The functional role of VEGFR2-signaling in CD4+ T cells in the pathogenesis of colorectal cancer

CD4 T 细胞中 VEGFR2 信号传导在结直肠癌发病机制中的功能作用

• 批准号: 319463961
• 负责人: Professor Dr. Maximilian Waldner, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/319463961?language=en
• 关键词: functional; role; VEGFR2; signaling; CD4+

Vascular endothelial growth factor is regarded as one of the most important mediators of angiogenesis in human cancers including colorectal cancer (CRC). However, recent data suggest additional roles for VEGF besides angiogenesis in tumor development. VEGF receptors such as VEGFR2 are expressed by various cancer cells and their activation promotes tumor cell proliferation. VEGF also acts on cells in the tumor microenvironment such as fibroblasts, myeloid cells and T cells, mainly to support tumor promoting-inflammation and inhibit the anti-tumor immune response. In preliminary experiments, we found an upregulation of VEGFR2 in effector T cells (Th1 and Th17) and natural regulator T cells. Using conditional knockout mice for VEGFR2 in CD4+ T cells, we could show that VEGFR2 signaling in CD4+ T cells has protective effects in a mouse model of sporadic CRC. These data clearly show that VEGF signaling plays a previously unrecognized role in adaptive immunity in cancer. This project will further analyze the functional role of VEGFR2 in CD4+ T cells during CRC development. In order to identify the functionally relevant VEGFR2 expressing CD4+ T cell subpopulation in the tumor microenvironment, we will analyze VEGFR2 reporter constructs restricted to CD4+ T cells with various in vivo imaging strategies in mouse CRC models. For functional analysis, we will expose conditional knockout mice for VEGFR2 together with or without its co-receptor neuropilin 1 in CD4+ T cells, FoxP3+ Tregs or RORgt+ Th17 cells to mouse models of sporadic and colitis-associated cancer. We will then analyze the biologial function and underlying molecular mechanisms of VEGFR2 signaling in relevant CD4+ T cell populations in vitro and in vivo. Together, the data acquired in this project will increase our knowledge about the effects of tumor derived VEGF on the tumor microenvironment, its role for tumor progression and possible consequences for anti-VEGF therapy in CRC.

血管内皮生长因子被认为是包括结直肠癌在内的人类肿瘤中最重要的血管生成介质之一。然而，最近的数据表明，除了血管生成，血管内皮生长因子在肿瘤发展中还有其他作用。VEGFR2等血管内皮生长因子受体由多种肿瘤细胞表达，它们的激活促进肿瘤细胞的增殖。血管内皮生长因子也作用于肿瘤微环境中的细胞，如成纤维细胞、髓系细胞和T细胞，主要支持肿瘤促炎和抑制抗肿瘤免疫反应。在初步实验中，我们发现VEGFR2在效应T细胞(Th1和Th17)和自然调节T细胞中上调。利用条件基因敲除小鼠的CD4+T细胞中的VEGFR2，我们可以证明在CD4+T细胞中的VEGFR2信号在散发性CRC小鼠模型中具有保护作用。这些数据清楚地表明，血管内皮生长因子信号在癌症获得性免疫中发挥着以前未被认识到的作用。本项目将进一步分析VEGFR2在结直肠癌发生发展过程中对CD4+T细胞的作用。为了确定在肿瘤微环境中表达CD4+T细胞亚群的功能相关的VEGFR2，我们将在小鼠结直肠癌模型中用不同的体内成像策略分析限制在CD4+T细胞上的VEGFR2报告结构。为了进行功能分析，我们将把VEGFR2的条件性基因敲除小鼠与其在CD4+T细胞、FoxP3+Tregs或RORgt+Th17细胞中的共同受体Neuropilin 1一起或不与其一起暴露给散发性和结肠炎相关癌症的小鼠模型。然后，我们将在体外和体内分析VEGFR2信号在相关的CD4+T细胞群中的生物学功能和潜在的分子机制。总之，本项目获得的数据将增加我们对肿瘤来源的血管内皮生长因子对肿瘤微环境的影响、其在肿瘤进展中的作用以及抗血管内皮生长因子治疗在结直肠癌中可能产生的后果的知识。