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.

癌症相关的成纤维细胞（CAF）包括包括结直肠癌（CRC）在内的各种癌症的微环境中的重要细胞类型。在过去的几年中，我们能够定义各种IKKB/NF-KB依赖性的髓样细胞和上皮细胞中的亲肿瘤功能，这些功能影响了结直肠肿瘤的启动，促进和进展。最近，在皮肤肿瘤模型中，乳腺癌和胰腺癌CAF被证明具有促炎性NF-KB签名，并建议提供促肿瘤功能。但是，在有效的结直肠癌遗传模型中对NF-KB信号的深入分析缺失。使用具有IKKB成纤维细胞特异性缺失的小鼠，我们获得了一些意外的结果，这表明在与结肠炎相关的致癌过程中，IKKB/NF-KB在成纤维细胞中具有抗肿瘤功能。在这里，我们旨在确定负责这种表型的基本分子机制，并在不同的体内炎症相关和零星结肠癌的体内模型中对该信号通路进行全面分析。