Xuejiao Yang1, Linlin Ma1, Zhujing Ye1, Wenyu Shi2,3, Liyuan Zhang2,3,4, Jingdong Wang1, Hongying Yang1,4. 1. 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. 2. Department of Radiotherapy and Oncology, Second Affiliated Hospital of Soochow University, Suzhou, PR China. 3. Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital of Soochow University, Suzhou, PR China. 4. Institute of Radiotherapy & Oncology of Soochow University, Suzhou, PR China.
Abstract
PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: RIBEs mediated by the exosomes from irradiated cancer cells could contribute to RICI and, therefore, could be a novel mechanism underlying RICI.
PURPOSE: 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. MATERIALS AND METHODS: The transwell co-culture method was used to investigate bystander effects in mouse NSCs induced by irradiated GL261mouseglioma 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. RESULTS: After co-culture with GL261glioma 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. CONCLUSION: RIBEs mediated by the exosomes from irradiated cancer cells could contribute to RICI and, therefore, could be a novel mechanism underlying RICI.