PDGF诱发血管内皮间质转化（Endo-MT）促进脑胶质瘤抗血管生成治疗耐药的机制研究

脑胶质瘤（GBM）的预后差，抗血管生成治疗是GBM的重要治疗策略，但短期内会发生耐药。肿瘤血管内皮间质转化（Endo-MT）是抗血管生成治疗耐药的重要原因，但Endo-MT的发生机理尚不明确。最近，我们发现PDGF通过介导Endo-MT下调VEGFR2表达，诱导耐药（Nat Commun和Cancer Res，第一作者），但PDGF通路在肿瘤Endo-MT中的作用机制尚不清楚。预实验提示：PDGF可能通过Snail调控VE-cadherin的表达进而诱导肿瘤血管Endo-MT形成，导致抗血管生成治疗的耐药。本课题拟应用肿瘤-内皮细胞共培养模型、基因敲除小鼠模型等，从体外实验-体内实验-临床分析三个层次，研究PDGF/Snail/VE-cadherin通路在GBM血管Endo-MT中的作用机制。所得结果对阐明Endo-MT的发生机理可能有重要作用，有望为克服抗血管生成治疗的耐药性开辟新途径。

The prognosis of glioblastoma multiforme (GBM) is poor. Antiangiogenic therapy is one of the new strategies for GBM treatment, but drug resistance will occur in the short term. Endothelial-mesenchymal transition (Endo-MT) is an important cause of drug resistance in antiangiogenic therapy, but the mechanism of Endo-MT is still unclear. Recently, we found that platelet-derived growth factor (PDGF) induces drug resistance by inducing Endo-MT and down-regulation of the expression of VEGFR2, which is the main target of antiangiogenic therapy (Nat Communications and Cancer Research, first author), but the role and mechanism of PDGF pathway in Endo-MT is still unclear. Our preliminary experiments suggest that PDGF may induce Endo-MT formation by up-regulating the expression of Snail and further regulating the expression of VE-cadherin, leading to resistance to antiangiogenic therapy. In this study, we intend to study the mechanism of PDGF/Snail/VE-cadherin pathways inducing Endo-MT in GBM using co-culture model of tumor-vascular endothelial cells and gene knock-out mice model, by in vitro and in vivo experiments and clinical methods. The results obtained in this study may have an important role in elucidating the mechanism of Endo-MT in malignancies, and it is expected to develop new methods for reversing the drug resistance of antiangiogenic therapy.