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: 10.45). 07/2003; 101(12):4816-22. DOI: 10.1182/blood-2002-06-1731
Source: PubMed


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.

14 Reads
  • Source
    • "Stimulation with HGF led to a significant increase in MET phosphorylation. For total MET expression, we observed two different MET protein bands, the 145 kDa beta-chain and the unprocessed 170 kDa precursor [25] [26] [27]. At all concentrations tested, Foretinib treatment led to a complete decrease in MET phosphorylation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that has emerged as an important cancer target. Consequently, a number of different inhibitors varying in specificity are currently in clinical development. However, to date, it has been difficult to visualize MET expression, intracellular drug distribution and small molecule MET inhibition. Using a bioorthogonal approach, we have developed two companion imaging drugs based on both mono- and polypharmacological MET inhibitors. We show exquisite drug and target co-localization that can be visualized at single-cell resolution. The developed agents may be useful chemical biology tools to investigate single-cell pharmacokinetics and pharmacodynamics of MET inhibitors.
    PLoS ONE 11/2013; 8(11):e81275. DOI:10.1371/journal.pone.0081275 · 3.23 Impact Factor
  • Source
    • "The HGF-HGFR/c-MET pathway is involved in cancer as well. Indeed, the activation of HGFR/c-MET has been reported to trigger cancer cell proliferation, migration and invasion and to promote tumor vessel angiogenesis, since HGF directly stimulates endothelial cell proliferation and migration [73–75]. Aberrant c-MET activation, including gene amplification, mutation, and overexpression, has been found in hematological malignancies and most solid tumors [76], including gastric, liver, and colon cancers [27,77]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The basic idea of displaying peptides on a phage, introduced by George P. Smith in 1985, was greatly developed and improved by McCafferty and colleagues at the MRC Laboratory of Molecular Biology and, later, by Barbas and colleagues at the Scripps Research Institute. Their approach was dedicated to building a system for the production of antibodies, similar to a naïve B cell repertoire, in order to by-pass the standard hybridoma technology that requires animal immunization. Both groups merged the phage display technology with an antibody library to obtain a huge number of phage variants, each of them carrying a specific antibody ready to bind its target molecule, allowing, later on, rare phage (one in a million) to be isolated by affinity chromatography. Here, we will briefly review the basis of the technology and the therapeutic application of phage-derived bioactive molecules when addressed against key players in tumor development and progression: growth factors and their tyrosine kinase receptors.
    International Journal of Molecular Sciences 12/2012; 13(4):5254-77. DOI:10.3390/ijms13045254 · 2.86 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 2.17 Impact Factor
Show more