Abstract
BackgroundOsteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents. Molecular analysis of a metastatic genetically engineered mouse model of osteosarcoma identified enhanced expression of Secreted Frizzled-Related Protein 2 (sFRP2), a putative regulator of Wnt signaling within metastatic tumors. Subsequent analysis correlated increased expression in the human disease, and within highly metastatic OS cells. However, the role of sFRP2 in osteosarcoma development and progression has not been well elucidated.MethodsStudies using stable gain or loss-of-function alterations of sFRP2 within human and mouse OS cells were performed to assess changes in cell proliferation, migration, and invasive ability in vitro, via both transwell and 3D matrigel assays. In additional, xenograft studies using overexpression of sFRP2 were used to assess effects on in vivo metastatic potential. ResultsFunctional studies revealed stable overexpression of sFRP2 within localized human and mouse OS cells significantly increased cell migration and invasive ability in vitro and enhanced metastatic potential in vivo. Additional studies exploiting knockdown of sFRP2 within metastatic human and mouse OS cells demonstrated decreased cell migration and invasion ability in vitro, thus corroborating a critical biological phenotype carried out by sFRP2. Interestingly, alterations in sFRP2 expression did not alter OS proliferation rates or primary tumor development.ConclusionsWhile future studies further investigating the molecular mechanisms contributing towards this sFRP2-dependent phenotype are needed, our studies clearly provide evidence that aberrant expression of sFRP2 can contribute to the invasive and metastatic potential for osteosarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2909-6) contains supplementary material, which is available to authorized users.
Highlights
Osteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents
Identification of increased Secreted Frizzled-Related Protein 2 (sFRP2) expression in metastatic osteosarcoma We have previously developed and characterized a genetically engineered mouse model of metastatic osteosarcoma [15] that revealed differential expression of several categorical genes within the primary metastatic tumors, including those involved in translational regulation, inflammation, and regulation of Wingless signaling pathway (Wnt) signaling
Exploration of sFRP2 expression in human osteosarcoma revealed enhanced expression compared to mesenchymal stem cells (MSCs) (Fig. 1b) [25]
Summary
Osteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents. Molecular analysis of a metastatic genetically engineered mouse model of osteosarcoma identified enhanced expression of Secreted Frizzled-Related Protein 2 (sFRP2), a putative regulator of Wnt signaling within metastatic tumors. Understanding disease biology and the molecular signaling pathways involved in osteosarcoma development and progression should lead to the identification of novel therapeutic targets. For the canonical signaling pathway, binding of Wnt ligands to Frizzled receptors, which are G protein-coupled receptors, leads to activation and translocation of β-catenin from the cytoplasm to nucleus. Subsequent binding to T cell factor (TCF)/lymphoid enhancer factor (LEF) leads to transcriptional activation of downstream target genes [9, 10]. Aberrant activation of Wnt signaling pathways has been reported in many types of cancer including colorectal, brain, and sarcomas [7, 11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
