title: Radiation induced non-targeted response: mechanism and potential clinical implications.
abstract: Generations of students in radiation biology have been taught that heritable biological effects require direct damage to DNA. Radiation-induced non-targeted/bystander effects represent a paradigm shift in our understanding of the radiobiological effects of ionizing radiation in that extranuclear and extracellular effects may also contribute to the biological consequences of exposure to low doses of radiation. Although radiation induced bystander effects have been well documented in a variety of biological systems, including 3D human tissue samples and whole organisms, the mechanism is not known. There is recent evidence that the NF-κB-dependent gene expression of interleukin 8, interleukin 6, cyclooxygenase-2, tumor necrosis factor and interleukin 33 in directly irradiated cells produced the cytokines and prostaglandin E2 with autocrine/paracrine functions, which further activated signaling pathways and induced NF-κB-dependent gene expression in bystander cells. The observations that heritable DNA alterations can be propagated to cells many generations after radiation exposure and that bystander cells exhibit genomic instability in ways similar to directly hit cells indicate that the low dose radiation response is a complex interplay of various modulating factors. The potential implication of the non-targeted response in radiation induced secondary cancer is discussed. A better understanding of the mechanism of the non-targeted effects will be invaluable to assess its clinical relevance and ways in which the bystander phenomenon can be manipulated to increase therapeutic gain in radiotherapy.
authors.affiliation: Center for Radiological Research, Department of Radiation Oncology, Columbia University Medical Center, Vanderbilt Clinic, New York, USA. tkh1@columbia.edu
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.forename: Hongning
authors.initials: H
authors.lastname: Zhou
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Chai
authors.forename: Brian
authors.initials: B
authors.lastname: Ponnaiya
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Ivanov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D024201:Bystander Effect / Q000528:radiation effects*; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D017629:Gap Junctions / Q000378:metabolism; D015870:Gene Expression / Q000528:radiation effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D016328:NF-kappa B / Q000378:metabolism; D011839:Radiation, Ionizing; D011853:Radiobiology; D017978:Receptors, Growth Factor / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017978:Receptors, Growth Factor; D004247:DNA