The intercellular communications mediating radiation-induced bystander effects and their relevance to environmental, occupational, and therapeutic exposures

Abstract

Purpose

The assumption that traversal of the cell nucleus by ionizing radiation is a prerequisite to induce genetic damage, or other important biological responses, has been challenged by studies showing that oxidative alterations extend beyond the irradiated cells and occur also in neighboring bystander cells. Cells and tissues outside the radiation field experience significant biochemical and phenotypic changes that are often similar to those observed in the irradiated cells and tissues. With relevance to the assessment of long-term health risks of occupational, environmental and clinical exposures, measurable genetic, epigenetic, and metabolic changes have been also detected in the progeny of bystander cells. How the oxidative damage spreads from the irradiated cells to their neighboring bystander cells has been under intense investigation. Following a brief summary of the trends in radiobiology leading to this paradigm shift in the field, we review key findings of bystander effects induced by low and high doses of various types of radiation that differ in their biophysical characteristics. While notable mechanistic insights continue to emerge, here the focus is on the many means of intercellular communication that mediate these effects, namely junctional channels, secreted molecules and extracellular vesicles, and immune pathways.

Conclusions

The insights gained by studying radiation bystander effects are leading to a basic understanding of the intercellular communications that occur under mild and severe oxidative stress in both normal and cancerous tissues. Understanding the mechanisms underlying these communications will likely contribute to reducing the uncertainty of predicting adverse health effects following exposure to low dose/low fluence ionizing radiation, guide novel interventions that mitigate adverse out-of-field effects, and contribute to better outcomes of radiotherapeutic treatments of cancer. In this review, we highlight novel routes of intercellular communication for investigation, and raise the rationale for reconsidering classification of bystander responses, abscopal effects, and expression of genomic instability as non-targeted effects of radiation.

Keywords:

• Out-of-field radiation effects
• radiation protection
• radiotherapy
• radiation dose
• linear energy transfer
• radiation-induced abscopal effects

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Acknowledgements

We thank Sonia M. de Toledo for her instrumental participation in our research on the radiation bystander effect. We also thank Roger W. Howell and members of the Division of Radiation Research at Rutgers New Jersey Medical School for the many helpful and instrumental discussions. EA thanks Walter Schimmerling for insightful conversation on classification of bystander effects.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work received support from the National Institutes of Health [Grants CA92262 and CA049062], the National Aeronautics and Space Administration [Grants NNJ06HD91G and NNX15AD62G], the US department of Energy Low Dose Radiation Research Program [DE-FG02-02ER63447], the New Jersey Commission on Cancer Research [Grant No. 02-1081-CCR-S2], and the Federal Nuclear Science and Technology Program at Canadian Nuclear Laboratories (Project FST-51320.50.19.06).

Notes on contributors

Manuela Buonanno

Manuela Buonanno received her B.Sc. in Physics from the University of Naples (Italy), and Ph.D. in Radiobiology from Rutgers University (USA). She is currently an Associate Research Scientist at the Center for Radiological Research at Columbia University, USA.

Géraldine Gonon

Géraldine Gonon received her engineering diploma in Biosciences from the Université Paris-Est Créteil in France, then her Ph.D. in radiobiology from Rutgers University (USA) and University of Franche-Comté, (France). She is currently a researcher at Institut de Radioprotection et de Sûreté Nucléaire (IRSN), France.

Badri N. Pandey

Badri N. Pandey completed his M.Sc. at Gorakhpur University (India) and his Ph.D. at Mumbai University (India). He pursued post-Doctoral research at Rutgers University (USA). Currently, he is Head of Radiation and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Edouard I. Azzam

Edouard I. Azzam completed his post-doctoral studies under the mentorship of the late Professor John B. Little. He is Professor Emeritus at Rutgers New Jersey Medical School (USA), and currently works as Research Scientist at Canadian Nuclear Laboratories, Chalk River, Canada.