Functional analysis of canonical NF-kB signaling in colorectal cancer-associated fibroblasts

结直肠癌相关成纤维细胞中典型 NF-kB 信号传导的功能分析

• 批准号: 262633972
• 负责人: Professor Dr. Florian R. Greten
• 金额: --
• 依托单位: Georg-Speyer-Haus, Institut für Tumorbiologie und experimentelle Therapie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/262633972?language=en
• 关键词: Functional; analysis; canonical; NF; kB

Cancer-associated fibroblasts (CAFs) comprise an important cell type in the microenvironment of various cancers including colorectal cancer (CRC). In the last years we were able to define various IKKb/NF-kB dependent pro-tumorigenic functions in myeloid and epithelial cells that affected colorectal tumor initiation, promotion and progression. Recently, in tumor models of skin, mammary and pancreatic cancer CAFS were shown to have a pro-inflammatory NF-kB signature and suggested to provide pro-tumorigenic functions. However, an in depth analysis of NF-kB signaling in a valid genetic model of colorectal cancer is missing. Using a mouse with fibroblast-specific deletion of IKKb we obtained some unexpected results suggesting an anti-tumorigenic function of IKKb/NF-kB in fibroblasts during colitis-associated carcinogenesis. Here we aim to identify the underlying molecular mechanisms responsible for this phenotype and to provide a comprehensive analysis of this signaling pathway in different in vivo models of inflammation-associated and sporadic colon cancer.

癌症相关成纤维细胞（CAF）在包括结直肠癌（CRC）在内的各种癌症的微环境中构成重要的细胞类型。在过去的几年中，我们能够确定各种IKKb/NF-κ B依赖性促肿瘤发生的功能，在骨髓和上皮细胞，影响结直肠肿瘤的启动，促进和发展。最近，在皮肤癌、乳腺癌和胰腺癌的肿瘤模型中，CAFS显示出具有促炎性NF-kB特征，并被认为提供促肿瘤发生功能。然而，在结直肠癌的有效遗传模型中，NF-kB信号转导的深入分析缺失。使用成纤维细胞特异性缺失IKKb的小鼠，我们获得了一些意想不到的结果，表明结肠炎相关癌发生过程中成纤维细胞中IKKb/NF-kB的抗肿瘤功能。在这里，我们的目标是确定潜在的分子机制，负责这种表型，并提供一个全面的分析，在不同的炎症相关的和散发性结肠癌的体内模型，这种信号通路。