Sedelnikova1, O.A., Nakamura1, A., Koturbash2, I., Kovalchuk3, O., Mitchell3, S.A., Marino3, S.A., Brenner3, D.J., Bonner1, W.M. 1Laboratory for Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD; 2Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada; 3Radiation Accelerator Research Facility, Center for Radiological Research, Columbia University, College of Physicians and Surgeons, New York, NY.

This study by researchers at the National Cancer Institute (NIH), University of Lethbridge (Canada) and Columbia University demonstrated that MatTek’s EpiDermFT and EpiAirway in vitro human tissue equivalents exhibited the “radiation-induced bystander response” thereby overcoming the deficiencies of cultured-cell studies. Irradiated cells can induce genomic instability in unirradiated neighboring cells in vitro. This phenomenon, called “radiation-induced bystander effect” has important implications for radiotherapy and diagnostic radiology and for low-dose radiation protection, as well as for human health. While the mechanism of this effect remains to be uncovered, studies with cultured cells have shown that, among a variety of end points, DNA double-strand breaks (DSBs) are induced in bystander cells and may to be responsible for downstream manifestations of the bystander effect. To overcome the deficiencies of cultured-cell studies, researchers at the National Cancer Institute (USA), the University of Lethbridge (Canada) and Columbia University’s College of Physicians and Surgeons (USA) examined human tissue models (EpiAirway and EpiDermFT, MatTek Corp.) which preserve the 3D geometric arrangement and communication of cells present in tissues in vivo. After microbeam irradiation of a thin plane of cells in these tissues, we report an extensive increase in the incidence of DNA DSBs involving 40-60% of the bystander cells present 1.5-2.5 mm away from the irradiation plane at 1-2 days post irradiation. The values remained elevated for several days. These increases in DSB formation were followed by increased amounts of apoptosis and micronucleus formation, by loss of nuclear DNA methylation and eventually by increased fraction of cells exhibiting characteristics of senescence. These findings demonstrate for the first time the widespread nature of the bystander response in tissue models. The long-term involvement of tissues surrounding the exposure sites may serve as a protective response in the whole organism to potentially carcinogenic DNA damage. The study points to the importance of indirect delayed biological effects of irradiation in the development of cancer risk models.


3D geometric arrangement, Apoptosis, Bystander effects, DNA double-strand breaks (DSBs), DNA methylation, EpiAirway, EpiDerm-FT, EpiDermFT, Ionizing, Irradiation, Micronucleus, Radiation-induced bystander effect, Senescence

Request a copy of this paper, click here.