State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, PR China.
Department of Radiotherapy and Oncology, Second Affiliated Hospital of Soochow University, Suzhou, PR China.
Int J Radiat Biol. 2021;97(3):329-340. doi: 10.1080/09553002.2021.1864498. Epub 2021 Jan 11.
Despite being a major treatment modality for brain cancer due to its efficiency in achieving cancer control, radiotherapy has long been known to cause long-term side effects, including radiation-induced cognitive impairment (RICI). Neurogenesis inhibition due to radiation-induced damage in neural stem cells (NSCs) has been demonstrated to be an important mechanism underlying RICI. Radiation-induced bystander effects (RIBEs) denote the biological responses in non-targeted cells after their neighboring cells are irradiated. We have previously demonstrated that RIBEs could play an important role in the skin wound healing process. Therefore, we aimed to investigate whether RIBEs contribute to RICI in this study.
The transwell co-culture method was used to investigate bystander effects in mouse NSCs induced by irradiated GL261 mouse glioma cells in vitro. The proliferation, neurosphere-forming capacity and differentiation potential of NSCs were determined as the bystander endpoints. The exosomes were extracted from the media used to culture GL261 cells and were injected into the hippocampus of C57BL/6 mice. Two months later, the neurogenesis of mice was assessed using BrdU incorporation and immunofluorescence microscopy, and cognitive function was evaluated by the Morris Water Maze.
After co-culture with GL261 glioma cells, mouse NSCs displayed inhibited proliferation and reduced neurosphere-forming capacity and differentiation potential. The irradiated GL261 cells caused greater inhibition and reduction in NSCs than unirradiated GL261 cells. Moreover, adding the exosomes secreted by GL261 cells into the culture of NSCs inhibited NSC proliferation, suggesting that the cancer cell-derived exosomes may be critical intercellular signals. Furthermore, injection of the exosomes from GL261 cells into the hippocampus of mice caused significant neurogenesis inhibition and cognitive impairment two month later, and the exosomes from irradiated GL261 cells induced greater inhibitory effects.
RIBEs mediated by the exosomes from irradiated cancer cells could contribute to RICI and, therefore, could be a novel mechanism underlying RICI.
尽管放疗因其在控制癌症方面的高效性而成为治疗脑癌的主要方法，但它长期以来一直被认为会导致长期的副作用，包括放射性认知障碍（RICI）。已经证明，放射诱导的神经干细胞（NSC）损伤导致的神经发生抑制是 RICI 的重要机制。辐射诱导的旁观者效应（RIBE）表示在其相邻细胞被照射后，非靶向细胞中的生物学反应。我们之前已经证明，RIBE 可以在皮肤伤口愈合过程中发挥重要作用。因此，我们旨在研究 RIBE 是否在本研究中导致 RICI。
使用体外共培养法研究了照射的 GL261 小鼠神经胶质瘤细胞诱导的小鼠 NSC 中的旁观者效应。将 NSC 的增殖、神经球形成能力和分化潜能作为旁观者终点。从用于培养 GL261 细胞的培养基中提取外泌体，并将其注射到 C57BL/6 小鼠的海马体中。两个月后，通过 BrdU 掺入和免疫荧光显微镜评估小鼠的神经发生，通过 Morris 水迷宫评估认知功能。
与 GL261 神经胶质瘤细胞共培养后，小鼠 NSC 的增殖受到抑制，神经球形成能力和分化潜能降低。与未照射的 GL261 细胞相比，照射的 GL261 细胞导致 NSC 的抑制和减少更为明显。此外，将 GL261 细胞分泌的外泌体添加到 NSC 的培养物中会抑制 NSC 的增殖，表明癌细胞衍生的外泌体可能是关键的细胞间信号。此外，两个月后，将 GL261 细胞的外泌体注射到小鼠海马体中会导致明显的神经发生抑制和认知障碍，并且照射的 GL261 细胞的外泌体诱导出更大的抑制作用。
由照射癌细胞的外泌体介导的 RIBE 可能导致 RICI，因此可能是 RICI 的新机制。
