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.

Atzori, M.g., Tentori, L., Ruffini, F., Ceci, C., Lisi, L., Bonanno, E., et al. (2017). The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 36(1), 106-120 [10.1186/s13046-017-0577-2].

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

Tentori L.;Ceci C.;Bonanno E.;Scimeca M.;Graziani G.
2017

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14
English
Angiogenesis; Glioblastoma; Molecular marker; Molecular medicine; PlGF; VEGF-A; VEGFR-1
Atzori, M.g., Tentori, L., Ruffini, F., Ceci, C., Lisi, L., Bonanno, E., et al. (2017). The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 36(1), 106-120 [10.1186/s13046-017-0577-2].
Atzori, Mg; Tentori, L; Ruffini, F; Ceci, C; Lisi, L; Bonanno, E; Scimeca, M; Eskilsson, E; Daubon, T; Miletic, H; Ricci Vitiani, L; Pallini, R; Navarra, P; Bjerkvig, R; D'Atri, S; Lacal, Pm; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/190156
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