Vascular endothelial growth factor receptor 1 in glioblastoma‑associated microglia/macrophages

Lisi,Lucia; Pia Ciotti,Gabriella Maria; Chiavari,Marta; Ruffini,Federica; Lacal,Pedro M.; Graziani,Grazia; Navarra,Pierluigi

doi:10.3892/or.2020.7553

Vascular endothelial growth factor receptor 1 in glioblastoma‑associated microglia/macrophages

Authors:
- Lucia Lisi
- Gabriella Maria Pia Ciotti
- Marta Chiavari
- Federica Ruffini
- Pedro M. Lacal
- Grazia Graziani
- Pierluigi Navarra
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Affiliations: Institute of Pharmacology, Catholic University Medical School, I‑00168 Rome, Italy, Laboratory of Molecular Oncology, IDI‑IRCCS, I‑00167 Rome, Italy, Department of Systems Medicine, University of Rome Tor Vergata, I‑00133 Rome, Italy
Published online on: March 19, 2020 https://doi.org/10.3892/or.2020.7553
Pages: 2083-2092

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Abstract

The anti‑vascular endothelial growth factor‑A (VEGF‑A) monoclonal antibody (mAb) bevacizumab is an FDA‑approved monotherapy for the treatment of recurrent glioblastoma (GB), a highly angiogenic and infiltrative tumour. However, bevacizumab does not increase overall survival and blockade of VEGF‑A/VEGF receptor (VEGFR)‑2 signal transduction is associated with severe adverse effects due to inhibition of physiological angiogenesis. Conversely, VEGFR‑1 does not play a relevant role in physiological angiogenesis in the adult. VEGFR‑1 is activated by both VEGF‑A and placenta growth factor (PlGF), a protein involved in tumour growth and progression. In previous studies, it was demonstrated that inhibition of VEGFR‑1 using a specific mAb developed in our laboratories reduced angiogenesis and GB cell chemotaxis and increased the survival of tumour‑bearing mice. Failure of treatments directed toward the VEGF‑A/VEGFR‑2 axis could in part be due to inefficient targeting of the tumour microenvironment. In the present study, VEGFR‑1 expression was investigated in GB‑associated microglia/macrophages (GAMs) by analysing surgical specimens collected from 42 patients with GB. Data obtained from The Cancer Genome Atlas (TCGA) database revealed that upregulation of the VEGFR‑1 ligands VEGF‑A and PlGF was associated with a significant reduction in overall survival for patients with GB, highlighting the potential relevance of this receptor in the aggressiveness of GB. Immunohistochemical analysis indicated that VEGFR‑1 is expressed not only in GB tissue but also in GAMs. Furthermore, the percentage of VEGFR‑1‑positive GAMs was significantly higher in the tumour region compared with that noted in the surrounding parenchyma. Thus, VEGFR‑1 represents a potential therapeutic target for the treatment of GB, being present not only in GB and endothelial cells, but also in GAMs that are involved in tumour progression.

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