Radiation-induced effects in unirradiated cells: a review and implications in cancer.

A long-held central dogma of radiation biology has been that the carcinogenic effects of ionizing radiation (IR) are induced by the direct and radiolytic actions of IR on nuclear DNA. Numerous investigations, however, have revealed that several cancer relevant effects of IR can occur in cells that have received only cytoplasmic or plasmalemmal membrane exposure to IR. Further, mounting evidence now indicates that many effects that have been attributed to IR-induced damage to nuclear DNA or that occur following irradiation of the cytoplasmic compartment of cells can also occur in cells that have received no direct exposure to IR per se. These so-called <bystander effects>, i.e., radiation-induced effects in unirradiated cells, include cell killing, increases in intracellular reactive oxygen species, the induction of mutations, enhanced cell growth, the induction of apoptosis, the induction of genomic instability and neoplastic transformation. In this report, we summarize the evidence that demonstrates IR can cause this array of effects in non-irradiated cells, and we discuss recent findings concerning the potential mechanisms that may underlie IR-induced effects in unirradiated, or cells. Additionally, we discuss IR-induced bystander effects and their possible relationship to some in vivo observations, how bystander effects may pertain to carcinogenesis the treatment of tumors with radiotherapy, and how effects in bystander cells contribute to uncertainties in assessing cancer risks associated with exposure to IR.