| First Author | Martin M | Year | 2015 |
| Journal | Eur J Immunol | Volume | 45 |
| Issue | 6 | Pages | 1667-79 |
| PubMed ID | 25820779 | Mgi Jnum | J:229705 |
| Mgi Id | MGI:5753021 | Doi | 10.1002/eji.201444915 |
| Citation | Martin M, et al. (2015) RORgammat(+) hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice. Eur J Immunol 45(6):1667-79 |
| abstractText | Colorectal cancer (CRC) is one of the most common tumor entities. In patients with inflammatory bowel diseases, the development of colitis-associated colon cancer is considered a dangerous long-term complication. IL-17A and the transcription factor retinoic acid receptor-related orphan receptor gammat (RORgammat) play fundamental roles in the pathogenesis of inflammatory bowel diseases; in human studies, we detected a dense infiltration of RORgammat-dependent CD4(+) IL17A(+) T helper (Th)17 cells in specimens of CRC, ulcerative colitis, and ulcerative colitis-associated colorectal cancer. However, the mechanistic role of RORgammat(+) hematopoietic cells in colitis-associated tumorigenesis remains unclear. To investigate colitis-associated colon tumorigenesis, we conducted studies in the AOM+DSS mouse model that revealed the importance of RORgammat for colon tumor progression. In the absence of RORgammat-dependent Th17 lymphocytes, mice showed signs of intense chronic colitis, but developed significantly fewer macroscopic tumor nodules. The reduction of tumor development in RORgammat(-/-) mice was not due to reduced colon tumor initiation. However, the proliferation rate of tumor cells was reduced in the absence of RORgammat-dependent Th17 cells and tumor cells showed pronounced signs of senescence-associated epigenetic and lysosomal changes. These results indicate an important role for the immunological milieu in colitis-associated cancer, which is shaped in-part by RORgammat-dependent Th17 lymphocytes that support CRC growth. |
