Abstract
Proton radiotherapy has gained more favor among oncologists as a treatment option for localized and deep-seated tumors. In addition, protons are a major constituent of the space radiation astronauts receive during space flights. The potential for these exposures to lead to, or enhance cancer risk has not been well studied. Our objective is to study the biological effects of low energy protons on epithelial cells and its propensity to enhance transforming growth factor beta 1 (TGFβ1)-mediated epithelial-mesenchymal transition (EMT), a process occurring during tumor progression and critical for invasion and metastasis. Non-transformed mink lung epithelial cells (Mv1Lu) and hTERT- immortalized human esophageal epithelial cells (EPC) were used in this study. EMT was identified by alterations in cell morphology, EMT-related gene expression changes determined using real-time PCR, and EMT changes in specific cellular markers detected by immunostaining and western blotting. Although TGFβ1 treatment alone is able to induce EMT in both Mv1Lu and EPC cells, low energy protons (5 MeV) at doses as low as 0.1 Gy can enhance TGFβ1 induced EMT. Protons alone can also induce a mild induction of EMT. SD208, a potent TGFβ Receptor 1 (TGFβR1) kinase inhibitor, can efficiently block TGFβ1/Smad signaling and attenuate EMT induction. We suggest a model for EMT after proton irradiation in normal and cancerous tissue based on our results that showed that low and high doses of protons can sensitize normal human epithelial cells to mesenchymal transition, more prominently in the presence of TGFβ1, but also in the absence of TGFβ1.
Highlights
Proton irradiation has grown in importance as a modality for cancer treatment in part because of its ability to spare normal tissues as compared to conventional radiation [1,2]
We investigated the potential of protons exposure, both in the presence of elevated transforming growth factor beta 1 (TGFb1) and in its absence to elicit epithelial-mesenchymal transition (EMT) in exposed cells
Prompt cellular response to TGFb1 and proton radiation was observed in epithelial cells
Summary
Proton irradiation has grown in importance as a modality for cancer treatment in part because of its ability to spare normal tissues as compared to conventional radiation [1,2]. 100,000 patients have been treated with protons for prostate, esophageal, lung, head and neck, and other cancers, and there are a growing number of proton treatment centers worldwide that will operate in the near future. Enhanced sparring of tissue is possible by careful placement within the tumor volume of the proton peak energy deposition, denoted as the Bragg peak, which occurs as a particle slows down before it comes to rest. Given that some proton exposure will still occur in tissue near the edges of the tumor, and the possibility that high linear energy transfer (LET) protons (LET. keV/mm) may produce qualitatively different biological effects compared to low LET radiation such as x-rays [4], it is important to study how protons may affect the cells and tissues
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