EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF

EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated. This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo. Computational docking analyses and mutagenesis studies identified a molecular binding site in the extracellular domain of EMMPRIN located close to the cell membrane and containing the amino acids 195/199. EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy.This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), La Ligue Nationale contre le Cancer (LNCC), La Société Française de Dermatologie and Université Paris Diderot. F.K was supported by a PhD fellowship from Cancéropôle-Ile de France and from Fondation ARC pour la Recherche sur le Cancer. L.P.C was supported by a FPU fellowship from Spanish Ministry of Science. This work was supported by grant BIO2010–22324 from Plan NacionalI+D+iMICINN. We thank the core facility of the Institut Universitaire d’Hématologie for confocal microscopy analyses. The core facility is supported by grants from the Association Saint-Louis, Conseil Regional d’Ile-de-France, and the Ministère de la Recherche.Peer ReviewedPostprint (published version

Soluble Isoforms of Vascular Endothelial Growth Factor Are Predictors of Response to Sunitinib in Metastatic Renal Cell Carcinomas

Angiogenesis is the target of several agents in the treatment of malignancies, including renal cell carcinoma (RCC). There is a real need for surrogate biomarkers that can predict selection of patients who may benefit from antiangiogenic therapies, prediction of disease outcome and which may improve the knowledge regarding mechanism of action of these treatments. Tyrosine kinase inhibitors (TKI) have proven efficacy in metastatic RCC (mRCC). However, the molecular mechanisms underlying the clinical response to these drugs remain unclear.The present study aimed to identify molecular biomarkers associated with the response to sunitinib, a Tyrosine kinase inhibitor. To evaluate this relationship, primary tumors from 23 metastatic RCC patients treated by sunitinib were analyzed for a panel of 16 biomarkers involved in tumor pathways targeted by sunitinib, using real-time quantitative reverse-transcriptase PCR. Nine of the 23 patients (39%) responded to sunitinib. Among transcripts analyzed, only the levels of vascular endothelial growth factor (VEGF) soluble isoforms (VEGF(121) and VEGF(165)) were associated with the response to sunitinib (P = 0.04 for both). Furthermore, the ratio of VEGF soluble isoforms (VEGF(121)/VEGF(165)) was significantly associated with prognosis (P = 0.02).This preliminary study provides a promising tool that might help in the management of metastatic RCC, and could be extended to other tumors treated by TKI

A Reliable Method for the Selection of Exploitable Melanoma Archival Paraffin Embedded Tissues for Transcript Biomarker Profiling

The source tissue for biomarkers mRNA expression profiling of tumors has traditionally been fresh-frozen tissue. The adaptation of formalin-fixed, paraffin-embedded (FFPE) tissues for routine mRNA profiling would however be invaluable in view of their abundance and the clinical information related to them. However, their use in the clinic remains a challenge due to the poor quality of RNA extracted from such tissues. Here, we developed a method for the selection of melanoma archival paraffin-embedded tissues that can be reliably used for transcript biomarker profiling. For that, we used qRT-PCR to conduct a comparative study in matched pairs of frozen and FFPE melanoma tissues of the expression of 25 genes involved in angiogenesis/tumor invasion and 15 housekeeping genes. A classification method was developed that can select the samples with a good frozen/FFPE correlation and identify those that should be discarded on the basis of paraffin data for four reference genes only. We propose therefore a simple and inexpensive assay which improves reliability of mRNA profiling in FFPE samples by allowing the identification and analysis of “good” samples only. This assay which can be extended to other genes would however need validation at the clinical level and on independent tumor series

EMMPRIN Promotes Melanoma Cells Malignant Properties through a HIF-2alpha Mediated Up-Regulation of VEGF-Receptor-2

EMMPRIN's expression in melanoma tissue was reported to be predictive of poor prognosis. Here we demonstrate that EMMPRIN up-regulated VEGF receptor-2 (VEGFR-2) in two different primary melanoma cell lines and consequently increased migration and proliferation of these cells while inhibiting their apoptosis. SiRNA inhibition of VEGFR-2 expression abrogated these EMMPRIN effects. EMMPRIN regulation of VEGFR-2 was mediated through the over-expression of HIF-2α and its translocation to the nucleus where it forms heterodimers with HIF-1β. These results were supported by an in vivo correlation between the expression of EMMPRIN with that of VEGFR-2 in human melanoma tissues as well as with the extent of HIF-2α localization in the nucleus. They demonstrate a novel mechanism by which EMMPRIN promotes tumor progression through HIF-2α/VEGFR-2 mediated mechanism, with an autocrine role in melanoma cell malignancy. The inhibition of EMMPRIN in cancer may thus simultaneously target both the VEGFR-2/VEGF system and the matrix degrading proteases to block tumor cell growth and invasion

Métalloproteinases matricielles et cicatrisation cornéenne (rôle D'EMMPRIN et des interactions epithélio-stromales)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Rôle des gélatinases dans l'angiogénèse tumorale

L'angiogénèse joue un rôle fondamental dans les phénomènes physiologiques (reproduction, cicatrisation) et pathologiques (développement tumoral, inflammation). La formation de néovaisseaux sanguins nécessite la dégradation de la matrice extracellulaire et la migration des cellules endothéliales. Les gélatinases A et B, membres de la famille des métalloprotéases matricielles, sont essentielles au processus angiogénique "in vivo". Souhaitant préciser l'implication des gélatinases dans l'angiogénèse et la progression tumorale, notre travail a eu pour objectifs : d'étudier le rapport entre la balance gélatinolytique et la capacité migratoire des cellules endothéliales...Angiogenesis plays a fundamental role in many physiological and pathological processes including wound healing and tumor growth. The formation of new vessels, which involves the migration of stimulated endothelial cells and subsequent tube formation, depends on a tightly controlled proteolysis of the components of the extracellular matrix...PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Rôle de molécules matricielles dans la signalisation et la minéralisation de la dentine et de l'émail

Les recherches portant d\u27abord sur les molécules de la matrice extracellulaire en tant qu\u27initiateurs de minéralisation étudient maintenant leurs propriétés en tant que molécules de signalisation. Nous résumons la composition des matrices amélaire et dentinaire et prenons deux exemples de multifonctionnalité. Les amélogénines sont impliquées dans l\u27organisation tridimensionnelle et dans la minéralisation initiale de l\u27émail natif. Des formes épissées de la molécule agissent comme molécule de signalisation pour les odontoblastes. La protéine de la matrice dentinaire-1 intervient dans la minéralisation dentinaire et dans la différenciation de cellules pulpaires embryonnaires en odontoblastes. Ces données éclairent la complexité de molécules matricielles.While the participation of the extracellular matrix protein in mineralisation processes has been extensively studied, a role for these proteins as signalling molecules has only been recently evoked. We report on the composition of enamel and dentin matrix, and discuss the multifunctionality of two molecules. Amelogenins are implicated in enamel three-dimensional organization and contribute to the initial mineralisation of the forming enamel. Some amelogenin spliced forms act as signalling molecules in odontoblasts. Dentin Matrix Protein-1 is also implicated in dentin mineralisation and in the differentiation of pulp embryonic cells into odontoblasts. This reveals a complex role of extracellular matrix molecules.</p