Radiation-Induced Senescence Bystander Effect: The Role of Exosomes

Abstract

Ionizing Radiation (IR), especially at high doses, induces cellular senescence in exposed cultures. IR also induces “bystander effects” through signals released from irradiated cells, and these effects include many of the same outcomes observed following direct exposure. Here, we investigate if radiation can cause senescence through a bystander mechanism. Control cultures were exposed directly to 0, 0.1, 2, and 10 Gy. Unirradiated cells were treated with medium from irradiated cultures or with exosomes extracted from irradiated medium. The level of senescence was determined post-treatment (24 h, 15 days, 30 days, and 45 days) by β-galactosidase staining. Media from cultures exposed to all four doses, and exosomes from these cultures, induced significant senescence in recipient cultures. Senescence levels were initially low at the earliest timepoint, and peaked at 15 days, and then decreased with further passaging. These results demonstrate that senescence is inducible through a bystander mechanism. As with other bystander effects, bystander senescence was induced by a low radiation dose. However, unlike other bystander effects, cultures recovered from bystander senescence after repeated passaging. Bystander senescence may be a potentially significant effect of exposure to IR, and may have both beneficial and harmful effects in the context of radiotherapy.

Radiobiological effects of wound fluid on breast cancer cell lines and human-derived tumor spheroids in 2D and microfluidic culture

“…Some cytokines may also act as mediators of bystander response, such as TNF-alpha, IL-8, and TGF-beta. This senescence-associated secretory phenotype (SASP) could induce paracrine senescence through DNA damages and arrest cells in G0/G1 phase 52 . DNA damage detection may cause cells to leave the cell cycle or undergo apoptosis, consequently not to reproduce irreparably damaged chromosomes 53 .…”

Ionizing Radiation-Induced Extracellular Vesicle Release Promotes AKT-Associated Survival Response in SH-SY5Y Neuroblastoma Cells

“…Our second aim was to investigate the effects of the EVs secreted by irradiated SH-SY5Y cells on proliferation, migration, and response to IRs. An autocrine EVs stimulating effect has been already reported in other tumor cell lines and in cancer patients [ 36 , 37 ]. We found that in SH-SY5Y cells, EVs10 stimulated proliferation, in line with what has been reported in different cell lines [ 34 ], although this effect has not been observed in all tumor cells [ 38 , 39 , 40 ].…”

Extracellular Vesicles Derived from Bone Marrow in an Early Stage of Ionizing Radiation Damage Are Able to Induce Bystander Responses in the Bone Marrow

“…An important finding was that EV-mediated effects were durable, and 3 months after EV treatment, cell depletion kinetics of most cell subpopulations (with the exception of MSCs and HSPCs) resembled effects seen in directly irradiated mice 3 months after irradiation. Other in vitro studies also reported EV-mediated long-term radiation-induced bystander effects [ 49 ]. Thus, we hypothesize that EVs isolated within 24 h of irradiation transmit signals which are able to induce acute cellular damage resembling direct irradiation.…”

“…Arscott et al observed increased abundance of EVs of human normal astrocytes after exposure to 4Gy [ 46 ]. In primary fibroblasts, Elbakrawy et al found that EV secretion peaked 1 h and 24 h following irradiation [ 49 ]. Furthermore, it was demonstrated by Cagatay et al that various organs (brain, heart, liver) and plasma have an increased rate of EV secretion 1 day and 15 days after total or partial body irradiation with 2Gy [ 50 ].…”