Non-linear response of cells to signals leads to revised characteristics of bystander effects inferred from their modelling.

Purpose: To analyze the response of naive cells to bystander signals, thus complementing previous studies on signal emission by irradiated cells and improving quantitative understanding of bystander effects. Materials and methods: Published data on reduced clonogenic survival and mutation induction in bystander experiments with undiluted and diluted irradiated cell-conditioned medium were analyzed using linear and non-linear response functions. Results: The data indicated a highly non-linear response of cells to bystander signals. It can be described with sigmoid response functions, involving only a single additional parameter compared to the linear response assumed in existing models. Accounting for this non-linearity significantly modifies bystander characteristics inferred from the modelling, such as signal lifetime or dose dependence of signal release. Some signal release models are even ruled out. Conclusions: The sigmoid response to signals reflects complex intracellular pathways triggered and, together with the non-linear release of signals, supports the involvement of cytokines and/or reactive oxygen species in bystander effects. Further research combining experimental and modelling approaches is needed to elucidate the mechanisms of intercellular communication and their modifications by radiation, in particular to determine the nature of bystander signals, dynamics of their release after irradiation, and cellular responses to these signals