Ionizing radiation-induced bystander effects, potential targets for modulation of radiotherapy.

Cells exposed to ionizing radiation show DNA damage, apoptosis, chromosomal aberrations or increased mutation frequency and for a long time it was generally accepted that these effects resulted from ionization of cell structures and the action of reactive oxygen species formed by water radiolysis. In the last few years, however, it has appeared that cells exposed to ionizing radiation and other genotoxic agents can release signals that induce very similar effects in non-targeted neighboring cells, phenomena known as bystander effects. These signals are transmitted to the neighboring non-hit cells by intercellular gap-junction communication or are released outside the cell, in the case of cultured cells into the medium. The signaling is mutual, and irradiated cells can also receive signals from non-irradiated neighbors. Most experiments show a decrease in survival of unirradiated bystander cells, but some studies of the influence of unirradiated or low dose-irradiated cells on those irradiated with higher doses show that intercellular bystander signaling can also increase the survival of irradiated cell populations. In the last few years, communication between irradiated and non-irradiated cells has attracted interest in many studies as a possible target for modulation of radiotherapy. Understanding the mechanisms underlying bystander effects is important for radiation risk assessment and for evaluation of protocols for cancer radiotherapy. In this review we describe different aspects of ionizing radiation-induced bystander effects: experimental examples, types of DNA damage, situations in vivo, and their possible role in adaptive response to irradiation, and we discuss their possible significance for anticancer therapy.