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dc.contributor.authorZandueta, Carolina-
dc.contributor.authorOrmazábal, Cristina-
dc.contributor.authorPerurena, Naiara-
dc.contributor.authorMartínez-Canarias, Susana-
dc.contributor.authorZalacaín, Marta-
dc.contributor.authorJulián, Mikel San-
dc.contributor.authorGrigoriadis, Agamemnon E.-
dc.contributor.authorValencia, Karmele-
dc.contributor.authorCampos-Laborie, Francisco J.-
dc.contributor.authorDe Las Rivas, Javier-
dc.contributor.authorVicent, Silvestre-
dc.contributor.authorPatiño-García, Ana-
dc.contributor.authorLecanda, Fernando-
dc.identifierdoi: 10.1002/path.4740-
dc.identifiere-issn: 1096-9896-
dc.identifierissn: 0022-3417-
dc.identifier.citationJournal of Pathology 239(4): 438-449 (2016)-
dc.description.abstractOsteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo-naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix-Gla protein (MGP), a non-collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans-endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFβ-induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep.usal.es/osteosarcoma/-
dc.description.sponsorshipThis study was supported by the Unión Temporal de Empresas (UTE) Project FIMA Agreement and Redes Temáticas de Investigación Cooperativa en Cáncer (RETICC) from the Instituto de Salud Carlos III (RTICC; Project Nos RD12/0036/0040 and RD12/0036/0068, and Grant No. PI042282 to FL). FL is the recipient of a Research Project Grant in Child Cancer, Asociación Española Contra el Cáncer (AECC) and the Grants in Aid Program (GAP) of the American Society for Bone and Mineral Research (ASBMR). AP was supported by the Spanish Research Sarcoma Group (GEIS; Grant No. FIS PI13/01476) and a Mari Paz Jimenez Casado Foundation Grant. NP was supported by a Formación de Profesorado Univ rsitario (FPU), AP2010-2197 from the Ministerio de Educación, Cultura y Deporte. CO was supported by a Torres Quevedo Programme from the Ministerio de Economía y Competitividad (MINECO) (PTQ-10-04248).-
dc.publisherJohn Wiley & Sons-
dc.subjectEndothelial adhesion-
dc.titleMatrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis-
dc.description.versionPeer Reviewed-
dc.contributor.funderEuropean Commission-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderAsociación Española Contra el Cáncer-
dc.contributor.funderAmerican Society for Bone and Mineral Research-
dc.contributor.funderMinisterio de Educación, Cultura y Deporte (España)-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
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