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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells

Authors: Maria Grazia Atzori, Lucio Tentori, Federica Ruffini, Claudia Ceci, Lucia Lisi, Elena Bonanno, Manuel Scimeca, Eskil Eskilsson, Thomas Daubon, Hrvoje Miletic, Lucia Ricci Vitiani, Roberto Pallini, Pierluigi Navarra, Rolf Bjerkvig, Stefania D’Atri, Pedro Miguel Lacal, Grazia Graziani

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

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Abstract

Background

Glioblastoma (GBM) is a highly migratory, invasive, and angiogenic brain tumor. Like vascular endothelial growth factor-A (VEGF-A), placental growth factor (PlGF) promotes GBM angiogenesis. VEGF-A is a ligand for both VEGF receptor-1 (VEGFR-1) and VEGFR-2, while PlGF interacts exclusively with VEGFR-1. We recently generated the novel anti-VEGFR-1 monoclonal antibody (mAb) D16F7 that diminishes VEGFR-1 homodimerization/activation without affecting VEGF-A and PlGF binding.

Methods

In the present study, we evaluated the expression of VEGFR-1 in human GBM tissue samples (n = 42) by immunohistochemistry, in cell lines (n = 6) and GBM stem cells (GSCs) (n = 18) by qRT-PCR and/or western blot analysis. In VEGFR-1 positive GBM or GSCs we also analyzed the ability of D16F7 to inhibit GBM invasiveness in response to VEGF-A and PlGF.

Results

Most of GBM specimens stained positively for VEGFR-1 and all but one GBM cell lines expressed VEGFR-1. On the other hand, in GSCs the expression of the receptor was heterogeneous. D16F7 reduced migration and invasion of VEGFR-1 positive GBM cell lines and patient-derived GSCs in response to VEGF-A and PlGF. Interestingly, this effect was also observed in VEGFR-1 positive GSCs transfected to over-express wild-type EGFR (EGFRwt+) or mutant EGFR (ligand binding domain-deficient EGFRvIII+). Furthermore, D16F7 suppressed intracellular signal transduction in VEGFR-1 over-expressing GBM cells by reducing receptor auto-phosphorylation at tyrosine 1213 and downstream Erk1/2 activation induced by receptor ligands.

Conclusion

The results from this study suggest that VEGFR-1 is a relevant target for GBM therapy and that D16F7-derived humanized mAbs warrant further investigation.
Appendix
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Metadata
Title
The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells
Authors
Maria Grazia Atzori
Lucio Tentori
Federica Ruffini
Claudia Ceci
Lucia Lisi
Elena Bonanno
Manuel Scimeca
Eskil Eskilsson
Thomas Daubon
Hrvoje Miletic
Lucia Ricci Vitiani
Roberto Pallini
Pierluigi Navarra
Rolf Bjerkvig
Stefania D’Atri
Pedro Miguel Lacal
Grazia Graziani
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0577-2

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