Exposure to ionizing radiation elicits significant lung tissue perturbations and creates a tumour-supportive microenvironment


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Emma Nolan1,Ilaria Malanchi1
1Francis Crick Institute

Abstract

Background

Radiation therapy is a treatment modality used for many types of cancer, with almost half of all cancer patients undergoing radiotherapy as part of their treatment plan in the UK. Off-target exposure of healthy tissue to ionizing radiation remains a significant challenge for the treatment of cancer, since it can lead to severe side effects such as lung fibrosis. Importantly, it is also thought to play a role in promoting tumour recurrence and resistance. The aim of this work is to understand how healthy lung tissue responds to radiation-induced injury, and to uncover the mechanisms by which these perturbations can influence fibrosis development and cancer cell behaviour.

Method

Female mice aged 8-12 weeks received targeted lung irradiation at a dose of 13Gy using a collimator attached to the radiation source. Lungs were harvested 7 days after irradiation to assess tissue perturbations. To determine the impact of radiation exposure on metastatic colonization, cancer cells were seeded in sham or pre-irradiated lungs via tail-vein injections or subcutaneous mammary fat-pad injections, and lungs analyzed 7 days later.

Results

Radiation exposure led to significant alterations in the endothelial, epithelial and mesenchymal compartments of the lung, as well as perturbations in the composition of the extracellular matrix. These alterations resulted in a tissue microenvironment that was favourable for cancer cell growth, since a striking increase in metastatic colonization was observed in irradiated lungs. Notably, the induction of the tissue response and the subsequent tumour-supportive microenvironment appears to be partly mediated by inflammatory components, with the inhibition of these components reducing metastatic burden in irradiated lungs.

Conclusion

The striking perturbations detected in radiation-exposed lungs could have implications for patient response, particularly the formation of a tumour-supportive environment. Importantly, the influence of inflammatory components on this process raises the possibility of a therapeutic intervention for off-target effects.