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 γt (RORγt) play fundamental roles in the pathogenesis of inflammatory bowel diseases; in human studies, we detected a dense infiltration of RORγt-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 RORγt + 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 RORγt for colon tumor progression. In the absence of RORγt-dependent Th17 lymphocytes, mice showed signs of intense chronic colitis, but developed significantly fewer macroscopic tumor nodules. The reduction of tumor development in RORγt −/− mice was not due to reduced colon tumor initiation. However, the proliferation rate of tumor cells was reduced in the absence of RORγt-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 RORγt-dependent Th17 lymphocytes that support CRC growth.Keywords: AOM+DSS r Colitis-associated colorectal cancer r Th17 cells r IL-17 r RORγtAdditional supporting information may be found in the online version of this article at the publisher's web-site
IntroductionColorectal cancer (CRC) is the third most common malignancy in humans, with high frequencies observed in North America, Correspondence: Dr. Stefan Fichtner-Feigl e-mail: stefan.fichtner@ukr.deEurope, and Australia [1]. The promotion of colorectal adenocarcinoma is an important long-term consequence of ulcerative colitis (UC) and Crohn's disease, the two main forms of human chronic inflammatory bowel diseases. These inflammation-associated cancers are generally characterized by a rapid clinical progression [2][3][4][5] Eur. J. Immunol. 2015. 45: 1667-1679 chronic disorders of the immune system and tumor development in various animal models, it is thought that chronic inflammation provides an immunological environment favoring tumor cell proliferation [6][7][8][9][10][11]. The nuclear hormone receptor retinoic acid receptor-related orphan receptor γt (RORγt) encoded by the RORc gene has been identified as the key transcription factor determining the differentiation of naïve T helper (Th) [20][21][22]. Currently, it is known that Th17 lymphocytes and their associated cytokines, in particular IL-17A, play a fundamental role in the pathogenesis of different autoimmune and chronic disorders such as inflammatory bowel diseases. While IL-17A is produced in the healthy gut, higher expression has been reported in inflamed intestin...