Rawal Komal N, Degorre Charlotte, Tofilon Philip J
Radiation Oncology Branch, National Cancer Institute, 10 Center Drive-MSC 1002, Building 10, B3B406, Bethesda, MD 20892, USA.
Cancers (Basel). 2025 Aug 28;17(17):2817. doi: 10.3390/cancers17172817.
: 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. : 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. 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. 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.
绝大多数胶质母细胞瘤（GBM）在包括放疗在内的标准治疗后2年内复发。癫痫发作和癫痫在GBM患者中很常见，提示肿瘤细胞诱导的神经元毒性。此外，肿瘤细胞与神经元在肿瘤发展过程中相互作用；然而，肿瘤细胞对神经元的影响仍不清楚。将表达绿色荧光蛋白（GFP）的胶质母细胞瘤干细胞（GSC）原位移植到裸鼠右纹状体，在植入35天后进行照射（10 Gy），随后进行免疫组织化学（IHC）以研究肿瘤细胞与神经元的相互作用。此外，我们建立了人GSC与从人诱导多能干细胞（iPSC）衍生的神经祖细胞（NPC）分化而来的神经元的直接共培养体系，以研究肿瘤细胞对神经元的影响。监测神经元细胞计数以评估神经毒性。通过细胞因子谱分析培养上清液（CM）。在未治疗的小鼠中，肿瘤侵袭至右半球（RH），与小鼠神经元的细胞接触增加。在接受照射的小鼠中，肿瘤再生长的侵袭性较小且神经元较少。在体外，GSC在直接共培养中诱导神经元死亡。同样，直接共培养的CM导致显著的神经元死亡。细胞因子分析显示，共培养体系独特地向CM中分泌白细胞介素-8（IL-8）。此外，用重组（r）人IL-8处理导致显著的神经元死亡，而IL-8阻断抗体可预防共培养中的这种神经毒性。本研究表明，放疗后复发的GBM肿瘤缺乏神经元，GSC与神经元之间的直接相互作用对于GSC介导的神经毒性是必要的，可能涉及IL-8导致神经元死亡。
