Ding S, Merkulova-Rainon T, Han ZC et al.HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood 101:4816-4822

Institut des Vaisseaux et du Sang, Centre de Recherche de l'Association Claude Bernard, Paris, France.
Blood (Impact Factor: 10.43). 07/2003; 101(12):4816-22. DOI: 10.1182/blood-2002-06-1731
Source: PubMed

ABSTRACT Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic growth factor and a powerful stimulator of angiogenesis, which acts on cells by binding to the c-met receptor. The exact role of the endogenous HGF/c-met system in one or more steps of the angiogenic process is not completely understood. To contribute to this question we used immunocytochemical analysis, Western blotting, and reverse transcription-polymerase chain reaction to study the expression of c-met in endothelial cells cultured in different growth conditions. We found that c-met is not colocalized with vascular endothelial (VE)-cadherin in cell-cell junctions. c-met and VE-cadherin were shown to be inversely regulated by cell density, at both the protein and the mRNA levels. We established that c-met is up-regulated during the in vitro recapitulation of several steps of angiogenesis. The c-met expression was increased shortly after switching to angiogenic growth conditions and remained high during the very first steps of angiogenesis, including cell migration, and cell proliferation. The endothelial cells in which the expression of c-met was up-regulated were more responsive to HGF and exhibited a higher rate of morphogenesis. Moreover, the antibody directed against the extracellular domain of the c-met inhibited angiogenesis in vitro. Our results suggest that c-met is a marker of angiogenic phenotype for endothelial cells and represents an attractive target for the development of new antiangiogenic therapies.

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    • "c- Met, a tyrosine kinase receptor that binds HGF (Jiang et al. 2005), also interacts with NRP1. Hepatocyte growth factor ⁄ c-met signalling plays a vital role in the development and regeneration of several organ systems (Birchmeier et al. 2003) and regulation of endothelial cell survival, proliferation and migration (Ding et al. 2003). Recent studies have demonstrated that NRP1 and NRP2 act as a functional co-receptor for HGF, enhancing HGF ⁄ c-met binding and Figure 4 Vascular endothelial growth factor (VEGF) interaction with VEGF-R2 and neuropilin-1 (NRP-1) and downstream signalling. "
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    ABSTRACT: Initially found expressed in neuronal and then later in endothelial cells, it is well established that the transmembrane glycoproteins neuropilin-1 (NRP1) and neuropilin-2 (NRP2) play essential roles in axonal growth and guidance and in physiological and pathological angiogenesis. Neuropilin expression and function in epithelial cells has received little attention when compared with neuronal and endothelial cells. Overexpression of NRPs is shown to enhance growth, correlate with invasion and is associated with poor prognosis in various tumour types, especially those of epithelial origin. The contribution of NRP and its ligands to tumour growth and metastasis has spurred a strong interest in NRPs as novel chemotherapy drug targets. Given NRP's role as a multifunctional co-receptor with an ability to bind with disparate ligand families, this has sparked new areas of research implicating NRPs in diverse biological functions. Here, we review the growing body of research demonstrating NRP expression and role in the normal and neoplastic epithelium.
    International Journal of Experimental Pathology 04/2012; 93(2):81-103. DOI:10.1111/j.1365-2613.2012.00810.x · 2.05 Impact Factor
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    • "c-Met belongs to a subfamily of receptor tyrosine kinases (RTKs) [15]. The activation of c-Met has been reported to trigger cancer cell proliferation, migration and invasion [16], and promote tumor vessel angiogenesis [17] because HGF directly stimulates endothelial cell proliferation and migration [18]. Aberrant c-Met activation , including gene amplification, mutation, and overexpression, has been found in clinical cases involving hematological malignancies and most solid tumors [19]. "
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    ABSTRACT: Aberrantly expressed c-Met, the receptor for hepatocyte growth factor (HGF), has been implicated in human lung cancer as well as malignancy, metastasis and drug-resistance in other human cancers. Thus, this molecule could be a potential target for antibody-based cancer therapy. Targeting delivery of compound to tumor represented benefit for cancer detection and therapy. In this study, we utilized phage display to identify human single chain variable fragment (scFv) antibodies that specifically bound to c-Met protein. The anti-c-Met scFvs selectively bound to and internalized in several lung cancer cell lines expressing c-Met. Conjugation of anti-c-Met scFv with PEGylated liposomes enabled the efficient delivery of doxorubicin into cancer cells where it exerted cytotoxic activity by inducing apoptosis pathway. In addition, in vivo fluorescent imaging by scFv-conjugated quantum dots showed higher tumor uptake and increased tumor-normal tissue ratios. In a tumor xenograft model, anti-c-Met immunoliposome was found to selectively increase tumor accumulation of a chemotherapeutic drug and enhance its antitumor activity. Taken together, our results suggest that anti-c-Met scFv-mediated drug delivery systems show great promise in tumor-targeted therapy and imaging.
    Biomaterials 02/2011; 32(12):3265-74. DOI:10.1016/j.biomaterials.2010.12.061 · 8.31 Impact Factor
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    • "HGF activates migration and proliferation of endothelial cells and induces angiogenesis . The angiogenic activity of HGF is mediated through its direct actions on endothelial cells [3] [4], and its indirect actions that occur through an increase of endothelial cell mitogens [4] [5]. Because of this angiogenic activity, HGF is known to improve coronary and peripheral artery diseases [6] [7]. "
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    ABSTRACT: The effects of IL-17A on mucin production and growth of airway epithelial cells were examined. Histological and immunohistochemical analyses revealed that IL-17A increased the mucin production and number of tracheal epithelial cells in air-liquid interface cultures. The biological property of IL-17A to stimulate the mucin production by tracheal epithelial cells was determined using an ELISA. The mitogenic effect of IL-17A on tracheal epithelial cells was confirmed with Calcein-AM assay. The growth-stimulatory effect of IL-17A was dose-dependent and mediated via the ERK MAP kinase pathway. Inhibitors of MEK abrogated the mitogenic effect of IL-17A, whereas an inhibitor of p38 or JNK displayed no significant inhibitory effect. Moreover, relatively lower doses of IL-13 also significantly increased the growth of tracheal epithelial cells through a distinct signaling pathway from that of IL-17A. These findings provide the first evidence that IL-17A stimulates the growth of airway epithelial cells through the ERK MAP kinase pathway.
    Biochemical and Biophysical Research Communications 10/2006; 347(4):852-8. DOI:10.1016/j.bbrc.2006.06.137 · 2.28 Impact Factor
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