal Stem Cells Promotes Colon Tumorigenesis in a Preclinical Model of Colitis-Associated Cancer.
abstract: p53 has been shown to mediate cancer stem-like cell function by suppressing pluripotency and cellular dedifferentiation. However, there have been no studies to date that have addressed the specific effects of p53 loss in colonic adult stem cells. In this study, we investigated the consequences of conditionally ablating p53 in the highly relevant Lgr5(+) stem cell population on tumor initiation and progression in the colon. In a mouse model of carcinogen (AOM)-induced colon cancer, tamoxifen-inducible Lgr5-driven deletion of p53 reduced apoptosis and increased proliferation of crypt stem cells, but had no effect on tumor incidence or size. Conversely, in a mouse model of colitis-associated cancer, in which mice are exposed to AOM and the potent inflammation inducer DSS, stem cell-specific p53 deletion greatly enhanced tumor size and incidence in the colon. These novel findings suggest that the loss of p53 function in stem cells enables colonic tumor formation only when combined with DNA damage and chronic inflammation. Furthermore, we propose that stem cell targeting approaches are valuable for interrogating prevention and therapeutic strategies that aim to specifically eradicate genetically compromised stem cells.
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Davidson
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Evelyn S
authors.initials: ES
authors.lastname: Callaway
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Eunjoo
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Veterinary Pathobiology, College Station, Texas.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Weeks
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Yang-Yi
authors.initials: YY
authors.lastname: Fan
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Center for Translational Environmental Health Research, Texas A&M University, College Station, Texas.
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Allred
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas. Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Center for Translational Environmental Health Research, Texas A&M University, College Station, Texas. r-chapkin@tamu.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003092:Colitis / Q000150:complications; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D014411:Neoplastic Stem Cells / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53