Sedelnikova1, O.A., Nakamura1, A., Kovalchuk2, O., Koturbash2, I., Mitchell3, Marino3, S.A., Brenner3, D.J., and Bonner1, W.M. 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; 2Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada; and 3Radiological Research Accelerator Facility, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York.

This study by researchers at the National Cancer Institute (NIH), University of Lethbridge (Canada) and Columbia University demonstrated the ability to use MatTek’s EpiDermFT and EpiAirway in vitro human tissue equivalents as accurate in vitro surrogates to study phenomena known to be deleterious to human health – in this example, the DNA-damaging “bystander effect” of ionizing radiation on human tissues. The ‘‘radiation-induced bystander effect’’, in which irradiated cells can induce genomic instability in unirradiated neighboring cells, has important implications for cancer radiotherapy and diagnostic radiology as well as for human health in general. Although the mechanisms of this effect remain to be elucidated, we reported previously that DNA double-strand breaks (DSBs), directly measured by ã-H2AX focus formation assay, are induced in bystander cultured cells. To overcome the deficiencies of cultured cell studies, researchers at the National Cancer Institute (NIH), University of Lethbridge (Canada) and Columbia University (USA) examined á-particle microbeam irradiation–induced bystander effects in MatTek’s EpiDermFT and EpiAirway human tissue models, which preserve the three-dimensional geometric arrangement and communication of cells present in tissues in vivo. In marked contrast to DNA DSB dynamics in irradiated cells, in which maximal DSB formation is seen 30 min after irradiation, the incidence of DSBs in bystander cells reached a maximum by 12 to 48 h after irradiation, gradually decreasing over the 7-day time course. At the maxima, 40% to 60% of bystander cells were affected, a 4- to 6-fold increase over controls. These increases in bystander DSB formation were followed by increased levels of apoptosis and micronucleus formation, by loss of nuclear DNA methylation, and by an increased fraction of senescent cells. These findings show the involvement of DNA DSBs in tissue bystander responses and support the notion that by-stander DNA DSBs are precursors to widespread downstream effects in human tissues. Bystander cells exhibiting post-irradiation signs of genomic instability may be more prone than unaffected cells to become cancerous. Thus, this study points to the importance of considering the indirect biological effects of radiation in cancer risk assessment.


AIR-100, Apoptosis assay, Bystander cells, Cancer radiotherapy, Cancer risk assessment, Caspase-3, DNA Double-Strand Breaks, DNA methylation, EFT-300, EpiAirway , EpiDerm-FT, EpiDermFT , Gamma-H2AX focus formation assay, Immunocytochemistry, Microbeam irradiation, Micronucleus assay, Nuclear DNA methylation, PCNA, Radiation-induced bystander effect, SA-beta-gal staining, Senescence

Materials Tested

He ions, Microbeam

Request a copy of this paper, click here.