title: Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis.
abstract: Osteosarcoma (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/ Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Zandueta
authors.affiliation: Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ormazábal
authors.affiliation: Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Perurena
authors.affiliation: Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Martínez-Canarias
authors.affiliation: Department of Paediatrics, Clínica Universidad de Navarra (CUN), School of Medicine, University of Navarra, Pamplona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Zalacaín
authors.affiliation: Department of Orthopaedics, Clínica Universidad de Navarra (CUN), School of Medicine, University of Navarra, Pamplona, Spain.
authors.forename: Mikel San
authors.initials: MS
authors.lastname: Julián
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, Guy's Hospital, King's College, London, UK.
authors.forename: Agamemnon E
authors.initials: AE
authors.lastname: Grigoriadis
authors.affiliation: Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Karmele
authors.initials: K
authors.lastname: Valencia
authors.affiliation: Bioinformatics and Functional Genomics Research Group, Cancer Research Centre (IBMCC-CIC), CSIC, and University of Salamanca (CSIC/USAL), Salamanca, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Campos-Laborie
authors.affiliation: Bioinformatics and Functional Genomics Research Group, Cancer Research Centre (IBMCC-CIC), CSIC, and University of Salamanca (CSIC/USAL), Salamanca, Spain.
authors.forename: Javier De Las
authors.initials: Jde L
authors.lastname: Rivas
authors.affiliation: Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Silvestre
authors.initials: S
authors.lastname: Vicent
authors.affiliation: Department of Paediatrics, Clínica Universidad de Navarra (CUN), School of Medicine, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Patiño-García
authors.affiliation: Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000378:metabolism / Q000556:secondary*; D010766:Phosphorylation; D011379:Prognosis; D051785:Smad Proteins / Q000378:metabolism; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D020782:Matrix Metalloproteinases; D051785:Smad Proteins; D000097568:Matrix Gla Protein
keywords: biomarker; endothelial adhesion; metalloproteinase; transmigration