Sema6A调控小胶质细胞M1/M2极化型抑制胶质母细胞瘤进展的机制研究

Glioblastoma(GBM) is one of the most malignant intracranial tumors, the high recurrence rate is the main reason for the poor prognosis and the mechanism is still not clear. Semaphorin(Sema) as a signalling molecule which is widely spread in the nervous system, it is found to play special roles in tumor neuroimmunological function. Our previous studies suggested that Sema6A was an independent prognostic biomarker in GBM as its expression was robustly related with survival of patients. Further experiments revealed that cultured microglia with Sema6A can induce M1 phenotype and suppress M2 phenotype ,the conditioned medium can inhibit the proliferation,migration and invasion of GBM cell in vitro. Based on the previous studies, we hypothesize that Sema6A has the anti-GBM effect by regulating the M1/M2 phenotype of microglia which affect the downstream cytokine formation.We will validate this idea through multiple levels of researches from cultured cells, animals and clinic specimens, it is planned to reveal the roles of Sema6A in microglia activation, observe the effect of distinct phenotype on the growth and angiogenesis of GBM and explore the downstream target molecules.The completion of this project can provide not only a new way of thinking on how semaphorin carry out its function, but also a new potential drug target for treating GBM.

胶质母细胞瘤(GBM)是恶性程度最高的颅内肿瘤之一，高复发率是其预后差的主要原因，但其进展机制尚不明确。最新研究指出信号素(Sema)作为神经系统中的轴突导向因子，在肿瘤神经免疫中具有独特功能。我们前期发现，GBM临床标本中Sema6A表达程度与患者的生存期呈正相关，进一步细胞实验显示，应用Sema6A培养小胶质细胞可激活M1极化型,抑制M2极化型，此条件培养基能够抑制GBM细胞的增殖、迁移及侵袭。鉴此，我们推测：Sema6A通过其受体促进小胶质细胞由M2型向M1型转变，从而影响下游多种细胞因子的产生，达到抑制GBM进展的作用。本研究通过细胞、动物及临床研究验证这一理论，应用分子生物学等多种技术，揭示Sema6A在诱发小胶质细胞激活中的作用，观察小胶质细胞不同极化型对GBM增殖及血管生成的影响，并寻找下游靶分子。本课题不但为研究信号素的功能提供新思路，也为抗GBM药物研发寻找特异性靶点。

神经胶质瘤是颅内最常见的恶性肿瘤，治疗效果大多不佳，尤其是胶质母细胞瘤患者预后极差。随着肿瘤中免疫微环境研究的不断深入，发现小胶质细胞作为神经系统内固有免疫细胞，对胶质瘤生物学行为发展起到一定作用。我们在前期工作的基础上，通过体外细胞实验、分子生物学研究探讨小胶质细胞的激活条件及其与胶质瘤细胞间作用关系，并在动物模型上验证结论。利用临床组织标本检测相关指标，行患者预后生存分析，同时应用生物信息学技术，结合实验结果分析预测作用机制和功能富集的相关性。研究数据表明：一、信号素Sema6A可作为胶质母细胞瘤患者预后的标记物，与生存期呈现正相关。二、Sema6A可调控microglia极化，并相互作用抑制GBM的进展。三、microglia可影响肿瘤的侵袭及血管形成。四、肿瘤相关microglia通过P2ry2受体发挥功能，其相关通路影响肿瘤纯度及药物治疗敏感度。本研究过程中共协助培养科研人员3名，项目资助发表文章4篇，并有1项成果转化专利在申请之中。该课题不但为神经免疫在肿瘤中的研究提供新的思路，同时为胶质瘤的治疗提供新的靶点。