文章：

胶质母细胞瘤细胞在体内外诱导神经元丧失

Glioblastoma Cells Induce Neuron Loss In Vivo and In Vitro

原文发布日期：28 August 2025

DOI: 10.3390/cancers17172817

类型: Article

开放获取: 是

英文摘要：

Background: The vast majority of GBMs recur within 2 years following standard treatment, including radiotherapy. Seizures and epilepsy are common in GBM patients, suggesting tumor-cell-induced neuron toxicity. Additionally, the tumor cells and neurons interact during tumor development; however, the effects of tumor cells on the neurons remain unclear.Methods: Orthotopic xenografts initiated from GSCs expressing GFP implanted into the right striatum of nude mice were irradiated (10 Gy) 35 days after implantation, followed by immunohistochemistry (IHC) to investigate the tumor cell–neuron interactions. Moreover, we established a direct coculture of human GSCs and neurons differentiated from human iPSC-derived neural progenitor cells (NPCs) to investigate the impact of the tumor cells on the neurons. Neuronal cell counts were monitored to assess neurotoxicity. Culture CM were analyzed through cytokine profiling.Results:In untreated mice, tumors invaded across the right hemisphere (RH), with increased cell contact with the mouse neurons. In irradiated mice, the tumor regrowth was less invasive and had fewer neurons. In vitro, the GSCs induced neuronal death in the direct coculture. Similarly, the CM from the direct cocultures caused significant neuronal death. The cytokine analysis revealed that the cocultures uniquely secreted IL-8 into the CM. Furthermore, treatment with recombinant (r) human IL-8 caused significant neuron death, while IL-8 blocking antibodies prevented this neurotoxicity in the coculture.Conclusions:This study demonstrates that GBM tumors regrown after radiation lack neurons, and direct interaction between GSCs and the neurons is necessary for GSC-mediated neurotoxicity, likely involving IL-8 in neuronal death.

摘要翻译： 

背景：绝大多数胶质母细胞瘤（GBM）在包括放疗在内的标准治疗后两年内复发。癫痫发作在GBM患者中较为常见，提示肿瘤细胞可能诱导神经元毒性。此外，肿瘤细胞与神经元在肿瘤发展过程中存在相互作用，但肿瘤细胞对神经元的具体影响尚不明确。 方法：将表达绿色荧光蛋白（GFP）的胶质瘤干细胞（GSCs）原位异种移植至裸鼠右侧纹状体，移植后35天进行放射治疗（10 Gy），随后通过免疫组织化学（IHC）技术研究肿瘤细胞与神经元的相互作用。此外，我们建立了人GSCs与人诱导多能干细胞（iPSC）来源的神经祖细胞（NPCs）分化而来的神经元直接共培养体系，以探究肿瘤细胞对神经元的影响。通过监测神经元细胞计数评估神经毒性，并对培养上清液（CM）进行细胞因子谱分析。 结果：在未治疗小鼠中，肿瘤侵袭至右侧大脑半球（RH），且与小鼠神经元的细胞接触增加。在放疗小鼠中，肿瘤再生侵袭性较低，神经元数量减少。体外实验中，GSCs在直接共培养中诱导神经元死亡。同样，直接共培养的上清液也导致显著的神经元死亡。细胞因子分析显示，共培养体系特异性地向上清液中分泌白细胞介素-8（IL-8）。此外，重组人IL-8处理可引起显著的神经元死亡，而IL-8阻断抗体在共培养中能有效阻止这种神经毒性。 结论：本研究表明，放疗后再生的GBM肿瘤缺乏神经元，且GSCs与神经元的直接相互作用是GSCs介导神经毒性的必要条件，IL-8可能在此过程中参与诱导神经元死亡。

原文链接：

Glioblastoma Cells Induce Neuron Loss In Vivo and In Vitro