Radiation-induced bystander effects may contribute to radiation-induced cognitive impairment

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.

Keywords:

• Radiation-induced bystander effect
• radiation-induced cognitive impairment
• neural stem cells
• exosomes
• neurogenesis

Acknowledgments

The authors thank Dr Sarah Lumpkins (MEI Technologies) for editing the manuscript.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China under Grants U1632270 and 81773362 and the Priority Academic Program Development of Jiangsu Higher Education Institution (PARD).

Notes on contributors

Xuejiao Yang

Xuejiao Yang, MD, her research interest is the biological effects of ionizing radiation.

Linlin Ma

Linlin Ma, MD candidate, her research field is radiation medicine.

Zhujing Ye

Zhujing Ye, MD candidate, her research field is radiation medicine.

Wenyu Shi

Wenyu Shi, MD, her research interest is the biological effects of ionizing radiation.

Liyuan Zhang

Liyuan Zhang, PhD, MD, his research field is radiation oncology.

Jingdong Wang

Jingdong Wang, MS, is a research technologist of the State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University.

Hongying Yang

Hongying Yang, PhD, is a professor of State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University.