| First Author | Keerthivasan S | Year | 2014 |
| Journal | Sci Transl Med | Volume | 6 |
| Issue | 225 | Pages | 225ra28 |
| PubMed ID | 24574339 | Mgi Jnum | J:213675 |
| Mgi Id | MGI:5585566 | Doi | 10.1126/scitranslmed.3007607 |
| Citation | Keerthivasan S, et al. (2014) beta-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells. Sci Transl Med 6(225):225ra28 |
| abstractText | The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORgammat (retinoic acid-related orphan receptor-gammat), the signature transcription factor of T(H)17 cells. We report that Wnt/beta-catenin signaling in T cells promotes expression of RORgammat. Expression of beta-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of beta-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORgammat, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of beta-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/beta-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer. |
