Radiation-induced bystander signalling in cancer therapy

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.

Figure 1. Direct DNA damage radiation model

The schematic shows the standard model of DNA damage responses to radiation in biological systems, with direct DNA damage having a central role and the production of DNA double strand breaks (DSBs) leading to downstream biological consequences. Cells have complex pathways for sensing DNA damage and correctly repairing the DNA damage to survive the radiation exposure. If the DNA damage is not repaired, there is a high probability of cell death. DNA damage that is misrepaired can lead to mutations, increasing the probability of transformation and carcinogenesis.

Figure 2. Key aspects of radiation-induced bystander responses

Typical dose response curves for direct (a) and bystander (b) responses are shown, highlighting the commonly observed saturation of response for bystander effects.

Figure 3. Key pathways affecting bystander signals

Cells respond to direct radiation (red cell) by producing bystander responses through two key routes. One involves direct cell–cell communication through gap junctions and the second release of cytokine signals into the extracellular matrix. Not all cells respond (for example, the blue cell). In vivo, macrophages may be important mediators, which in response to radiation-induced tissue damage release bystander signals that affect non-irradiated cells (yellow cells). Some of the key pathways and mechanisms are now being elucidated, with roles for cytokine-mediated signalling, signal transduction through MAPKs and nuclear factor-κB (NF-κB) alongside the production of reactive oxygen and nitrogen species. COX2, cyclooxygenase 2; DR5, death receptor 5 (also known as TNFRSF10B); IL, interleukin; JNK, Jun N-terminal kinase; NO, nitric oxide; NOS2, NO synthase 2; ROS, reactive oxygen species; TGFβ, transforming growth factor-β; TGFβR, TGFβ receptor; TNFα, tumour necrosis factor-α; TRAIL, TNF-related apoptosis-inducing ligand.

Figure 4. Defining tumours for external beam targeting

For external beam radiotherapy it is usual to define the site of the tumour in terms of a gross tumour volume (GTV), which is where the tumour is located and includes a region of subclinical disease that is partially infiltrated by the tumour. Together this gives the clinical target volume (CTV), which is the volume in which there is a malignancy. The planning target volume (PTV) is then used to define the area that needs to be irradiated. In the future, it may be possible to define regions within the tumour, such as areas of hypoxia, and define a biological target volume (BTV) that could receive additional dose. A simplistic representation of the dose profile across the region is given, showing a low dose area with the PTV and an additional high dose area within the GTV, covering the BTV.

Figure 5. Treating cancer with radiation

The figure shows the two potential routes by which bystander responses may affect clinical therapies. For external beam therapies (such as intensity-modulated radiotherapy), dose gradient-dependent responses may influence the effect. Tumour heterogeneity may also lead to non-linear responses within the treatment field and to longer-range, abscopal or systemic effects. For radionuclide approaches (such as those tagged to monoclonal antibodies), the signals from a few labelled cells may be amplified by bystander signals within tumours and may also have long-range, abscopal or systemic effects.