Abstract
The aim of the study was to investigate the role of a microenvironment in the induction of epithelial-to-mesenchymal transition (EMT) as a sign of early stages of carcinogenesis in human lung epithelial cell lines after protracted low-dose rate γ-radiation exposures. BEAS-2B and HBEC-3KT lung cell lines were irradiated with low-dose rate γ-rays (137Cs, 1.4 or 14 mGy/h) to 0.1 or 1 Gy with or without adding TGF-β. TGF-β-treated samples were applied as positive EMT controls and tested in parallel to find out if the radiation has a potentiating effect on the EMT induction. To evaluate the effect of the stromal component, the epithelial cells were irradiated in cocultures with stromal MRC-9 lung fibroblasts. On day 3 post treatment, the EMT markers: α-SMA, vimentin, fibronectin, and E-cadherin, were analyzed. The oxidative stress levels were evaluated by 8-oxo-dG analysis in both epithelial and fibroblast cells. The protracted exposure to low Linear Energy Transfer (LET) radiation at the total absorbed dose of 1 Gy was able to induce changes suggestive of EMT. The results show that the presence of the stromal component and its signaling (TGF-β) in the cocultures enhances the EMT. Radiation had a minor cumulative effect on the TGF-β-induced EMT with both doses. The oxidative stress levels were higher than the background in both epithelial and stromal cells post chronic irradiation (0.1 and 1 Gy); as for the BEAS-2B cell line, the increase was statistically significant. We suggest that the induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure and the presence of stromal component might enhance the effect through free radical production and accumulation.
Highlights
Ionizing radiation has been pointed out as the second leading cause for lung cancer after smoking [1]
A low-dose rate irradiation facility was used to perform a series of protracted irradiation experiments with two bronchial epithelial cell lines (BEAS-2B and HBEC-3KT)
We have shown that the main target for radiation-induced oxidative stress is the intracellular nucleotide pool, dNTP, where different types of modified dNTP can be produced, e.g., 8-oxo-dGTP. 8-oxo-dGTP release from cells such as 8-oxo-dG can be detected as a measurement of oxidative stress [31, 32]
Summary
Ionizing radiation has been pointed out as the second leading cause for lung cancer after smoking [1]. There are no detailed mechanistic models for the early stages of radiation-induced lung carcinogenesis so far. Over the last fifteen years, the important role of the tissue microenvironment (stroma) for the early stages of carcinogenesis and the role of microenvironment in radiation-induced breast cancer have been highlighted [2,3,4,5]. The stroma of the tissue provides the “soil” for the transformed cells to grow and invade distant from their origin causing metastasis. It produces specific chemokines and signaling molecules such as transforming growth factor beta (TGF-β), epidermal growth factor (EGF), and hepatocyte growth factor (HGF) during tumorigenesis [2, 3].
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