Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo

Abstract

Ionizing radiation is a genotoxic agent and human carcinogen. Recent work has questioned long-held dogmas by showing that cancer-associated genetic alterations occur in cells and tissues not directly exposed to radiation, questioning the robustness of the current system of radiation risk assessment. In vitro, diverse mechanisms involving secreted soluble factors, gap junction intercellular communication (GJIC) and oxidative metabolism are proposed to mediate these indirect effects. In vivo, the mechanisms behind long-range 'bystander' responses remain largely unknown. Here, we investigate the role of GJIC in propagating radiation stress signals in vivo, and in mediating radiation-associated bystander tumorigenesis in mouse central nervous system using a mouse model in which intercellular communication is downregulated by targeted deletion of the connexin43 (Cx43) gene. We show that GJIC is critical for transmission of oncogenic radiation damage to the non-targeted cerebellum, and that a mechanism involving adenosine triphosphate release and upregulation of Cx43, the major GJIC constituent, regulates transduction of oncogenic damage to unirradiated tissues in vivo. Our data provide a novel hypothesis for transduction of distant bystander effects and suggest that the highly branched nervous system, similar to the vascular network, has an important role.

Embryos of the zebrafish Danio rerio in studies of non-targeted effects of ionizing radiation

“…Although the mechanisms underlying the RIBE are not fully understood, gap-junction intercellular communication [3,4] and the secretion of soluble factors from irradiated cells to the bystander cells were found to play important roles [5,6]. Reactive oxygen species (ROS), which were generated from irradiated cells, were among the reported bystander signals, which could lead to oxidative stress and DNA damage in nearby unirradiated cells.…”

Purinergic Signaling Is a Novel Mechanism of the Cellular Response to Ionizing Radiation

“…5,47,48) In addition, a recent study has suggested the involvement of both Cx43 and ATP in long-range bystander radiation damage and oncogenesis in vivo. 49) However, the relationship between Cx43 and ATP in the bystander effect was unknown.…”

“…Our results provide a novel insight into the mechanisms of ATP release induced by irradiation. 18,23) Since a radiation-induced bystander effect mediated by both ATP and Cx43 has been suggested in vivo, 49) recognition of the importance of ATP in this radiation-induced biological effect is now increasing.…”

Glioblastoma after radiotherapy for childhood acute lymphoblastic leukemia: Review

“…Transmission of radiationinduced signals between irradiated cells and adjacent non-irradiated cells might cause generation of reactive oxygen/nitrogen species in the nonirradiated cells, which might promote tumorigenesis. This is called as "by stander effect" and the mechanisms underlying bystander effect are not well defined, however some cytokines and/or intercellular gap junctions are considered responsible (25)(26)(27).…”