HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro

Ding, Shunli; Merkulova-Rainon, Tatyana; Han, Zhongchao; Tobelem, Gérard

doi:10.1182/blood-2002-06-1731

Cited by 160 publications

(111 citation statements)

References 37 publications

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“…This pathway governs the tumor cell scattering, hence it regulates cell motility and metastatic spread (33). HGF is released by mesenchymal-derived cells, whereas cMET is expressed by several cell types, including vascular endothelial cells (34) and accessory cells (pericytes; ref. 35).…”

Section: Discussionmentioning

confidence: 99%

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

Ferrucci

Moschetta

Frassanito

et al. 2014

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group). Experimental Design: The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo. Results: Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo. Conclusions: An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma. Clin Cancer Res; 20(22); 5796–807. ©2014 AACR.

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Section: Discussionmentioning

confidence: 99%

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

Ferrucci

Moschetta

Frassanito

et al. 2014

Clinical Cancer Research

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“…HGF, originally identified as a growthpromoting factor for mature hepatocytes 42) , is a multi-functional growth factor that simulates the proliferation and migration of endothelial cells and has angiogenic properties 43,44) . The HGF receptor c-Met is expressed in endothelial cells and is up-regulated after switching to angiogenic growth conditions 45) . Endothelial cells with increased c-Met expression were more responsive to HGF 45) .…”

Section: The Effect Of Hgf On Angiogenesis During Bone Regeneration Imentioning

confidence: 99%

“…The HGF receptor c-Met is expressed in endothelial cells and is up-regulated after switching to angiogenic growth conditions 45) . Endothelial cells with increased c-Met expression were more responsive to HGF 45) . HGF implants in mouse subcutaneous tissue and rat corneas have resulted in an in-growth of new blood vessels 46) .…”

Section: The Effect Of Hgf On Angiogenesis During Bone Regeneration Imentioning

confidence: 99%

Combined Administration of BMP-2 and HGF Facilitate Bone Regeneration through Angiogenic Mechanisms

Masuda

Otsu

Kumakami-Sakano

et al. 2015

J. Hard Tissue Biology.

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Promotion of bone repair contributes to the shortening of the treatment period and improvement of the therapeutic effect in large bone defects. The purpose of the present study was to determine the optimal condition for the administration of growth factors to facilitate bone repair and explore the significance of angiogenesis in bone regeneration in vivo. Critical-size calvarial defects were created in the parietal bones of adult ddY mice, and the defects were treated with gelatin sponges impregnated with growth factors BMP-2, FGF-2, and HGF, alone or in combination. The bone regeneration at 1, 2, 3, and 4 weeks was evaluated using micro-computed tomography and histological observation. Critical-size calvarial defects were also created in Flk1-GFP mice to analyze angiogenesis in the early phase of bone repair. The proliferation of Flk1-GFP positive endothelial cells during bone repair was quantitatively evaluated using immunohistochemistry for Ki67. Treatment with a combination of BMP-2 and HGF (BMP-2+HGF) significantly induced more new bone formation within the bone defects compared with the other groups. Compared with BMP-2 alone, bone regeneration was rapidly increased by BMP-2+HGF from 3 weeks of the beginning of the treatment. The number of FLK1-GFP and Ki67 double positive cells in the defect areas of mice administered BMP-2+HGF at 1 week was larger than that in those administered BMP-2 alone. These results indicate that the combination of BMP-2 and HGF was markedly efficient in bone regeneration due to the promotion of angiogenesis in the early phase of bone repair.

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“…30 Endothelial cells undergoing angiogenesis have the highest levels of c-met receptor expression. 42 HGF signals through c-met to regulate endothelial cell survival, proliferation, migration, matrix deposition, and degradation, together with the formation of capillary-like structures. In vivo, HGF stimulates angiogenesis in several animal models of ischemia, with an efficiency similar to, or even greater than that of VEGF-A 165 .…”

Section: Introductionmentioning

confidence: 99%

Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity

Sulpice

Plouët

Bergé

et al. 2008

Blood

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151

130

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Neuropilin-1 and -2 (NRP1 and NRP2) are the transmembrane glycoproteins interacting with 2 types of ligands: class III semaphorins and several members of the VEGF family, the main regulators of blood and lymphatic vessel growth. We show here that both NRP1 and NRP2 can also bind hepatocyte growth factor (HGF). HGF is a pleiotropic cytokine and potent proangiogenic molecule that acts on its target cells by binding to the c-met receptor. We IntroductionNeuropilins (NRPs) are transmembrane glycoproteins that play an important role in various biological processes, including axonal guidance, angiogenesis, tumorigenesis, and the immunologic response. [1][2][3][4] NRPs have been characterized as coreceptors for 2 unrelated families of extracellular secreted ligands-class III semaphorins and several members of the vascular endothelial growth factor (VEGF) family, the main regulators of blood and lymphatic vessel growth. 5 NRP acts in conjunction with membraneassociated signal transducers, such as the VEGF receptor tyrosine kinases (VEGFR-1, -2, and -3) 6,7 and plexins, the transmembrane receptors of the semaphorin family. 8 In higher eukaryotes, 2 neuropilin genes, NRP1 and NRP2, have been identified. 9 They code for proteins displaying about 44% amino-acid sequence identity, with a similar domain structure. 10 Both NRP1 and NRP2 contain a large extracellular region and a short cytoplasmic tail of about 40 amino acids, lacking any enzymatic activity. The extracellular region of neuropilins contains 5 different structural domains-2 CUB motifs, a1 and a2, homologous to complement components C1r/C1s, 2 coagulation factor V/VIII homology domains b1 and b2, and one c domain (MAM, homologous to meprin, A5, ). 11 The high-affinity binding site for VEGF-A 165 has been localized to the b1 and b2 domains of NRP1 12,13 and NRP2, 14 whereas the binding of semaphorins requires both the a1a2 and b1b2 repeats. 12 NRP1 and NRP2 interact selectively with different members of the VEGF and semaphorin families and have nonoverlapping expression patterns. Thus, among the VEGF members, NRP1 binds VEGF-A 165 , VEGF-B, VEGF-E, and placental growth factor (PlGF), whereas NRP2 binds VEGF-A 165 ,VEGF-A 145 , VEGF-C, and PlGF. 15 The non-heparin-binding isoforms of VEGF, such as VEGF-A 121 , have long been considered unable to interact with NRPs. Current evidence suggests, however, that VEGF-A 121 does bind NRP1 via the C-terminal sequence of 6 amino acids encoded by exon 8. [16][17][18][19] During the development of the cardiovascular system, NRP1 is detected primarily in the arterial endothelial cells, and NRP2 is detected in the venous and lymphatic endothelial cells. 20 Genetic studies in mice have shown that both the overexpression of NRP1 21 and the targeted inactivation of the NRP1 gene 22,23 are lethal, provoking, in addition to neuronal defects, disorganization of the vascular network and defects in heart development. Inactivation of the NRP2 gene has less severe consequences, limited to defects in the formation of small lymphatic vessel...

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HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro

Cited by 160 publications

References 37 publications

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

Combined Administration of BMP-2 and HGF Facilitate Bone Regeneration through Angiogenic Mechanisms

Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity

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