Low-dose photon irradiation induces invasiveness through the SDF-1α/CXCR4 pathway in malignant mesothelioma cells

Yoshikane Yamauchi,Hans Hoffmann,Adriane Gardyan,Klaus-Josef Weber,Martin Eichhorn,Stephan Brons,Seyer Safi,Lena Orschiedt,Peter E Huber,Nils H Nicolay,Jürgen Debus,Felix J.F Herth,Juliane Rieber,Hendrik Dienemann,Stefan Rieken

doi:10.18632/oncotarget.19134

Abstract

BackgroundLow-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.MethodsH28 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.ResultsThe 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.ConclusionOur 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.

Highlights

Malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm that has been the subject of considerable attention given its strong relationship to asbestos and its dismal outcome despite continuous efforts to intensify its treatment
The migration of malignant pleural mesothelioma (MPM) cells was stimulated by both fetal bovine serum and by stromal cell-derived factor 1α (SDF-1α)
Hypermigration was inhibited by the administration of CXC chemokine receptor 4 (CXCR4) antagonist, AMD3100

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm that has been the subject of considerable attention given its strong relationship to asbestos and its dismal outcome despite continuous efforts to intensify its treatment. Chemotherapy, radiotherapy, and surgery have been proven ineffective as single treatment modalities, but combined modality regimes have yielded minor improvement in disease progression [1]. It is reported that, despite some small improvements in local control of patients with postoperative radiation, regional relapse remains the predominant pattern of tumor recurrence after multimodality treatment [8]. 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

Objectives

Methods

Results

Conclusion