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

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.