扶正解毒法对Ang-Tie2介导的TEMs在肿瘤免疫抑制微环境下血管重塑的调控研究

项目名称： 扶正解毒法对Ang-Tie2介导的TEMs在肿瘤免疫抑制微环境下血管重塑的调控研究

项目编号： No.81473463

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李杰

作者单位： 中国中医科学院广安门医院

项目金额： 72万元

中文摘要： 肿瘤微环境下血管生成是肿瘤治疗失败和转移复发的重要影响因素。Tie2表达的单核巨噬细胞（TEMs）是肿瘤相关巨噬细胞（TAM）的重要亚群，与肿瘤微环境下血管生成密切相关。Ang-Tie2介导的Rheb/mTOR/p70S6K1信号通路是TEMs促进肿瘤微血管生成的主要途径。扶正解毒法是临床防治肿瘤转移复发的重要法则，前期研究显示：扶正解毒方是通过mTOR介导的信号通路重塑TAM表型，逆转肿瘤微环境的免疫抑制和乏氧状态，干预TEMs功能及抑制血管生成可能是其新的作用机制，本课题拟通过LDPI、Hypoxyprobe、FCM、高内涵分析等技术及低氧工作站、共培养等手段，从体内外，带瘤和术后复发转移模型观察扶正解毒法对Ang-Tie2介导的TEMs在肿瘤免疫抑制微环境下血管重塑的影响，从调控免疫抑制细胞和肿瘤细胞非折叠蛋白反应抑制血管生成的新视角，进一步揭示扶正解毒法防治肿瘤复发转移的分子机制。

中文关键词： 扶正解毒法；Tie2表达的单核巨噬细胞（TEM）；微血管重塑；肿瘤复发转移；非折叠蛋白反应（UPR）

英文摘要： Angiogenesis in the tumor microenvironment is the important influencing factor of tumor metastasis and relapse to treatment failure. The Tie2 expressing monocyte/macrophage(TEMs) are the important subset of the tumor- associated macrophage(TAM), and relate to the tumor immune escape and micro- angiogenesis. The Ang-Tie2 mediated Rheb/mTOR/p70S6K1 signal pathway is vital for the carcinogenesis functions of TEMs. Principle of Strengthening the body resistance and disintoxication plays an important role in cancer prevention and treatment of metastasis and relapse, previous study shows Fuzheng Jiedu Formula (FZJD) remodels TAM's phenotypes and reverses tumor immunomicroenvironment suppression and hypoxia station via mTOR pathway. Acting on TEMs and inhibiting their tumor angiogenesis function could be a neo-antitumor mechanism.We design this study by using laser Doppler perfusion imaging(LDPI), hypoxyprobe, flow cytometry, high content screening(HCS) analysis, immunohistochemistry assay, co-culture technique and hypoxia workstation to observe the intervention of FZJD on micro-angiogenesis around the tumor immune suppressive microenvironment, from the multi-aspect of vivo and vitro,tumor bearing and recurrence models, TEMs and tumor cells. On the new sight of regulation on immune suppressive cells and tumor cell unfold protein reaction(UPR)，this study will provide scientific evidence for the application of FZJD formula in cancer prevention and treatment guided by the strengthening the body resistance and disintoxication theory of TCM, and explore its molecular mechanisms in preventing and treating tumor metastasis and recurrence.

英文关键词： Principle of Strengthening the body resistance and Disintoxication;Tie2 expressing monocyte/macrophages（TEMs）;micro-vascular remodeling;tumor recurrence and metastasis;Unfolded protein response