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

Abstract

The vascular endothelial growth factor (VEGF) family members, VEGF-A, placenta growth factor (PlGF), and to a lesser extent VEGF-B, play an essential role in tumor-associated angiogenesis, tissue infiltration, and metastasis formation. Although VEGF-A can activate both VEGFR-1 and VEGFR-2 membrane receptors, PlGF and VEGF-B exclusively interact with VEGFR-1. Differently from VEGFR-2, which is involved both in physiological and pathological angiogenesis, in the adult VEGFR-1 is required only for pathological angiogenesis. Besides this role in tumor endothelium, ligand-mediated stimulation of VEGFR-1 expressed in tumor cells may directly induce cell chemotaxis and extracellular matrix invasion. Furthermore, VEGFR-1 activation in myeloid progenitors and tumor-associated macrophages favors cancer immune escape through the release of immunosuppressive cytokines. These properties have prompted a number of preclinical and clinical studies to analyze VEGFR-1 involvement in the metastatic process. The aim of the present review is to highlight the contribution of VEGFs/VEGFR-1 signaling in the progression of different tumor types and to provide an overview of the therapeutic approaches targeting VEGFR-1 currently under investigation.

Keywords: Flt-1; PlGF; VEGF-A; VEGFR-1; angiogenesis; cancer; immune escape; melanoma; metastasis.

Figure 1

VEGF family members and their receptors. VEGF-A proangiogenic signaling is mediated via interaction with VEGFR-2 or VEGFR-1. The soluble VEGFR-1 form (sVEGFR-1) functions as a decoy receptor, preventing membrane receptor activation. VEGF-B and PlGF only bind to VEGFR-1, playing a key role in pathological angiogenesis and inflammation. Furthermore, VEGFR-1 activation contributes to the recruitment of tumor-associated macrophages (TAMs) and cancer immune escape. VEGFR-1 and VEGFR-2 activation in tumor cells directly stimulates migration and extracellular matrix (ECM) invasion. VEGF-C and VEGF-D mainly activate VEGFR-3, which is required for developmental and pathological lymphangiogenesis. The VEGF-E, a selective VEGFR-2 ligand, and VEGF-F, a VEGFR-1 and VEGFR-2 ligand, have been omitted from the drawing; VEGF-E is a VEGF homolog of viral origin and VEGF-F is a snake venom VEGF.