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.

The cancer‐related transcription factor RUNX2 modulates expression and secretion of the matricellular protein osteopontin in osteosarcoma cells to promote adhesion to endothelial pulmonary cells and lung metastasis

“…The latter indicates that osteosarcoma cells may be adhering to pulmonary endothelial cells and perhaps are invading pulmonary stromal tissue. This finding is in accordance with previous studies showing that osteosarcoma cells are retained and can bind to lung endothelium in vivo within 30 min to 6 hr and start it extravasation within 24-48 hr after it inoculation through the lateral tail vein, showing a extravasation rate of 0.1-0.2%, thus colonizing the lung tissue (S. Y Kim et al, 2008;Kimura et al, 2012;Mojiri et al, 2017;Tome et al, 2016;Tomonaga et al, 2012;Zandueta et al, 2016)…”

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment

“…POSTN, the most well-characterized Gla-protein family member, was shown to be a major determinant in proliferation for a number of aggressive, advanced solid tumors with poor prognosis (22). MGP is much less known than POSTN, but is gradually emerging as a determinant in cancer progression, exhibiting increased expression in colorectal, glioblastoma, breast, cervical, osteosarcoma and skin cancers with unfavorable prognosis (93)(94)(95)(96)(97). SPARC has been reported to mediate a variety of signaling pathways.…”

“…Given their significance for breast cancer cell dissemination to the lungs, it remains possible that both POSTN and TN-C are interdependent in promoting colonization of the metastatic niche, since POSTN anchors TN-C to the ECM (208). MGP was also recently shown to influence the metastatic niche by promoting osteosarcoma adhesion, extravasation and MMP activities in murine lung endothelium in vitro (94).…”

An Immunohistochemical Study of Stathmin 1 Expression in Osteosarcoma Shows an Association with Metastases and Poor Patient Prognosis

“…Osteosarcoma is one of the most common forms of malignancy of bone and is characterized by early metastasis [ 1 ]. Children and adolescents between the ages of 10–20 years have the highest morbidity and mortality from osteosarcoma [ 2 ]. Osteosarcoma has a broad spectrum of histological subtypes, which are considered to have different biological behavior [ 3 ].…”