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

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.

microRNA-214 prevents traits of cutaneous squamous cell carcinoma via VEGFA and Bcl-2

“…For exploring the mechanism through which miR-214 affects the properties of CSCC cells, we identi ed that VEGFA and Bcl-2 are two targets of miR-214 and could predict dismal survival of patients with CSCC. The Cancer Genome Atlas database disclosed that upregulation of VEGFA was related with a signi cant decline in overall survival for patients with glioblastoma [17]. Further, we discovered that the OD values, number of migration and invasion rates were elevated in A431 and SCC13 cells harboring overexpressing miR-214 and VEGFA/Bcl-2 compared to those cells overexpressing miR-214 only.…”

Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models

“…Therefore, bevacizumab should be combined with therapies targeting GAMs to prevent their expansion. In this regard, by analyzing surgical specimens collected from glioblastoma patients, we recently demonstrated that GAMs expressed VEGFR-1 and the percentage of VEGFR-1 positive GAMs was higher in the tumor tissue than in the surrounding parenchyma [154]. Thus, VEGFR-1 targeting might synergize with anti-VEGF-A therapies counteracting the rebound-proangiogenic effects mediated by GAMs and delaying resistance development.…”

Fasten the seat belt: Increasing safety of CAR T‐cell therapy

“…[38] Looking at the current target antigens in clinical trials running for advanced stage melanoma patients, for instance, we can also observe that these target antigens are not exclusively expressed on melanocytes or melanoma cells ( TA B L E 1 Clinical trials for melanoma using chimeric antigen receptors (as of April 21st, 2020) clinical trials include, for example the tyrosine-protein kinase c-MET and vascular endothelial growth factor (VEGF).While c-MET is normally expressed by cells of epithelial origin (healthy and malignant tissues), [39][40][41] VEGF activity is restricted mainly to cells of the vascular endothelium, although it is known that it also has effects on other cell types, for example monocytes and macrophages. [42][43][44] Thus, the results of these clinical studies must first be evaluated in order to be able to decide-apart from the clinical benefit-if the use of these antigens is safe or if it leads to severe on-target/off-tumor toxicities.…”

“…Target antigens in these clinical trials include, for example the tyrosine‐protein kinase c‐MET and vascular endothelial growth factor (VEGF).While c‐MET is normally expressed by cells of epithelial origin (healthy and malignant tissues), [ 39‐41 ] VEGF activity is restricted mainly to cells of the vascular endothelium, although it is known that it also has effects on other cell types, for example monocytes and macrophages. [ 42‐44 ] Thus, the results of these clinical studies must first be evaluated in order to be able to decide—apart from the clinical benefit—if the use of these antigens is safe or if it leads to severe on‐target/off‐tumor toxicities.…”