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  • Review Article
  • Published:

Radiation-induced bystander signalling in cancer therapy

Nature Reviews Cancer volume 9, pages 351–360 (2009)Cite this article

Key Points

  • Radiation-induced bystander responses are defined as the response of cells to their neighbours being irradiated. These have been observed in a range of cell types and measured for a range of end points.

  • Long-range, abscopal (out-of-field) effects have also been observed after the clinical use of radiation.

  • The main mechanisms involve direct cell–cell communication by gap junction intercellular communication and release of factors into the medium.

  • Bystander signalling has a key role in increasing the effectiveness of gene therapy approaches in which common mechanisms involving cytokine signalling and the production of reactive oxygen and nitrogen species have been used to maximize effectiveness.

  • With the development of suitable strategies, radiation-induced bystander responses may be used to enhance tumour cell kill or protect normal tissues from the damaging consequences of radiation exposure.

Abstract

Our understanding of how radiation kills normal and tumour cells has been based on an intimate knowledge of the direct induction of DNA damage and its cellular consequences. What has become clear is that, as well as responses to direct DNA damage, cell–cell signalling — known as the bystander effect — mediated through gap junctions and inflammatory responses may have an important role in the response of cells and tissues to radiation exposure and also chemotherapy agents. This Review outlines the key aspects of radiation-induced intercellular signalling and assesses its relevance for existing and future radiation-based therapies.

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Figure 1: Direct DNA damage radiation model.
Figure 2: Key aspects of radiation-induced bystander responses.
Figure 3: Key pathways affecting bystander signals.
Figure 4: Defining tumours for external beam targeting.
Figure 5: Treating cancer with radiation.

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Acknowledgements

The authors acknowledge the extensive literature they were not able to cite owing to space limits. They are grateful to Cancer Research UK grant number C1513/A7047, the European Union NOTE project (FI6R 036465) and the US National Institutes of Health (5P01CA095227-02) for funding their work.

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  1. Centre for Cancer Research & Cell Biology, Queen's University Belfast, Lisburn Road, Belfast, BT9 7BL, UK

    Kevin M. Prise & Joe M. O'Sullivan

  2. The Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, BT9 7AB, UK

    Joe M. O'Sullivan

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Correspondence to Kevin M. Prise.

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Glossary

Photodynamic therapy

A therapeutic approach in which photosensitive chemicals are taken up into tumours and then activated by laser or other light source to produce damaging free radicals

Ganciclovir

A synthetic analogue of 2′-deoxyguanosine that becomes phosphorylated when taken up by cells and is incorporated into DNA by DNA polymerase and leads to chain termination of the replicating DNA strands.

Clastogenic factors

A species that can break chromosomes.

Sister chromatid exchanges

Exchange of chromosomal material between the chromatids of a chromosome.

Lindane

A neurotoxin that can inhibit gap-junctional intercellular communication.

Reconstruct models

In vitro models in which individual cell types can be co-cultured and used to form three-dimensional representations of the original tissue.

Bilateral pneumonitis

Inflammation of lung tissue in both lungs.

Radionuclide therapy

The use of radioisotopes tagged to molecules or proteins for treating cancer

Dose rate

The amount of dose delivered per unit time.

Intensity-modulated radiation therapy

IMRT. An advanced mode of radiotherapy that uses multiple modulated beams in which the intensity is varied to allow maximal conformation of the beam delivery to the tumour in three dimensions.

Linear accelerator

A device for the acceleration of subatomic particles that can produce electron beams for radiotherapy.

Heavy ion particle therapies

The use of accelerated beams of high-atomic-mass elements (for example, carbon) for therapy.

Microplanar X-ray microbeams

Parallel beams of X-rays only a few micrometres across that are used for localized irradiation.

Auger electron cascades

Decay of radioactive isotopes by K-shell electron capture leads to the Auger effect, resulting in the loss of several orbital electrons.

Linear no-threshold hypothesis

A model used for radiation protection that aims to describe the relationship between radiation dose and risk, a linear relationship that has no dose threshold for increased risk.

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Prise, K., O'Sullivan, J. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer 9, 351–360 (2009). https://doi.org/10.1038/nrc2603

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