RORγt(+) hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice

Eur J Immunol. 2015 Jun;45(6):1667-79. doi: 10.1002/eji.201444915. Epub 2015 May 15.


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; Colitis-associated colorectal cancer; IL-17; RORγt; Th17 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology*
  • Cell Transformation, Neoplastic / metabolism*
  • Colitis / complications
  • Colitis / genetics
  • Colitis / immunology*
  • Colitis / metabolism*
  • Colonic Neoplasms / etiology*
  • Colonic Neoplasms / pathology
  • Disease Models, Animal
  • Humans
  • Interleukin-17 / metabolism
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Tumor Burden / genetics
  • Tumor Burden / immunology


  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3