神经元-胶质瘤网络调控前神经型胶质瘤干细胞沿白质纤维侵袭

Invading along specific anatomical structures such as white matter fiber is the most remarkable invasive characters of glioma. Recent studies have found that neurotrophic factors released by neurons can provide growth advantages for glioma cells. And crucially, unlike most cancer cells, when nearing to nerve fiber, some glioma cells can invade along white matter fiber and metastasis to distant areas instead of settling down. But the specific mechanism is unclear. According to the literature, database analysis and preliminary results of our research team, we found that proneural glioma stem cells have stronger ability to invade along white matter fiber and express higher gap junction protein 43. Therefore, we speculate that: heterologous gap junction channels formed between the neuron and proneural glioma stem cell, and invade along the white matter fiber. This study will investigate the formation of heterogeneous gap junction channels between neurons and proneural glioma stem cells, its role in regulating glioma cells invasion along the white matter fiber, and evaluate the significance of clinical diagnosis and treatment by co-culture neurons with proneural glioma stem cells, animal models and glioma patient specimens. The obtained results of the study will not only helpful for understanding the mechanism of the aggressive growth of glioma, but also provide a new experimental basis for exploring the diagnostic and therapeutic targets of glioma.

胶质瘤具有沿着白质纤维等特定解剖结构侵袭的特点。近期发现，神经元释放的神经营养因子可使胶质瘤细胞获得生长优势。但并非所有的胶质瘤细胞靠近神经纤维后即停止迁移并开始增殖，部分胶质瘤细胞会沿着白质纤维侵袭到远处并形成新的肿瘤灶，其具体机制不明。根据文献、数据库分析及课题组前期预实验结果，我们发现前神经型胶质瘤干细胞（PN-GSC）具有更强的沿白质纤维侵袭的能力且高表达间隙连接蛋白43。因此我们推测：PN-GSC亚群可与神经元形成异源型间隙连接，促进其沿着白质纤维侵袭。本研究拟用神经元与PN-GSC体外共培养模型、动物模型和胶质瘤病人标本观察体内外异源型间隙连接的形成情况，及其在调控PN-GSC沿着白质纤维侵袭中的作用，并评估临床诊断治疗意义。研究结果有助于深入认识胶质瘤侵袭性生长的发生机制，进而为探寻胶质瘤的诊疗靶点提供新的实验依据。

胶质瘤具有沿着白质纤维等特定解剖结构侵袭的特点，但是其涉及的具体机制目前并不清楚，深入探讨上述科学问题有助于进一步认识胶质瘤侵袭性生长的发生机制，进而为探寻胶质瘤的诊疗靶点提供新的实验依据。本课题通过一系列实验研究发现，胶质瘤干细胞是一个混合群体。其中，前神经型胶质瘤干细胞（PN-GSC）相较于间充质胶质瘤干细胞（Mes-GSC）更易沿着神经元散在分布。此外，PN型胶质瘤细胞还可以与共培养神经元生成隧道纳米管结构，并上调间隙连接蛋白43的表达。上述结构为胶质瘤细胞获得神经元细胞中的线粒体提供助力，进而促进其向Mes-GSC细胞转化，促进胶质瘤细胞的恶性。研究结果有助于我们进一步的认识胶质瘤沿着神经纤维侵袭性生长的发生机制，进而为探寻胶质瘤的诊疗靶点提供新的实验依据。