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Title

Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis

AuthorsZandueta, Carolina; Ormazábal, Cristina; Perurena, Naiara; Martínez-Canarias, Susana; Zalacaín, Marta; Julián, Mikel San; Grigoriadis, Agamemnon E.; Valencia, Karmele; Campos-Laborie, Francisco J.; De Las Rivas, Javier ; Vicent, Silvestre; Patiño-García, Ana; Lecanda, Fernando
KeywordsMetalloproteinase
Biomarker
Endothelial adhesion
Transmigration
Issue Date2016
PublisherJohn Wiley & Sons
CitationJournal of Pathology 239(4): 438-449 (2016)
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/
URIhttp://hdl.handle.net/10261/168609
Identifiersdoi: 10.1002/path.4740
e-issn: 1096-9896
issn: 0022-3417
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