Vascular endothelial growth factor receptor 1 in glioblastoma‑associated 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.