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

2020 ◽  
Vol 21 (4) ◽  
pp. 1388 ◽  
Author(s):  
Claudia Ceci ◽  
Maria Grazia Atzori ◽  
Pedro Miguel Lacal ◽  
Grazia Graziani
Keyword(s):  
Growth Factor ◽  
Immune Escape ◽  
Metastatic Cancer ◽  
Membrane Receptors ◽  
Pathological Angiogenesis ◽  
Tumor Endothelium ◽  
Vegf Family Members ◽  
Preclinical And Clinical Studies ◽  
Tumor Types ◽  
Endothelial Growth Factor

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.

scholarly journals Application of nintedanib and other potential anti-fibrotic agents in fibrotic diseases

2019 ◽  
Vol 133 (12) ◽  
pp. 1309-1320 ◽  
Author(s):  
Feng Liu ◽  
George Bayliss ◽  
Shougang Zhuang
Keyword(s):  
Growth Factor ◽  
Animal Models ◽  
Epithelial Mesenchymal Transition ◽  
Growth Factor Receptor ◽  
Growth Factor Receptors ◽  
Inhibitory Effect ◽  
Mesenchymal Transition ◽  
Fibrotic Diseases ◽  
Preclinical And Clinical Studies ◽  
Endothelial Growth Factor

Abstract Nintedanib, a Food and Drug Administration-approved drug for the treatment of patients with idiopathic pulmonary fibrosis (IPK), inhibits both tyrosine kinase receptors and non-receptor kinases, and block activation of platelet-derived growth factor receptors, fibroblast growth factor receptor, vascular endothelial growth factor receptors, and Src family kinases. Preclinical and clinical studies have revealed the potent anti-fibrotic effect of nintedanib in IPK in human and animal models. Recent preclinical studies have also demonstrated the inhibitory effect of nintedanib on the development and progression of tissue fibrosis in other organs, including liver, kidney, and skin. The anti-fibrotic actions of nintedanib occur through a number of mechanisms, including blocking differentiation of fibroblasts to myofibroblasts, inhibition of epithelial–mesenchymal transition, and suppression of inflammation and angiogenesis. In this article, we summarize the mechanisms and efficacy of nintedanib in the treatment of fibrotic diseases in animal models and clinical trials, provide an update on recent advances in the development of other novel antifibrotic agents in preclinical and clinical study, and offer our perspective about the possible clinical application of these agents in fibrotic diseases.

scholarly journals An unexpected tail of VEGF and PlGF in pre-eclampsia

2011 ◽  
Vol 39 (6) ◽  
pp. 1576-1582 ◽  
Author(s):  
David O. Bates
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Activation ◽  
Placental Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Physiological Changes ◽  
Vegf Family Members ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms

PET (pre-eclamptic toxaemia), characterized by pregnancy-related hypertension and proteinuria, due to widespread endothelial dysfunction, is a primary cause of maternal morbidity. Altered circulating factors, particularly the VEGF (vascular endothelial growth factor) family of proteins and their receptors, are thought to be key contributors to this disease. Plasma from patients with PET induces numerous cellular and physiological changes in endothelial cells, indicating the presence of a circulating imbalance of the normal plasma constituents. These have been narrowed down to macromolecules of the VEGF family of proteins and receptors. It has been shown that responses of endothelial cells in intact vessels to plasma from patients with pre-eclampsia is VEGF-dependent. It has recently been shown that this may be specific to the VEGF165b isoform, and blocked by addition of recombinant human PlGF (placental growth factor). Taken together with results that show that sVEGFR1 (soluble VEGF receptor 1) levels are insufficient to bind VEGF-A in human plasma from patients with pre-eclampsia, and that other circulating macromolecules bind, but do not inactivate, VEGF-A, this suggests that novel hypotheses involving altered bioavailability of VEGF isoforms resulting from reduced or bound PlGF, or increased sVEGFR1 increasing biological activity of circulating plasma, could be tested. This suggests that knowing how to alter the balance of VEGF family members could prevent endothelial activation, and potentially some symptoms, of pre-eclampsia.

scholarly journals Utility of Vascular Endothelial Growth Factor Inhibitors in the Treatment of Ovarian Cancer: From Concept to Application

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Afshin Amini ◽  
Samar Masoumi Moghaddam ◽  
David L. Morris ◽  
Mohammad H. Pourgholami
Keyword(s):  
Ovarian Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Treatment Options ◽  
Malignant Ascites ◽  
Vascular Endothelial ◽  
Chemotherapeutic Drugs ◽  
Gynecologic Malignancy ◽  
Preclinical And Clinical Studies ◽  
Endothelial Growth Factor

Despite recent advances in the management of ovarian cancer, it remains the most lethal gynecologic malignancy. Vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in the progression of ovarian cancer leading to the eventual development of malignant ascites. On this basis, agents rendering VEGF ineffective by neutralizing VEGF (bevacizumab), blocking its receptors (aflibercept), or interfering with the postreceptor signaling pathways (sunitinib) provide us with the rational treatment options. These agents are generally used in combination with the standard chemotherapeutic drugs. Here, we discuss the basis of and the logic behind the use of these agents in the treatment of epithelial ovarian cancer, as well as their evaluation in different preclinical and clinical studies.

scholarly journals Intraocular injection of KH902 alleviates retinal hypoxia in a mouse model of oxygen-induced retinopathy

2021 ◽  
pp. 38-38
Author(s):  
Ning Yang ◽  
Xuejun He ◽  
Ningzhi Zhang ◽  
Yiqiao Xing
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Mouse Model ◽  
Vascular Endothelial ◽  
Ocular Diseases ◽  
Vegf Expression ◽  
Pathological Angiogenesis ◽  
Intraocular Injection ◽  
Oxygen Induced Retinopathy ◽  
Endothelial Growth Factor

Inhibition of vascular endothelial growth factor (VEGF) has been widely applied in antineovascularization therapies. As a novel anti-VEGF agent, KH902 (conbercept) is designed to restrain pathological angiogenesis. However, the effects of KH902 on retinal hypoxia have not been well studied. In a mouse model of oxygen-induced retinopathy (OIR), we assessed retinal hypoxia at postnatal days 14 (P14) and P17, as well as retinal neovascularization (RNV) at P17. In addition, we evaluated the protein level of VEGF and galectin-1 (Gal-1). Changes of the neuroretinal structure were also examined. Our results indicated that KH902 could remit retinal hypoxia in OIR at P14 and P17, which was an exciting novel finding for KH902 function. Additionally, we confirmed that KH902 markedly reduces RNV. Our results indicated that administration of KH902 downregulated VEGF expression, as well as Gal-1. Damage of neuroretinal structure after KH902 injection was not observed, which was also an encouraging result. Our study suggests that KH902 plays a role in alleviating retinal hypoxia and that it could be used for the treatment of other neovascular ocular diseases.

scholarly journals The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Christian SM Helker ◽  
Annika Schuermann ◽  
Cathrin Pollmann ◽  
Serene C Chng ◽  
Friedemann Kiefer ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
De Novo ◽  
Vascular Endothelial ◽  
Pathological Angiogenesis ◽  
Medial Migration ◽  
Apelin Receptor ◽  
Endothelial Growth Factor ◽  
Endothelial Precursors ◽  
Hormonal Peptide

A key step in the de novo formation of the embryonic vasculature is the migration of endothelial precursors, the angioblasts, to the position of the future vessels. To form the first axial vessels, angioblasts migrate towards the midline and coalesce underneath the notochord. Vascular endothelial growth factor has been proposed to serve as a chemoattractant for the angioblasts and to regulate this medial migration. Here we challenge this model and instead demonstrate that angioblasts rely on their intrinsic expression of Apelin receptors (Aplr, APJ) for their migration to the midline. We further show that during this angioblast migration Apelin receptor signaling is mainly triggered by the recently discovered ligand Elabela (Ela). As neither of the ligands Ela or Apelin (Apln) nor their receptors have previously been implicated in regulating angioblast migration, we hereby provide a novel mechanism for regulating vasculogenesis, with direct relevance to physiological and pathological angiogenesis.

scholarly journals Capillary Morphogenesis gene 2 mediates multiple pathways of growth factor-induced angiogenesis by regulating endothelial cell chemotaxis

2019 ◽  
Author(s):  
Lorna Cryan ◽  
Tsz-Ming Tsang ◽  
Jessica Stiles ◽  
Lauren Bazinet ◽  
Sai Lun Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Corneal Neovascularization ◽  
Tube Formation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
The Novel ◽  
Capillary Morphogenesis ◽  
Pathological Angiogenesis ◽  
Endothelial Tube Formation ◽  
Endothelial Growth Factor

AbstractPathological angiogenesis contributes to diseases as varied as cancer and corneal neovascularization. The vascular endothelial growth factor (VEGF) - VEGF receptor 2 (KDR/VEGFR2) axis has been the major target for treating pathological angiogenesis. However, VEGF-targeted therapies exhibit reduced efficacy over time, indicating that new therapeutic strategies are needed. Therefore, identifying new targets that mediate angiogenesis is of great importance. Here, we report that one of the anthrax toxin receptors, capillary morphogenesis gene 2 (ANTXR2/CMG2), plays an important role in mediating angiogenesis induced by both bFGF and VEGF. Inhibiting physiological ligand binding to CMG2 results in significant reduction of corneal neovascularization, endothelial tube formation and cell migration. We also report the novel finding that CMG2 mediates angiogenesis by regulating the direction of endothelial chemotactic migration without affecting overall cell motility.

Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and gemcitabine/cisplatin (GC) for the treatment of advanced solid malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13005-13005 ◽  
Author(s):  
J. Crawford ◽  
H. A. Burris III ◽  
M. Stein ◽  
J. Stephenson ◽  
J. Gilbert ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
Human Monoclonal Antibody ◽  
Growth Factor Receptor ◽  
Dose Finding ◽  
Prior Chemotherapy Regimen ◽  
Finding Study ◽  
History Of ◽  
Tumor Types ◽  
Endothelial Growth Factor

13005 Background: AMG 706 is an investigational, oral, multi-kinase inhibitor with both antiangiogenic and direct antitumor activity targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Kit receptors. Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr) and has shown efficacy and tolerability in pts with solid tumors. The primary objectives of the first part of this multicenter, 2-part, dose-finding study were to establish the safety and tolerability of AMG 706 + panitumumab with GC. Secondary objectives included PK of all agents. Methods: Pts were sequentially enrolled in 1 of 5 AMG 706 dose cohorts: no AMG 706, 50 mg, 75 mg, 100 mg, and 125 mg QD; all pts received panitumumab (9 mg/kg i.v. on day 1), G (1250 mg/m2 i.v. on days 1 and 8), and C (75 mg/m2 i.v. on day 1) Q3W. Pts had advanced cancer for which GC is indicated, ECOG of 0 or 1, no symptomatic or untreated CNS metastases, no history of venous thrombosis, and no more than 1 prior chemotherapy regimen for advanced disease. Results: As of 8/05, 15 pts were enrolled (n = 7, no AMG 706; n = 8, AMG 706 50 mg QD). Baseline characteristics included 8M/7F, median (range) age of 61 (32, 72) years, 9 with ECOG 0 and 6 with ECOG 1. Tumor types included: non-small cell lung (8), pancreatic (3), esophageal (2), ovarian (1), and unknown (1). Safety for all 15 pts is presented (see table ). The PK of AMG 706 at 50 mg when coadministered with panitumumab/GC was similar to the PK for AMG 706 monotherapy at the same dose. Conclusions: These data suggest that AMG 706 can be safely combined with panitumumab and GC with no effect on the PK of AMG 706 at 50 mg QD. Updated safety and PK data will be presented. [Table: see text] [Table: see text]

PlGF and sVEGFR-1 in chronic subdural hematoma: implications for hematoma development

2013 ◽  
Vol 118 (2) ◽  
pp. 353-357 ◽  
Author(s):  
Theodosis Kalamatianos ◽  
Lampis C. Stavrinou ◽  
Christos Koutsarnakis ◽  
Christina Psachoulia ◽  
Damianos E. Sakas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Subdural Hematoma ◽  
Chronic Subdural Hematoma ◽  
Serum Levels ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Pathological Angiogenesis ◽  
Enhanced Expression ◽  
Endothelial Growth Factor

Object A considerable body of evidence indicates that inflammation and angiogenesis play a significant role in the development and progression of chronic subdural hematoma (CSDH). While various experimental and clinical studies have implicated placental growth factor (PlGF) in the processes that underpin pathological angiogenesis, no study has thus far investigated its expression in CSDH. The actions of PlGF and its related proangiogenic vascular endothelial growth factor (VEGF) are antagonized by a high-affinity soluble receptor, namely soluble VEGF receptor–1 (sVEGFR-1), and thus the ratio between sVEGFR-1 and angiogenic factors provides an index of angiogenic capacity. Methods In the present study, using an automated electrochemiluminescence assay, levels of PlGF and sVEGFR-1 were quantified in serum and hematoma fluid obtained in 16 patients with CSDH. Results Levels of PlGF and sVEGFR-1 were significantly higher in hematoma fluid than in serum (p < 0.0001). In serum, levels of sVEGFR-1 were higher than those of PlGF (p < 0.0001), whereas in hematoma fluid this difference was not apparent. Furthermore, the ratio of sVEGFR-1 to PlGF was significantly lower in hematoma fluid than in serum (p < 0.0001). Conclusions Given previous evidence indicating a role for PlGF in promoting angiogenesis, inflammatory cell chemotaxis, and stimulation, as well as its ability to amplify VEGF-driven signaling under conditions favoring pathological angiogenesis, enhanced expression of PlGF in hematoma fluid suggests the involvement of this factor in the mechanisms of inflammation and angiogenesis in CSDH. Furthermore, a reduced ratio of sVEGFR-1 to PlGF in hematoma fluid is consistent with the proangiogenic capacity of CSDH. Future studies are warranted to clarify the precise role of PlGF and sVEGFR-1 in CSDH.

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