Abstract
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase transmembrane receptor that has also a soluble isoform containing most of the extracellular ligand binding domain (sVEGFR-1). VEGF-A binds to both VEGFR-2 and VEGFR-1, whereas placenta growth factor (PlGF) interacts exclusively with VEGFR-1. In this study we generated an anti-VEGFR-1 mAb (D16F7) by immunizing BALB/C mice with a peptide that we had previously reported to inhibit angiogenesis and endothelial cell migration induced by PlGF. D16F7 did not affect binding of VEGF-A or PlGF to VEGFR-1, thus allowing sVEGFR-1 to act as decoy receptor for these growth factors, but it hampered receptor homodimerization and activation. D16F7 inhibited both the chemotactic response of human endothelial, myelomonocytic and melanoma cells to VEGFR-1 ligands and vasculogenic mimicry by tumor cells. Moreover, D16F7 exerted in vivo antiangiogenic effects in a matrigel plug assay. Importantly, D16F7 inhibited tumor growth and was well tolerated by B6D2F1 mice injected with syngeneic B16F10 melanoma cells. The antitumor effect was associated with melanoma cell apoptosis, vascular abnormalities and decrease of both monocyte/macrophage infiltration and myeloid progenitor mobilization. For all the above, D16F7 may be exploited in the therapy of metastatic melanoma and other tumors or pathological conditions involving VEGFR-1 activation.
Highlights
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor (TKR) that binds to VEGF family members VEGF-A, VEGF-B and placenta growth factor (PlGF) [1, 2]
These data demonstrate that D16F7 mAb possesses antiangiogenic activity and is able to cross-react with murine VEGFR-1
In the present study we described a novel mAb (i.e., D16F7) that recognizes VEGFR-1 and hampers its activation by VEGF-A or the VEGFR-1 specific ligand PlGF
Summary
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor (TKR) that binds to VEGF family members VEGF-A, VEGF-B and placenta growth factor (PlGF) [1, 2]. VEGF-A interacts with VEGFR-2, a TKR responsible for the activation of signal transduction pathways that mediate most VEGF-A biological effects [3]. VEGFR-1 is expressed in endothelial cells, during vessel formation and remodeling, macrophages and myoepithelial cells, favoring cell migration and survival [4,5,6]. It is involved in the mobilization of myeloid bone marrow-derived cells that generate tumorassociated macrophages [1] and is frequently expressed in a variety of human cancers, of which it predicts poor prognosis and recurrence [1, 4]. VEGFR-1 neutralization by an antibody that blocks ligand binding prolongs survival of tumor bearing mice [10]
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