Vascular endothelial growth factor receptor 1 in glioblastoma­associated microglia/macrophages.

The anti­vascular endothelial growth factor­A (VEGF­A) monoclonal antibody (mAb) bevacizumab is an FDA­approved monotherapy for the treatment of recurrent glioblastoma (GB), a highly angiogenic and infiltrative tumour. However, bevacizumab does not increase overall survival and blockade of VEGF­A/VEGF receptor (VEGFR)­2 signal transduction is associated with severe adverse effects due to inhibition of physiological angiogenesis. Conversely, VEGFR­1 does not play a relevant role in physiological angiogenesis in the adult. VEGFR­1 is activated by both VEGF­A and placenta growth factor (PlGF), a protein involved in tumour growth and progression. In previous studies, it was demonstrated that inhibition of VEGFR­1 using a specific mAb developed in our laboratories reduced angiogenesis and GB cell chemotaxis and increased the survival of tumour­bearing mice. Failure of treatments directed toward the VEGF­A/VEGFR­2 axis could in part be due to inefficient targeting of the tumour microenvironment. In the present study, VEGFR­1 expression was investigated in GB­associated 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 VEGFR­1 ligands VEGF­A 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 VEGFR­1 is expressed not only in GB tissue but also in GAMs. Furthermore, the percentage of VEGFR­1­positive GAMs was significantly higher in the tumour region compared with that noted in the surrounding parenchyma. Thus, VEGFR­1 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.