Department of Surgery, University of Regensburg, Regensburg, Germany.
Clinic of Gynecology and Obstetrics, University of Regensburg, Regensburg, Germany.
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.
结直肠癌（CRC）是最常见的肿瘤实体之一。在炎症性肠病患者中，结肠炎相关结肠癌的发展被认为是一种危险的长期并发症。IL-17A 和转录因子维甲酸受体相关孤儿受体 γt（RORγt）在炎症性肠病的发病机制中起着重要作用；在人体研究中，我们在 CRC、溃疡性结肠炎和溃疡性结肠炎相关结直肠癌的标本中检测到密集浸润的 RORγt 依赖性 CD4（+）IL17A（+）辅助性 T（Th）17 细胞。然而，RORγt（+）造血细胞在结肠炎相关肿瘤发生中的机制作用尚不清楚。为了研究结肠炎相关的结肠癌发生，我们在 AOM+DSS 小鼠模型中进行了研究，该模型揭示了 RORγt 在结肠肿瘤进展中的重要性。在缺乏 RORγt 依赖性 Th17 淋巴细胞的情况下，小鼠表现出强烈的慢性结肠炎迹象，但形成的宏观肿瘤结节明显较少。在缺乏 RORγt 依赖性 Th17 细胞的情况下，肿瘤发展的减少并不是由于结肠肿瘤起始减少所致。然而，在缺乏 RORγt 依赖性 Th17 细胞的情况下，肿瘤细胞的增殖速度降低，并且肿瘤细胞表现出明显的与衰老相关的表观遗传和溶酶体变化迹象。这些结果表明，免疫环境在结肠炎相关癌症中起着重要作用，部分由支持 CRC 生长的 RORγt 依赖性 Th17 淋巴细胞塑造。
