Low-dose photon irradiation induces invasiveness through the SDF-1α/CXCR4 pathway in malignant mesothelioma cells
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Yoshikane Yamauchi1, Seyer Safi1, Lena Orschiedt2,4, Adriane Gardyan2,4,5, Stephan Brons3,4, Juliane Rieber2,3,4, Nils H. Nicolay2,3,4,5, Peter E. Huber2,4,5, Martin Eichhorn1, Hendrik Dienemann1, Felix J.F. Herth6,7, Klaus-Josef Weber2,3,4, Jürgen Debus2,3,4, Hans Hoffmann1 and Stefan Rieken2,3,4
1Department of Thoracic Surgery, Thorax Clinic, Heidelberg University, Heidelberg, Germany
2Department of Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
3Heidelberg Ion Treatment Facility (HIT), Heidelberg, Germany
4Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany
5Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany
6Pneumology and Critical Care Medicine, Thorax Clinic, Heidelberg University, Heidelberg, Germany
7Translational Lung Research Center Heidelberg (TLRCH), Heidelberg, Germany, Member of the German Center for Lung Research (DZL)
Stefan Rieken, email: Stefan.Rieken@med.uni-heidelberg.de
Keywords: mesothelioma, photon irradiation, carbon ion irradiation, CXCR4, SDF-1α
Received: September 06, 2016 Accepted: June 10, 2017 Published: July 10, 2017
Background: Low-dose photon irradiation has repeatedly been suspected to increase a risk of promoting local recurrence of disease or even systemic dissemination. The purpose of this study was to investigate the motility of malignant pleural mesothelioma (MPM) cell lines after low-doses of photon irradiation and to elucidate the mechanism of the detected phenotype.
Methods: H28 and H226 MPM cells were examined in clonogenic survival experiments and migration assays with and without various doses of photon and carbon ion irradiation. C-X-C chemokine receptor type 4 (CXCR4), SDF-1α, β1 integrin, α3 integrin, and α5 integrin expressions were analyzed by quantitative FACS analysis, ELISA and western blots. Apoptosis was assessed via Annexin-V-staining.
Results: The migration of MPM cells was stimulated by both fetal bovine serum and by stromal cell-derived factor 1α (SDF-1α). Low doses of photon irradiation (1 Gy and 2 Gy) suppressed clonogenicity, but promoted migration of both H28 and H226 cells through the SDF-1α/CXCR4 pathway. Hypermigration was inhibited by the administration of CXCR4 antagonist, AMD3100. In contrast, corresponding doses of carbon ion irradiation (0.3 Gy and 1 Gy) suppressed clonogenicity, but did not promote MPM cell migration.
Conclusion: Our findings suggest that the co-administration of photon irradiation and the CXCR4-antagonist AMD3100 or the use of carbon ions instead of photons may be possible solutions to reduce the risk of locoregional tumor recurrence after radiotherapy for MPM.
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