Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis
Zandueta C (1), Ormazábal C (1), Perurena N (1), Martínez-Canarias S (1), Zalacaín M (2), San Julián M (3), Grigoriadis AE (4), Valencia K (1), Campos-Laborie FJ (5), Rivas JL (5), Vicent S (1,6), Patiño-García A (3,6), Lecanda F (1,6).
(1) Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Spain.
(2) Departments of Pediatrics, Orthopedics, Clínica Universidad de Navarra (CUN), School of Medicine, University of Navarra, Pamplona, Spain.
(3) Orthopedics, Clínica Universidad de Navarra (CUN), School of Medicine, University of Navarra, Pamplona, Spain.
(4) Department of Craniofacial Development and Stem Cell Biology, Guy's Hospital, King's College, London, UK.
(5) Bioinformatics and Functional Genomics Research Group. Cancer Research Center (IBMCC-CIC), CSIC and University of Salamanca (CSIC/USAL), Salamanca, Spain.
(6) IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
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 from 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, transendothelial migration in vitro and tumour cell extravasation ability in vivo.
Furthermore, Mgp modulated metalloproteinase activities and TGF-β-induced Smad2/3 phosphorylation. In the clinical setting, OS patients that 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.
CITATION J Pathol. 2016 May 12. doi: 10.1002/path.4740