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Integrin-based meningioma cell migration is promoted by photon but not by carbon-ion irradiation

Förderung der integrinbasierten Meningeomzellmigration durch Bestrahlung mit Photonen, nicht jedoch durch Bestrahlung mit Kohlenstoffionen

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Abstract

Purpose

Sublethal doses of photon irradiation (IR) are suspected to increase tumor cell migration and support locoregional recurrence of disease, which has already been shown in other cell lines. This manuscript describes the effect of photon and carbon-ion IR on WHO class I meningioma cell migration and provides an approach to the underlying cellular mechanisms.

Materials and methods

Meningioma cells were gained operatively at the university hospital in Homburg/Saar, Germany. For migration, membranes (8-µm pore sizes) were coated with collagen I, with collagen IV, and with fibronectin. Cells were analyzed in migration experiments with or without serum stimulation, with or without photon and carbon IR 24 h prior to experiments, and with or without integrin antibodies. Fluorescence-activated cell sorting (FACS) analyses of the integrins ανβ1, ανβ3, and ανβ5 were performed without IR and 6, 12 and 24 h after IR. Enzyme-linked immunosorbent assay (ELISA) analyses of matrix metalloproteinases (MMP)-2 and MMP-9 were realized with and without IR after cells were cultured on collagen I, collagen IV, or fibronectin for 24 h. Cells and supernatants for FACS and ELISA were stored at − 18 °C. The significance level was set at 5 % using both Student’s t test and two-way ANOVA.

Results

Migration of meningioma cells was serum-inducible (p < 0.001). It could be increased by photon IR (p < 0.02). The integrins ανβ1 and ανβ5 showed a 21 and 11 % higher expression after serum stimulation (not significant), respectively, and ανβ1 expression was raised by 14 % (p = 0.0057) after photon IR. Antibody blockage of the integrins ανβ1 and ανβ5 inhibited serum- and photon-induced migration. Expression of MMP-2 and MMP-9 remained unchanged after both IR and fetal bovine serum (FBS). Carbon-ion IR left both integrin expression and meningioma cell migration unaffected.

Conclusion

Photon but not carbon-ion IR promotes serum-based meningioma cell migration. Fibronectin receptor integrin ανβ1 signaling can be identified as an important mechanism for serum- and photon-induced migration of WHO class I meningioma cells.

Zusammenfassung

Zielsetzung

Subletale Photonendosen werden für die Induktion von Tumorzellmigration und die Förderung regionaler Tumorrekurrenz verantwortlich gemacht. Dies wurde bereits in anderen Zelllinien gezeigt. Dieses Manuskript beschreibt den Effekt von Photonen- und Kohlenstoffionen-Strahlung auf die Migration von Meningeomzellen der WHO-Klasse I und liefert einen Zugang zu den zugrundeliegenden zellulären Mechanismen.

Material und Methoden

Die Meningeomzellen wurden operativ am Universitätsklinikum Homburg/Saar, Deutschland, gewonnen. Für die Migration wurden Membranen (Porendurchmesser 8 µm) mit Kollagen I und IV sowie Fibronektin beschichtet. Das Verhalten der Zellen bei den Transmigrationsversuchen wurde mit oder ohne Serumstimulation, mit oder ohne der Versuchsdurchführung vorausgehende Photonen- oder Kohlenstoffionenbestrahlung und mit oder ohne Integrinantikörpern analysiert. Die Durchflusszytometrie (FACS) der Integrine ανβ1, ανβ3 und ανβ5 wurde ohne Bestrahlung sowie 6 h, 12 h und 24 h nach Bestrahlung durchgeführt. „Enzyme-linked immunosorbent Assays“ (ELISA) der Matrixmetalloproteinasen (MMP) 2 und 9 fanden mit oder ohne Bestrahlung statt, nachdem die Zellen für 24 h auf Kollagen I, IV oder Fibronektin kultiviert worden waren. Zellen und Überstände für FACS und ELISA wurden bei − 18 °C gelagert. Das Signifikanzniveau liegt bei 5%, wobei zur Bestimmung der Studentsche t-Test und die 2-faktorielle Varianzanalyse (2-way ANOVA) verwendet wurden.

Ergebnisse

Die Migration von Meningeomzellen ist seruminduzierbar (p < 0,001). Sie kann durch Photonenbestrahlungen gesteigert werden (p < 0,02). Die Integrine ανβ1 und ανβ5 zeigen nach Serumstimulation eine um 21 und 11 % höhere Expression (nichtsignifikant), die Expression von ανβ1 ist nach Photonenbestrahlung um 14 % (p = 0,0057) gesteigert. Eine Antikörperblockierung der Integrine ανβ1 und ανβ5 hemmt die serum- und photoneninduzierte Migration. Die Expression von MMP-2 und -9 bleibt nach Photonenbestrahlung und nach Serumstimulation (FBS) unverändert. Die Bestrahlung mit Kohlenstoffionen beeinflusst weder die Integrinexpression noch die Migration der Meningeomzellen.

Schlussfolgerung

Die Bestrahlung mit Photonen, nicht jedoch mit Kohlenstoffionen, fördert die serumbasierte Migration von Meningeomzellen. Der Signalweg des Fibronektinrezeptors Integrin ανβ1 kann als wichtiger Mechanismus der serum- und photoneninduzierten Migration von WHO-Klasse-I-Meningeomzellen identifiziert werden.

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Acknowledgments

We would like to thank Mrs. Sonja Hoffmann for the primary culturing of the meningioma cell lines at the University Hospital Homburg/Saar (Germany) and organizing their transport to Heidelberg.

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Authors and Affiliations

  1. Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Florian Simon, Jan-Oliver Dittmar M.D., Lena Orschiedt BTA,  Klaus-Josef Weber Ph.D.,  Jürgen Debus M.D. Ph.D. & Stefan Rieken M.D.

  2. Heidelberg Ion Treatment Facility (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany

    Stephan Brons Ph. D.

  3. Department of Neurosurgery, University Hospital of Homburg/Saar, Kirrberger Straße Gebäude 90.5, 66421, Homburg-Saar, Germany

    Steffi Urbschat M.D.

  4. Department of Radiation Oncology, University Hospital Munich (TU), Ismaninger Str. 22, 81675, Munich, Germany

    Stephanie E. Combs M.D.

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  1. Florian Simon
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  2. Jan-Oliver Dittmar M.D.
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  3. Stephan Brons Ph. D.
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  8. Stephanie E. Combs M.D.
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Correspondence to Florian Simon.

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Conflict of interest

F. Simon, J-O. Dittmar, S. Brons, L. Orschiedt, S. Urbschat, K-J. Weber, J. Debus, S.E. Combs, and S. Rieken state that there are no conflicts of interest.

Additional information

Stephanie E. Combs and Stefan Rieken shared senior authorship.

This work was presented in part at the Annual Meeting of the German Society of Radiation Oncology (DEGRO) in Berlin, Germany in May 2013.

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Simon, F., Dittmar, JO., Brons, S. et al. Integrin-based meningioma cell migration is promoted by photon but not by carbon-ion irradiation. Strahlenther Onkol 191, 347–355 (2015). https://doi.org/10.1007/s00066-014-0778-y

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