Signaling factors for irradiated glioma cells induced bystander responses in fibroblasts

The aim of this study was to investigate the signaling factor and its pathway involved in the targeted irradiation-induced bystander response from glioblastoma cells to primary fibroblasts. After co-culturing with a glioblastoma T98G population where a fraction of cells had been individually irradiated with a precise number of helium particles, additional micronucleus (MN) were induced in the non-irradiated human fibroblasts AG01522 cells and its yield was independent of irradiation dose. This bystander MN induction was eliminated by treating the cells with either aminoguanidine (AG), an iNOS inhibitor, or anti-transforming growth factor-β1 (anti-TGF-β1). In addition, TGF-β1 could be released from irradiated T98G cells but this release was inhibited by AG. In consistent, TGF-β1 could also be induced from T98G cells treated with diethylamine nitric oxide (DEANO), a donor of nitric oxide (NO). Moreover, the effect of TGF-β1 on bystander AG01522 cells was investigated. It was found that reactive oxygen species (ROS) and MN were induced in AG01522 cells after TGF-β1 treatment. Our results indicate that, downstream of NO, TGF-β1 plays an important role in the targeted T98G cells induced bystander response to AG0 cells by further causing DNA damage in vicinal fibroblasts through a ROS related pathway. This study may have implications for properly evaluating the secondary effects of radiotherapy.