Radiation-induced bystander and systemic effects serve as a unifying model system for genotoxic stress responses.

This review summarises our current understanding of the radiation-induced bystander/systemic effect (RIBE) as well as other types of intercellular reactions induced by malignant tumours, chemotherapy, photodynamic stress and the microbiome. On the basis of striking similarities between these different types of responses RIBE is proposed as a prototype model of a unifying genotoxic stress response system. The early bystander response is initiated by a mitochondria-dependent increase of reactive oxygen species (ROS) and triggers a complex intercellular signalling cascade leading to a sustained increase of cellular DNA damage. The susceptibility to this DNA damage-inducing signal depends on the genetic make-up of the recipient cell population where ATR/ATM- and FA/BRCA-dependent DNA damage response pathways are key players. Long distance bystander/systemic effects observed in in vivo-models are sustained by macrophage-mediated inflammation. Of clinical importance is the potential contribution of bystander DNA damage to an increased risk of malignancies. Defects in DNA damage repair pathways are frequently observed in tumours, which may affect their susceptibility to bystander DNA damage. The potential role for molecular targeted inhibitors in the therapeutic exploitation of bystander responses as well as their differential modulation of targeted and non-targeted effects is also discussed in this context.