title: The death-inducing effect and genomic instability.
abstract: Exposure to ionizing radiation can induce a heritable change in the unirradiated progeny of irradiated cells. This non-targeted effect of ionizing radiation manifests as genomic instability, and although there is some debate as to the role of genomic instability in the carcinogenic process, it is thought by some to be an early step in radiation carcinogenesis. Although the mechanism of induction of genomic instability is not clearly understood, evidence suggests that secreted factors from irradiated cells may be involved. We have previously identified another non-targeted effect of ionizing radiation, the death-inducing effect. Exposure of unirradiated GM10115 cells to medium from chromosomally unstable clones was generally found to be cytotoxic. However, occasionally cells will survive in medium from unstable clones and can be clonally expanded. The absolute yield of survivors is independent of the initial number of cells plated when cell densities reached 5,000 or more cells/dish. After cytogenetic analysis of the surviving colonies, we found chromosomal instability in three of 40 clones analyzed, while some clones exhibited increased micronucleus frequency and HPRT mutation frequency. These data suggest that our chromosomally unstable GM10115 cells secrete factors that are cytotoxic to the majority of stable, parental cells but are also capable of inducing a heritable change in some of the survivors that can manifest as delayed genomic instability. These results suggest a mechanism whereby instability can be perpetuated through the influences of potentially cytotoxic factors produced by genomically unstable clones.
authors.affiliation: Radiation Oncology Research Laboratory, University of Maryland, Baltimore, MD 21201-1559, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Nagar
authors.forename: William F
authors.initials: WF
authors.lastname: Morgan
mesh_terms: D000818:Animals; D019921:Biotinylation; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000528:radiation effects* / Q000648:ultrastructure; D006224:Cricetinae; D003470:Culture Media; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003582:Cytogenetics; D004247:DNA / Q000528:radiation effects*; D042822:Genomic Instability; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D015162:Micronucleus Tests; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D010641:Phenotype; D013997:Time Factors
chemical_list: D003470:Culture Media; D017077:Culture Media, Conditioned; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase