Abstract
BackgroundDespite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to high-dose radiation have not been fully characterized. This study was designed to identify molecular changes induced by focal high-dose irradiation using a mouse model of SBRT.ResultsCentral areas of the mouse left lung were focally-irradiated (3 mm in diameter) with a single high-dose of radiation (90 Gy). Temporal changes in gene expression in the irradiated and non-irradiated neighboring lung regions were analyzed by microarray. For comparison, the long-term effect (12 months) of 20 Gy radiation on a diffuse region of lung was also measured. The majority of genes were down-regulated in the focally-irradiated lung areas at 2 to 3 weeks after irradiation. This pattern of gene expression was clearly different than gene expression in the diffuse region of lungs exposed to low-dose radiation. Ontological and pathway analyses indicated these down-regulated genes were mainly associated with organ development. Although the number was small, genes that were up-regulated after focal irradiation were associated with immune-related functions. The temporal patterns of gene expression and the associated biological functions were also similar in non-irradiated neighboring lung regions, although statistical significance was greatly reduced when compared with those from focally-irradiated areas of the lung. From network analysis of temporally regulated genes, we identified inter-related modules associated with diverse functions, including organ development and the immune response, in both the focally-irradiated regions and non-irradiated neighboring lung regions.ConclusionsFocal exposure of lung tissue to high-dose radiation induced expression of genes associated with organ development and the immune response. This pattern of gene expression was also observed in non-irradiated neighboring areas of lung tissue, indicating a global lung response to focal high-dose irradiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0338-9) contains supplementary material, which is available to authorized users.
Highlights
Despite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to highdose radiation have not been fully characterized
Radiation was delivered with an X-RAD 320 (Precision, North Branford, CT, USA), equipped with a collimator system composed of 5-cmthick copper to produce focal radiation beams
Fibrotic changes in the lung tissues focally irradiated with high-dose radiation (90 Gy) We carefully checked the animal status during the experiments and no death or apparent adverse effects were not detected
Summary
Despite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to highdose radiation have not been fully characterized. Stereotactic body radiotherapy (SBRT) is considered an alternative treatment option for medically inoperable early-staged NSCLC patients, in which a high-dose of radiation is delivered repeatedly to tumor targets with great precision over one to five treatments [1, 2]. The efficacy of radiotherapy for lung cancer is severely compromised by the frequent occurrence of side effects, such as radiation-induced lung pneumonitis and fibrosis, which typically develop 6–24 months post-irradiation [3]. The internal target volume and mean doses of radiation-exposed lung are major predictors of a higher pneumonitis incidence after SBRT [5, 6]
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