title: RORγt(+) hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice.
abstract: 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.
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Martin
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Kesselring
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Balam
authors.initials: B
authors.lastname: Saidou
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Brunner
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schiechl
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Verena F
authors.initials: VF
authors.lastname: Mouris
authors.affiliation: Clinic of Gynecology and Obstetrics, University of Regensburg, Regensburg, Germany.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Wege
authors.affiliation: Department of Pathology, University of Regensburg, Regensburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Rümmele
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.|Regensburg Center of Interventional Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fichtner-Feigl
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D003092:Colitis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
keywords: AOM+DSS; Colitis-associated colorectal cancer; IL-17; RORγt; Th17 cells