New insights on cell death from radiation exposure

Summary

Ionising radiation has been an important part of cancer treatment for almost a century, being used in external-beam radiotherapy, brachytherapy, and targeted radionuclide therapy. At the molecular and cellular level, cell killing has been attributed to deposition of energy from the radiation in the DNA within the nucleus, with production of DNA double-strand breaks playing a central part. However, this DNA-centric model has been questioned because cell-death pathways, in which direct relations between cell killing and DNA damage diverge, have been reported. These pathways include membrane-dependent signalling pathways and bystander responses (when cells respond not to direct radiation exposure but to the irradiation of their neighbouring cells). New insights into mechanisms of these responses coupled with technological advances in targeting of cells in experimental systems with microbeams have led to a reassessment of the model of how cells are killed by ionising radiation. This review provides an update on these mechanisms.

Introduction

Radiotherapy is based on the idea that exposure to a sufficient quantity (dose) of ionising radiation kills or sterilises cells. The first clinical use of radiation for the treatment of tumours was recorded in 1897, and during the past 50 years the specialty of radiation biology has led to the development of ideas that form a mechanistic framework of the predicted pathways between energy deposition in a tumour cell and probability of cell survival.¹ Fundamental to this mechanism has been the dogma that initial damage to the DNA within a cell nucleus is central to the killing of a cell by reproductive cell death. This idea has resulted in much investigation of how cells prevent perpetuation of damage to their DNA by a complex series of pathways, to recognise and repair DNA damage.

Despite the wealth of information on DNA-damage-mediated mechanisms of cell killing by ionising radiation, a new framework is now emerging. During the past 10 years, there has been a shift away from a totally DNA-centric approach to include models that invoke complex signalling pathways in cells and between cells within tissues (figure 1). Several newly recognised responses have been classified as so-called non-targeted responses,² in which biological effects are not directly related to the amount of energy deposited in the DNA of the cells traversed by the radiation. The effects include signalling pathways that are not dependent on DNA damage, bystander responses,³ adaptive responses,⁴ low-dose hypersensitivity,⁵ genomic instability,³ and the inverse dose-rate effect.⁶ A common feature is that most of these responses manifest themselves after exposure to low doses of radiation (<0·5 Gy) or in conditions when cells have not been exposed uniformly or irradiated directly. Given findings that the patterns of gene expression after radiation exposure are highly dose dependent, with different patterns of genes expressed after low doses from those expressed after high doses,⁷ many of the non-targeted responses could be a consequence of differential gene expression, cell signalling, or epigenetic responses predominating at low doses.

The aims of this review are to reassess some of these findings on mechanisms of cell killing and to put them into a clinical context. The delivery of radiation in a clinical setting is rapidly changing with the advent of approaches such as intensity-modulated radiotherapy, proton and heavy-ion treatment, improved imaging, and new combinations of radiation with chemoagents.⁸ New insights into mechanisms of radiation effects in tumours and healthy tissues need to be coupled to these other advances to maximise future therapeutic benefit.