Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells.
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.
Garrett
Wendy S
WS
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. wendy_garrett@dfci.harvard.edu
Punit
Shivesh
S
Gallini
Carey A
CA
Michaud
Monia
M
Zhang
Dorothy
D
Sigrist
Kirsten S
KS
Lord
Graham M
GM
Glickman
Jonathan N
JN
Glimcher
Laurie H
LH
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
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor