TGFβ介导小胶质细胞促GSCs向血管周细胞转化的血管新生机制研究

Glioblastoma multiforme (GBM) is highly vascular malignant brain tumor which characterized with extremely poor prognosis. Antiangiogenic therapy has also been developed and considered as an optimistic strategy for glioma patients. Targeting endothelial cells alone，and ignoring the role of pericytes result in the failure of most current antiangiogenic therapeutics. Recent researches demonstrated that human GSCs generate the majority of vascular pericytes. However, the mechanism is still unclear. Microglia, especially its M2 phenotype involved in the tumor microenvironment promotes glioma-associated neovascularization. Our preliminary data showed that microglia promoted the transformation of GSCs to pericytes in vitro.TGFβ, which has an essential role in the development of pericytes, is mainly secreted by microglia in brain. Based on the above, we hypothesize that microglia promotes generation of pericytes from human GSCs via TGFβ signaling pathway. With cell co-culture and animal model, we will try to clarify the internal relations between microglia and GSCs, to investigate the TGFβ signaling pathways upon action of specific TGFβ receptors on GSCs and its possible effect in transformation of GSCs into pericytes. Our work will illuminate the molecular mechanisms of the generation of pericytes, and thus provide potential targets for anti-angiogenesis therapy of GBM.

胶质母细胞瘤（GBM）是高度血管化的恶性脑肿瘤，预后极差。抑制血管新生是治疗GBM的重要策略，但现有抗血管生成治疗主要以血管内皮细胞为靶点，而忽视血管周细胞(pericyte)的作用，导致疗效不佳。研究表明人GBM中大多数血管周细胞由GSCs产生，但机制尚不明确。肿瘤微环境中小胶质细胞，尤其是M2型小胶质细胞促进GBM血管新生。申请者前期研究表明离体条件下小胶质细胞促GSCs向血管周细胞转化。TGFβ在血管周细胞发育中起重要作用，且脑内TGFβ主要来源于小胶质细胞。由此我们推测：TGFβ可能介导小胶质细胞促GSCs向血管周细胞转化。本课题拟采用细胞及动物实验研究小胶质细胞与GSCs的相互作用，探索TGFβ及其信号通路介导小胶质细胞促GSCs向血管周细胞转化的信号传递途径，以阐明血管周细胞生成的分子机制，为GBM抗血管生成治疗提供新的思路。

胶质母细胞瘤（GBM）是高度血管化的恶性脑肿瘤，预后极差。抑制血管新生是治疗GBM的重要策略，但现有抗血管生成治疗主要以血管内皮细胞为靶点，而忽视血管周细胞(pericyte)的作用，导致疗效不佳。研究表明人GBM中大多数血管周细胞由GSCs产生，但机制尚不明确。肿瘤微环境中小胶质细胞，尤其是M2型小胶质细胞促进GBM血管新生。申请者前期研究表明离体条件下小胶质细胞促GSCs向血管周细胞转化。TGFβ在血管周细胞发育中起重要作用，且脑内TGFβ主要来源于小胶质细胞。由此我们推测：TGFβ可能介导小胶质细胞促GSCs向血管周细胞转化。本课题拟采用细胞及动物实验研究小胶质细胞与GSCs的相互作用，探索TGFβ及其信号通路介导小胶质细胞促GSCs向血管周细胞转化的信号传递途径，以阐明血管周细胞生成的分子机制，为GBM抗血管生成治疗提供新的思路。