title: Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells.
abstract: We previously described a mouse model of ulcerative colitis linked to T-bet deficiency in the innate immune system. Here, we report that the majority of T-bet(-/-)RAG2(-/-) ulcerative colitis (TRUC) mice spontaneously progress to colonic dysplasia and rectal adenocarcinoma solely as a consequence of MyD88-independent intestinal inflammation. Dendritic cells (DCs) are necessary cellular effectors for a proinflammatory program that is carcinogenic. Whereas these malignancies arise in the setting of a complex inflammatory environment, restoration of T-bet selectively in DCs was sufficient to reduce colonic inflammation and prevent the development of neoplasia. TRUC colitis-associated colorectal cancer resembles the human disease and provides ample opportunity to probe how inflammation drives colorectal cancer development and to test preventative and therapeutic strategies preclinically.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. wendy_garrett@dfci.harvard.edu
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
authors.forename: Shivesh
authors.initials: S
authors.lastname: Punit
authors.forename: Carey A
authors.initials: CA
authors.lastname: Gallini
authors.forename: Monia
authors.initials: M
authors.lastname: Michaud
authors.forename: Dorothy
authors.initials: D
authors.lastname: Zhang
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Sigrist
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor