Roger Vassy
University of Paris
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Featured researches published by Roger Vassy.
The EMBO Journal | 2000
Roselyne Binétruy-Tournaire; Caroline Demangel; Bernard Malavaud; Roger Vassy; Sylvie Rouyre; Michel Kraemer; Jean Plouët; Claude Derbin; Gérard Y Perret; Jean Claude Mazie
Vascular endothelial growth factor (VEGF) binding to the kinase domain receptor (KDR/FLK1 or VEGFR‐2) mediates vascularization and tumor‐induced angiogenesis. Since there is evidence that KDR plays an important role in tumor angiogenesis, we sought to identify peptides able to block the VEGF–KDR interaction. A phage epitope library was screened by affinity for membrane‐expressed KDR or for an anti‐VEGF neutralizing monoclonal antibody. Both strategies led to the isolation of peptides binding KDR specifically, but those isolated by KDR binding tended to display lower reactivities. Of the synthetic peptides corresponding to selected clones tested to determine their inhibitory activity, ATWLPPR completely abolished VEGF binding to cell‐displayed KDR. In vitro, this effect led to the inhibition of the VEGF‐mediated proliferation of human vascular endothelial cells, in a dose‐dependent and endothelial cell type‐specific manner. Moreover, in vivo, ATWLPPR totally abolished VEGF‐induced angiogenesis in a rabbit corneal model. Taken together, these data demonstrate that ATWLPPR is an effective antagonist of VEGF binding, and suggest that this peptide may be a potent inhibitor of tumor angiogenesis and metastasis.
Blood | 2009
Sophie Lambert; Manuella Bouttier; Roger Vassy; Michel Seigneuret; Cari Petrow-Sadowski; Sébastien Janvier; Nikolaus Heveker; Francis W. Ruscetti; Gérard Y Perret; Kathryn S. Jones; Claudine Pique
Human T-cell lymphotropic virus type 1 (HTLV-1) entry involves the interaction between the surface (SU) subunit of the Env proteins and cellular receptor(s). Previously, our laboratories demonstrated that heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), a receptor of VEGF(165), are essential for HTLV-1 entry. Here we investigated whether, as when binding VEGF(165), HSPGs and NRP-1 work in concert during HTLV-1 entry. VEGF(165) binds to the b domain of NRP-1 through both HSPG-dependent and -independent interactions, the latter involving its exon 8. We show that VEGF(165) is a selective competitor of HTLV-1 entry and that HTLV-1 mimics VEGF(165) to recruit HSPGs and NRP-1: (1) the NRP-1 b domain is required for HTLV-1 binding; (2) SU binding to target cells is blocked by the HSPG-binding domain of VEGF(165); (3) the formation of Env/NRP-1 complexes is enhanced by HSPGs; and (4) the HTLV SU contains a motif homologous to VEGF(165) exon 8. This motif directly binds to NRP-1 and is essential for HTLV-1 binding to, internalization into, and infection of CD4(+) T cells and dendritic cells. These findings demonstrate that HSPGs and NRP-1 function as HTLV-1 receptors in a cooperative manner and reveal an unexpected mimicry mechanism that may have major implications in vivo.
Journal of Biological Chemistry | 2006
Andrew C. Lake; Roger Vassy; Mélanie Di Benedetto; Damien Lavigne; Catherine Le Visage; Gérard Y Perret; Didier Letourneur
Therapeutic induction of angiogenesis is a potential treatment for chronic ischemia. Heparan sulfate proteoglycans are known to play an important role by their interactions with proangiogenic growth factors such as vascular endothelial growth factor (VEGF). Low molecular weight fucoidan (LMWF), a sulfated polysaccharide from brown seaweeds that mimic some biological activities of heparin, has been shown recently to promote revascularization in rat critical hindlimb ischemia. In this report, we first used cultured human endothelial cells (ECs) to investigate the possible ability of LMWF to enhance the actions of VEGF165. Data showed that LMWF greatly enhances EC tube formation in growth factor reduced matrigel. LMWF is a strong enhancer of VEGF165-induced EC chemotaxis, but not proliferation. In addition, LMWF has no effect on VEGF121-induced EC migration, a VEGF isoform that does not bind to heparan sulfate proteoglycans. Then, with binding studies using 125I-VEGF165, we observed that LMWF enhances the binding of VEGF165 to recombinant VEGFR-2 and Neuropilin-1 (NRP1), but not to VEGFR-1. Surface plasmon resonance analysis showed that LMWF binds with high affinity to VEGF165 (1.2 nm) and its receptors (5-20 nm), but not to VEGF121. Pre-injection of LMWF on immobilized receptors shows that VEGF165 has the highest affinity for VEGFR-2 and NRP1, as compared with VEGFR-1. Overall, the effects of LMWF were much more pronounced than those of LMW heparin. These findings suggested an efficient mechanism of action of LMWF by promoting VEGF165 binding to VEGFR-2 and NRP1 on ECs that could help in stimulating therapeutic revascularization.
Biochimica et Biophysica Acta | 2009
Laure Bachelet; Isabelle Bertholon; Damien Lavigne; Roger Vassy; Martine Jandrot-Perrus; Frédéric Chaubet; Didier Letourneur
BACKGROUND P-selectin is an adhesion receptor expressed on activated platelets and endothelial cells. Its natural ligand, P-selectin glycoprotein ligand-1, is expressed on leucocytes and the P-selectin/PSGL-1 interaction is involved in leukocyte rolling. We have compared the interaction of P-selectin with several low molecular weight polysaccharides: fucoidan, heparin and dextran sulfate. METHODS Binding assays were obtained from the interaction of the polysaccharides with Sialyl Lewis X and PSGL-1 based constructs onto microtiter plates coated with P-selectin. SELDI TOF mass spectrometry was performed with anionic chips arrays coated with P-selectin in the absence or in the presence of polysaccharides. Kd were obtained from surface plasmon resonance experiments with immobilized P-selectin constructs, polysaccharides being injected in the mobile phase. Human whole blood flow cytometry experiments were performed with fluorescein isothiocyanate labelled polysaccharides with or without platelets activators. RESULTS The fucoidan prevented P-selectin binding to Sialyl Lewis X with an IC(50) of 20 nM as compared to 400 nM for heparin and <25000 nM for dextran sulfate. It exhibited the highest affinity for immobilized P-selectin with a KD of 1.2 nM, two orders of magnitude greater than the K(D) of the other polysaccharides. Mass spectrometry evidenced the formation of a complex between P-selectin and fucoidan. The intensity of the fucoidan binding to platelets was dependent on the level of platelet activation. Competition between fucoidan and an anti P-selectin antibody demonstrated the specificity of the interaction. GENERAL SIGNIFICANCE Low molecular weight fucoidan is a promising therapeutic agent of natural origin for biomedical applications.
Peptides | 2007
Anna Starzec; Patrick Ladam; Roger Vassy; Sabah Badache; Nadia Bouchemal; Alda Navaza; Catherine Hervé du Penhoat; Gérard Y Perret
Heptapeptide ATWLPPR (A7R), identified in our laboratory by screening a mutated phage library, was shown to bind specifically to neuropilin-1 (NRP-1) and then to selectively inhibit VEGF(165) binding to this receptor. In vivo, treatment with A7R resulted in decreasing breast cancer angiogenesis and growth. The present work is focused on structural characterization of A7R. Analogs of the peptide, obtained by substitution of each amino acid with alanine (alanine-scanning) or by amino acid deletion, have been systematically assayed to determine the relative importance of the side chains of each residue with respect to the inhibitory effect of A7R on VEGF(165) binding to NRP-1. We show here the importance of the C-terminal sequence LPPR and particularly the key role of C-terminal arginine. In solution, A7R displays significant secondary structure of the backbone adopting an extended conformation. However, the functional groups of arginine are very flexible in the absence of NRP-1 pointing to an induced fit upon binding to the receptor. A MD trajectory of the A7R/NRP-1 complex in explicit water, based on the recent tuftsin/NRP-1 crystal structure, has revealed the hydrogen-bonding network that contributes to A7Rs binding activity.
International Journal of Cancer | 2009
Maylis Dagouassat; Nadine Suffee; Hanna Hlawaty; Oualid Haddad; Faten Charni; Christelle Laguillier; Roger Vassy; Loı̈c Martin; Pierre-Olivier Schischmanoff; Liliane Gattegno; Olivier Oudar; Angela Sutton; Nathalie Charnaux
The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein‐1 (MCP‐1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP‐1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell‐conditioned medium (LI90‐CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP‐1/CCL2‐depleted LI90‐CM was used. We showed that MCP‐1/CCL2 induces Huh7 cell migration and invasion through its G‐protein–coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP‐1/CCL2 concentrations. MCP‐1/CCL2s chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)‐2 and MMP‐9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by β‐D‐xyloside treatment of cells and by anti‐syndecan‐1 and ‐4 antibodies. Finally, we developed a 3‐dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP‐1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma‐myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast‐derived MCP‐1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma.
British Journal of Pharmacology | 1997
Renée Germack; Anna Starzec; Roger Vassy; Gérard Y Perret
The pharmacological features of rat white adipocyte β‐adrenoceptor subtypes were investigated by saturation and β‐agonist competition studies with [3H]‐CGP 12177 and by lipolysis induced by β‐agonists as well as their inhibition by CGP 20712A (selective β1‐antagonist) and ICI 118551 (selective β2‐antagonist) in an attempt to establish a relationship between the functionality and binding capacity of β‐adrenoceptor subtypes. Two populations of binding sites were identified on adipocyte membranes, one with high affinity (0.22±0.07 nm) and the other with low affinity (23±7 nm). The low affinity binding sites constituted 90% of the total binding sites. The competition curves, with 15 nm [3H]‐CGP 12177, for the β‐agonists, isoprenaline (Iso), noradrenaline (NA) and adrenaline (Ad), and the selective β3‐agonist, BRL 37344 (BRL), were clearly biphasic (P<0.001). The rank orders of agonist potency (pKi) in competing for [3H]‐CGP 12177 high affinity and low affinity binding sites, respectively, were Iso (9.28±0.24)>NA (8.90±0.12)>Ad (8.65±0.12)>>BRL (4.53±0.17) and BRL (7.38±0.19)>>Iso (2.96±0.26)NA (2.80±0.17)>Ad (2.10±0.11) indicating the expression of β1‐ and β3‐adrenoceptor subtypes on rat white adipocytes, respectively. Inversely, competition studies with the selective β1‐agonist, xamoterol (Xam), provided evidence for a single homogeneous population of binding sites with low density (81±9 fmol mg−1) and high pKi value (7.23±0.26) confirming the presence of β1‐adrenoceptors. To assess a possible contribution of the β2‐subtype, procaterol (Proc), a selective β2‐agonist, was used to compete with 2 nm [3H]‐CGP 12177. A single low affinity (4.61±0.07) population of binding sites was identified. The density of these sites (71±12 fmol mg−1) was similar to the one obtained with Xam, suggesting that Proc displaced [3H]‐CGP 12177 from the β1‐subtype. The functional potency (pD2) order with BRL (9.07±0.20) and catecholamines (Iso: 7.26±0.06, NA: 6.89±0.02 and Ad: 6.32±0.07) was the same as that found for the low affinity binding sites in competition studies. Xam induced lipolysis with greater potency than dobutamine (Dob), 6.31±0.06 and 5.66±0.10, respectively. Proc stimulated lipolysis with a low potency (5.59±0.21). The lipolytic response to 0.001 μm BRL was inhibited by both, selective β1‐ and β2‐antagonist, in a monophasic manner with low potencies (CGP 20712A pKi: <4.5 and ICI 118551 pKi: 5.57±0.13). Similar monophasic profiles were obtained for inhibition of Xam‐ and Dob‐induced lipolysis. In this case, CGP 20712A was more potent (>10 times) than ICI 118551. The monophasic inhibition was also observed with ICI 118551 in the presence of 0.05 μm Iso or 0.13 μm NA. In contrast, two populations of sites were identified with CGP 20712A in the presence of Iso as well as NA. The pKi values for the first sites were 8.41±0.09 and 8.58±0.17, respectively, and for the second population of sites 4.73±0.22 and 4.27±0.27, respectively. The proportion of the first sites was low: 19±4 and 22±5%, respectively. Biphasic curves were obtained with both antagonists using 2.5 μm Proc (CGP 20712A: pKi1: 8.17±0.08, site1: 23±6%, pKi2: 4.77±0.14; ICI 118551: pKi1: 7.78±0.03, site1: 37±2%, pKi2: 5.35±0.25). Our results show that the radioligand [3H]‐CGP 12177 allows the characterization of β1‐ and β3‐adrenoceptor subtypes on rat white adipocytes. Lipolysis is highly dependent on β1‐ and β3‐adrenoceptors. Finally, binding and functional studies confirm that lipolysis is mainly driven by the β3‐subtype.
Biochimica et Biophysica Acta | 2009
Faten Charni; Véronique Friand; Oualid Haddad; Hanna Hlawaty; Loïc Martin; Roger Vassy; Olivier Oudar; Liliane Gattegno; Nathalie Charnaux; Angela Sutton
BACKGROUND We previously demonstrated that the CC-chemokine Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES)/CCL5 exerts pro-tumoral effects on human hepatoma Huh7 cells through its G protein-coupled receptor, CCR1. Glycosaminoglycans play major roles in these biological events. METHODS In the present study, we explored 1/ the signalling pathways underlying RANTES/CCL5-mediated hepatoma cell migration or invasion by the use of specific pharmacological inhibitors, 2/ the role of RANTES/CCL5 oligomerization in these effects by using a dimeric RANTES/CCL5, 3/ the possible involvement of two membrane heparan sulfate proteoglycans, syndecan-1 (SDC-1) and syndecan-4 (SDC-4) in RANTES/CCL5-induced cell chemotaxis and spreading by pre-incubating cells with specific antibodies or by reducing SDC-1 or -4 expression by RNA interference. RESULTS AND CONCLUSION The present data suggest that focal adhesion kinase phosphorylation, phosphoinositide 3-kinase-, mitogen-activated protein kinase- and Rho kinase activations are involved in RANTES/CCL5 pro-tumoral effects on Huh7 cells. Interference with oligomerization of the chemokine reduced RANTES/CCL5-mediated cell chemotaxis. This study also indicates that SDC-1 and -4 may be required for HepG2, Hep3B and Huh7 human hepatoma cell migration, invasion or spreading induced by the chemokine. These results also further demonstrate the involvement of glycosaminoglycans as the glycosaminoglycan-binding deficient RANTES/CCL5 variant, in which arginine 47 was replaced by lysine, was devoid of effect. GENERAL SIGNIFICANCE The modulation of RANTES/CCL5-mediated cellular effects by targeting the chemokine-syndecan interaction could represent a new therapeutic approach for hepatocellular carcinoma.
Angiogenesis | 2013
Romain Delcombel; Lauriane Janssen; Roger Vassy; Melissa Gammons; Oualid Haddad; Benjamin Richard; Didier Letourneur; David O. Bates; Céline Hendricks; Johannes Waltenberger; Anna Starzec; Nor Eddine Sounni; Agnès Noël; Christophe Deroanne; Charles Lambert; Alain Colige
VEGF-A is a crucial growth factor for blood vessel homeostasis and pathological angiogenesis. Due to alternative splicing of its pre-mRNA, VEGF-A is produced under several isoforms characterized by the combination of their C-terminal domains, which determines their respective structure, availability and affinity for co-receptors. As controversies still exist about the specific roles of these exon-encoded domains, we systematically compared the properties of eight natural and artificial variants containing the domains encoded by exons 1–4 and various combinations of the domains encoded by exons 5, 7 and 8a or 8b. All the variants (VEGF111a, VEGF111b, VEGF121a, VEGF121b, VEGF155a, VEGF155b, VEGF165a, VEGF165b) have a similar affinity for VEGF-R2, as determined by Surface plasmon resonance analyses. They strongly differ however in terms of binding to neuropilin-1 and heparin/heparan sulfate proteoglycans. Data indicate that the 6 amino acids encoded by exon 8a must be present and cooperate with those of exons 5 or 7 for efficient binding, which was confirmed in cell culture models. We further showed that VEGF165b has inhibitory effects in vitro, as previously reported, but that the shortest VEGF variant possessing also the 6 amino acids encoded by exon 8b (VEGF111b) is remarkably proangiogenic, demonstrating the critical importance of domain interactions for defining the VEGF properties. The number, size and localization of newly formed blood vessels in a model of tumour angiogenesis strongly depend also on the C-terminal domain composition, suggesting that association of several VEGF isoforms may be more efficient for treating ischemic diseases than the use of any single variant.
Molecular Cancer Therapeutics | 2007
Angela Sutton; Veronique Friand; Dulce Papy-Garcia; Maylis Dagouassat; Loïc Martin; Roger Vassy; Oualid Haddad; Odile Sainte-Catherine; Michel Kraemer; Line Saffar; Gérard Y Perret; José Courty; Liliane Gattegno; Nathalie Charnaux
The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein–coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein–coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by β-d-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma. [Mol Cancer Ther 2007;6(11):2948–58]