Radiation-induced bystander phenomenon: insight and implications in radiotherapy

Despite the extensive utilization of radiotherapy in cancer treatments, clinicians often face challenges in achieving desired outcomes. This is because of the existence of secondary radiation effects like bystander phenomenon that influence radiation nontargeted cells and tissues. The concept of bystander effects of radiation was first proposed in the latter half of the last century which led to a paradigm shift in classical dogma of radiation biology. This review primarily focuses on the diverse mechanisms of bystander signal production and response under the influence of different sources of radiation like α-, β-, γ rays as well as protons and ions. The dependency of bystander effects on cell type and linear energies are also reviewed. Furthermore, the reciprocal effects exerted by bystander cells on radiation-targeted cells have been discussed. Radiation-induced signaling in targeted cells stimulates the release of different mediators that induce a plethora of molecular effects on adjacent unirradiated cells, leading to cell death or proliferation. These responses are regulated by the cell type and linear energies of radiation. Different radiation sources have diverse damaging impacts on bystander cells wherein the complex interplay of signaling molecules, inflammation, apoptosis, necrosis, and autophagy determine the fate of the cells. Further, the feedback mechanism of bystander cells controls the severity of effects in radiation-targeted cells. From the existing literature, it is difficult to speculate how far the fundamental mechanisms of induction of bystander effects by irradiated cancer cells differ from that of normal cells, although cell-specific responses are observed in bystander cells. To have an accurate idea about the actual scenario, consideration of all possible variations of experimental conditions is necessary. This is crucial for optimal utilization of radiotherapy protocols to serve twofold purposes, increase radiotherapy efficiency while causing minimal health risks.