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.
Highlights
The evolution of numerous types of cancer is associated with the transition to the invasive phase, with the so-called angiogenic switch and metastatic spreading
By analyzing surgical specimens collected from glioblastoma patients, we recently demonstrated that Glioblastoma-associated microglia/macrophages (GAMs) expressed VEGFR-1 and the percentage of VEGFR-1 positive GAMs was higher in the tumor tissue than in the surrounding parenchyma [154]
VEGFR-1 as well VEGFR-2 expression levels in biopsy specimens have been recognized as prognostic factors for patients with cervical cancer: high VEGFR-1 expression was linked to distant metastases, together with poor overall survival (OS) and progression-free survival (PFS), whereas high VEGFR-2 expression correlated with increased tumor size and reduced OS [248]
Summary
The evolution of numerous types of cancer is associated with the transition to the invasive phase, with the so-called angiogenic switch and metastatic spreading. Among the proteins secreted by cancer cells or by cells of the tumor microenvironment that stimulate blood vessel formation, the vascular endothelial growth factors (VEGFs) play a key role in several tumors [1,2,3]. The members of the VEGF family exert their functions by binding and activating membrane receptors that exhibit tyrosine-kinase activity (RTKs), including vascular endothelial growth factor receptor 1 (VEGFR-1/Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4) [18,19] (Figure 1). In blood vascular endothelial cells, VEGF-A signaling is mainly mediated by the activation of VEGFR-2 [20]. PlGF/VEGFR-1 and VEGF-A/VEGFR-1 signaling pathways were later found to be responsible for the neovessel formation associated with a variety of pathologies, including cancer [23,24,25]. Sci. 2020, 21, 1388 pathways which eventually promote cell survival, proliferation, motility, and angiogenesis, both in non-malignant and malignant contexts [51,52,53,54,55]
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