关于胶质瘤微环境中星形细胞分泌保护性线粒体现象及机制的研究

Gliomas are among the most common lethal brain tumors found in humans. Though there has been many kinds of therapeutic plans, the prognosis of gliomas is still pessimistic. The median survival time is only 14.6 months and five-year survival rate is only 3.3%. The formation of glioma relies on a complex tumor-associated microenvironment, and astrocyte is one of the most important part in this microenvironment. Focusing on the relationship between astrocyte and glioma, our group is throughout the front of the world. One of the important role of astrocyte in glioma is adjusting the metabolism process, which is also a hot research spot. Based on previous experiment results, we found that astrocyte possessed the ability of transferring mitochondria into gliomas. As this phenomenon had been found to protect neuron after stroke, we considered these mitochondria could also protect the gliomas from hypoxia, starvation, chemotherapy when transferred into the tumor cells and result in the promotion of proliferation or invasion. During this project, we intend to explore this phenomenon with in vivo and in vitro experiments. Use FACS and TEM to confirm the mitochondria, and Seahorse XFe24, Brdu, transwell to observe the effect, and western blot、siRNA-Lentivirus to select the target, and NOD-SCID mouse to verify the treatment potential of this process. In all, our research would replenish the theory of microenvironment and shed o new light of tumor therapy.

胶质瘤是最常见的颅内原发恶性肿瘤预后较差，中位生存期仅为14.6个月。研究发现胶质瘤的发展需要复杂的肿瘤微环境，而星形细胞正是该微环境的重要组成部分。目前我们课题组关于胶质瘤及星形细胞的研究处于世界前沿。在前期的研究中我们发现星形细胞能够调节胶质瘤代谢过程，同时具有向胶质瘤转移自身线粒体的现象。由于线粒体转移在低氧条件下被发现对神经元具有保护作用。因而我们认为星形细胞向胶质瘤转移的线粒体也具有保护功能，可以抑制肿瘤细胞凋亡，增强其在恶劣环境下的生存能力，最终表现为胶质瘤增殖、侵袭能力的提高。通过设计课题，我们拟从体内、体外两方面入手，通过FACS、透射电镜明确线粒体转移的现象，能量代谢分析仪、Brdu、划痕明确转移线粒体的作用，免疫电泳、siRNA筛选转移的关键蛋白，构建原位植瘤小鼠，明确阻断线粒体转移对胶质瘤的治疗作用。最终为肿瘤代谢机制提供有效的补充，为目前抗肿瘤治疗提供新的理论基础。

胶质瘤是最常见的颅内原发恶性肿瘤预后较差，中位生存期仅为14.6个月。研究发现胶质瘤的发展需要复杂的肿瘤微环境，而星形细胞正是该微环境的重要组成部分。在前期的研究中我们发现星形细胞能够调节胶质瘤代谢过程，同时具有向胶质瘤转移自身线粒体的现象。通过本课题我们确认星形细胞具有分泌保护性线粒体的现象，且该现象的机制是：胶质瘤在遭遇低氧、饥饿或化疗药物时，通过mTOR-AKT通路调控Miro-1、CD38及SNPH的表达进而影响线粒体的转移从而起到逃避线粒体诱导凋亡的作用，而星形细胞则调控通过PINK1及LRRK2分子的表达影响了线粒体转移的效果进而起到了保护胶质瘤细胞的作用，而该进程由mir-98-3参与调控；另外Linc00665通过影响mir-98-3p的表达可以影响STING通路的激活并最终影响胶质瘤免疫治疗的效果。通过本课题的研究，我们明确了阻断线粒体转移对胶质瘤的治疗作用。最终为肿瘤代谢机制提供有效的补充，并为目前抗肿瘤的免疫治疗提供新的理论基础。