gms | German Medical Science

71. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
9. Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

21.06. - 24.06.2020

Transfer of mononuclear cells from seropositive CMV latent mice leads to PDGFR-beta mediated tumoritropic infection in a mouse glioblastoma model

Der Transfer mononukleärer Zellen aus CMV latenten Mäusen führt zu einerPDGF-Rezeptor beta vermittelten tumorspezifischen Infektion im murinen Glioblastommodell

Meeting Abstract

  • presenting/speaker Harald Krenzlin - Brigham and Women’s Hospital, Abteilung für Neurochirurgie, Boston, MA, United States; Universitätsmedizin Mainz, Mainz, Deutschland
  • Naureen Keric - Universitätsmedizin Mainz, Mainz, Deutschland
  • E. Antonio Chiocca - Brigham and Women’s Hospital, Department of Neurosurgery, Boston, MA, United States
  • Sean Lawler - Brigham and Women’s Hospital, Department of Neurosurgery, Boston, MA, United States
  • Florian Ringel - Universitätsmedizin Mainz, Mainz, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 71. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 9. Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie. sine loco [digital], 21.-24.06.2020. Düsseldorf: German Medical Science GMS Publishing House; 2020. DocV221

doi: 10.3205/20dgnc218, urn:nbn:de:0183-20dgnc2180

Published: June 26, 2020

© 2020 Krenzlin et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objective: Cytomegalovirus (CMV) has been linked to glioblastoma for over a decade. However, mechanisms how CMV tumour infection occurs, are poorly understood. CMV is carried within a small percentage of mononuclear myeloid and dendritic cell progenitors in the healthy seropositive host. Here we identify a possible infection pathway, involving mononuclear cells und the platelet derived growth factor receptor-beta (PDGFR-beta).

Methods: In vivo, mononuclear cells from blood and bone marrow of CMV latent mice were harvested and transferred to CMV naïve animals carrying orthotopic Gl261fluc glioblastoma. Viral infection was analysed using immunofluorescence. In vitro, viral entry into glioblastoma stem cells was monitored using viral fluorescence labelling (GFP CMV). Receptor expression was analysed using Western blot and qPCR. Receptor knockdown was performed via siRNA.

Results: Bone marrow and peripheral blood mononuclear cells from CMV latent animals stained CMV positive using two different immunofluorescence antibodies. Transfer of these cells into seronegative CMV naïve mice carrying Gl261 orthotopic tumors led to tumor infection and viral spreading within the glioblastoma. The known CMV entry receptor PDGFR-beta was found to be expressed in PN GSCs, while it is virtually absent in MES GSCs. Using GFP labelled CMV, proneural (PN) glioblastoma stem cells (GSCs) exhibited green fluorescence as indicator of viral entry at lower MOIs (MOI 0.1) and with higher fluorescence intensity, compared to mesenchymal (MES) GSCs (MOI 1). Inhibition of PDGFR-beta in PN GSCs using the small molecule inhibitor Imatinib lead to a 82+-4.9% (p < 0.05) decreased expression of GFP, while siRNA knock-down of PDGFR-beta decreased GFP expression by 95.8+-0.5% (p < 0.05).

Conclusion: Mononuclear cells are a potential site of latent CMV infection from where infection can spread to glioblastomas. One mechanism of viral entry into GSCs involves the PDGFR-beta receptor. Blocking or down regulation of PDGFR-beta leads to impaired viral entry and might thus represent a novel therapeutic target in glioblastoma therapy.