SOX9通过Wnt/β-Catenin调控干细胞内皮分化参与胶质母细胞瘤抗血管治疗抵抗的研究

Glioblastoma (GBM) is the most malignant primary and tumor in central nervous system, with poor outcome even undergone the standard surgical resection,radiotherapy and chemotherapy. Anti-angiogenesis therapy is important salvage treatment for GBM, while therapeutic resistance significantly harm the curative response and clinical efficacy. Previous studies indicated that endothelial differentiation of tumor stem cells act as crucial mechanisms for anti-angiogenesis resistance of GBM, and elucidating it is key to improve the curative effect. SOX9 is important molecular for stemness maintainence and differentiation regulation of tumor cells. Our team have found in previous studies that: SOX9 can induce endothelial differentiation of stem cells for GBM; the expression level of SOX9 was significantly and negatively associated with the curative response for the patients undergone the anti-angiogenesis therapy, and the SOX9 and β-Catenin demonstrated similar expression trend. Therefore, we inferred that SOX9 might induced the anti-angiogenesis resistance of GBM via regulating the endothelial differentiation of tumor stem cells, for which Wnt/β-Catenin posses the important signal transduction pathway. By applying several kinds of molecular biological methods , the present study plan to explore the regulatory role of SOX9for endothelial differentiation of stem cells during the anti-angiogenesis resistance of GBM at tissue, cell and animal levels, and further elucidate the detailed molecular pathway, for trying to construct the extensive multi-targeted interference strategy on SOX9-Wnt/β-Catenin pathway, and optimize the individual targeting therapeutic efficacy.

胶质母细胞瘤(GBM)是恶性程度最高、预后最差的神经系统原发肿瘤，抗血管治疗是其重要的挽救治疗手段，但治疗抵抗严重影响治疗反应率和临床疗效。研究显示肿瘤干细胞的血管内皮分化是抗血管治疗发生抵抗的重要途径，探索其具体机制可能成为提高疗效的关键。SOX9是维持肿瘤细胞干性和调节干细胞分化的重要分子，申请人前期研究发现GBM中SOX9能够诱导肿瘤干细胞的内皮分化；抗血管治疗抵抗患者SOX9表达与疗效显著负相关，并与β-Catenin高度一致。因此我们认为SOX9可能通过Wnt/β-Catenin通路调节肿瘤干细胞内皮分化在GBM抗血管治疗抵抗中发挥关键作用。本研究拟采用多种分子生物学研究方法，在组织、细胞、动物水平研究SOX9调节肿瘤干细胞内皮分化在GBM抗血管抵抗过程中的关键作用，阐明其详细的分子通路，建立基于SOX9-Wnt/β-Catenin的多靶点干预策略，切实提高个体化靶向治疗疗效。

胶质母细胞瘤(GBM)是恶性程度最高、预后最差的神经系统原发肿瘤，抗血管治疗是 其重要的挽救治疗手段，但治疗抵抗严重影响治疗反应率和临床疗效。研究显示肿瘤干细胞的血管内皮分化是抗血管治疗发生抵抗的重要途径，探索其具体机制可能成为提高疗效的关键。SOX9是维持肿瘤细胞干性和调节干细胞分化的重要分子，申请人研究发现GBM中TGFβ可通过稳定SOX9表达促进胶质瘤细胞生长和转移，进而促进胶质瘤恶性进展；探索了抗血管治疗抵抗的机制，明确SOX9表达参与抵抗的关键分子通路，并与β-Catenin高度一致。因此我们认为SOX9可通过Wnt/β-Catenin通路调节肿瘤干细胞内皮分化在GBM抗血管治疗抵抗中发挥关键作用。本研究采用多种分子生物学研究方法，在组织、细胞、动物水平研究SOX9调节肿瘤干细胞内皮分化在GBM抗血管抵抗过程中的关键作用，阐明其详细的分子通路，建立基于SOX9-Wnt/β-Catenin的多靶点干预策略，切实提高个体化靶向治疗疗效。