The Anti-Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1) D16F7 Monoclonal Antibody Inhibits Melanoma Adhesion to Soluble VEGFR-1 and Tissue Invasion in Response to Placenta Growth Factor

SIMPLE SUMMARY: Melanoma is an aggressive cancer type with a high tendency to spread to distant body sites, including bones. Despite the availability of effective therapies, many patients still do not fully benefit from treatment. The aim of our study was to evaluate the therapeutic potential of inhibiting the activation of the vascular endothelial growth factor receptor (VEGFR-1) by placenta growth factor (PlGF) using an investigational anti-VEGFR-1 monoclonal antibody (D16F7 mAb). The VEGFR-1 receptor is expressed by endothelial cells of blood vessels that nourish the tumor, protumoral macrophages and melanoma cells. Results indicate that PlGF stimulates the ability of melanoma to infiltrate the surrounding tissues and that treatment with D16F7 mAb counteracts melanoma properties, which contribute to tumor spread, reducing the invasiveness of the tumor and its tropism toward bone tissue. Therefore, blockade of VEGFR-1 stimulation by PlGF represents a suitable strategy to restrain the metastatic potential of melanoma. ABSTRACT: Placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family involved in tumor-associated angiogenesis and melanoma invasion of the extra-cellular matrix (ECM) through activation of membrane VEGF receptor 1 (VEGFR-1). A soluble VEGFR-1 (sVEGFR-1) form is released in the ECM, where it sequesters proangiogenic factors and stimulates endothelial or tumor cell adhesion and chemotaxis through interaction with α5β1 integrin. The anti-VEGFR-1 monoclonal antibody (D16F7 mAb) inhibits VEGF-A or PlGF-mediated signal transduction without affecting ligand interaction, thus preserving sVEGFR-1 decoy function. The aim of this study was to investigate whether D16F7 mAb hampers melanoma spread by in vitro analysis of cell adhesion to sVEGFR-1, ECM invasion, transmigration through an endothelial cell monolayer and in vivo evaluation of tumor infiltrative potential in a syngeneic murine model. Results indicate that D16F7 mAb significantly inhibits melanoma adhesion to sVEGFR-1 and ECM invasion, as well as transmigration in response to PlGF. Moreover, treatment of melanoma-bearing mice with the anti-VEGFR-1 mAb not only inhibits tumor growth but also induces a significant reduction in bone infiltration associated with a decrease in PlGF-positive melanoma cells. Furthermore, D16F7 mAb reduces PlGF production by melanoma cells. Therefore, blockade of PLGF/VEGFR-1 signaling represents a suitable strategy to counteract the metastatic potential of melanoma.