Abstract
Sarcomas represent a complex group of malignant neoplasms of mesenchymal origin and their heterogeneity poses a serious diagnostic and therapeutic challenge. There is therefore a need to elucidate the molecular mechanisms underpinning the pathogenesis of the more than 70 distinguishable sarcoma subtypes. The transcription factor TBX3, a critical developmental regulator, is overexpressed in several cancers of epithelial origin where it contributes to tumorigenesis by different molecular mechanisms. However, the status and role of TBX3 in sarcomas have not been reported. Here we show that a diverse subset of soft tissue and bone sarcoma cell lines and patient-derived sarcoma tissues express high levels of TBX3. We further explore the significance of this overexpression using a small interferring RNA approach and demonstrate that TBX3 promotes the migratory ability of chondrosarcoma, rhabdomyosarcoma and liposarcoma cells but inhibits fibrosarcoma cell migration. This suggested that TBX3 may play a key role in the development of different sarcoma subtypes by functioning as either an oncoprotein or as a brake to prevent tumour progression. To further explore this, TBX3 knockdown and overexpression cell culture models were established using chondrosarcoma and fibrosarcoma cells as representatives of each scenario, and the resulting cells were characterized with regard to key features of tumorigenesis. Results from in vitro and in vivo assays reveal that, while TBX3 promotes substrate-dependent and -independent cell proliferation, migration and tumour formation in chondrosarcoma cells, it discourages fibrosarcoma formation. Our findings provide novel evidence linking TBX3 to cancers of mesenchymal origin. Furthermore, we show that TBX3 may be a biomarker for the diagnosis of histologically dynamic sarcoma subtypes and that it impacts directly on their oncogenic phenotype. Indeed, we reveal that TBX3 may exhibit oncogene or tumour suppressor activity in sarcomas, which suggests that its role in cancer progression may rely on cellular context.
Highlights
Sarcomas are cancers derived from mesenchymal tissue and while they only account for a small percentage of neoplasms, they represent some of the most aggressive cancers in children, adolescents and young adults.[1,2] They contribute to a considerable loss of years of life in comparison with other cancers
Compared with the normal WI38 fibroblast cells, TBX3 was upregulated in transformed (CT-1 and SV40 transformed WI38 cells (SV-WI38)) fibroblasts as well as the naturally occurring HT1080 human fibrosarcoma cells (Figure 1a). We determined if this overexpression of TBX3 may be a feature of sarcomas and to this end we screened a panel of soft tissue and bone sarcomas for TBX3 protein
We show that TBX3 is highly expressed in a panel of soft tissue and bone sarcoma cell lines and patient-derived sarcoma tissue
Summary
Sarcomas are cancers derived from mesenchymal tissue and while they only account for a small percentage of neoplasms, they represent some of the most aggressive cancers in children, adolescents and young adults.[1,2] They contribute to a considerable loss of years of life in comparison with other cancers. The development of subtype or pathway-specific therapies is a rapidly evolving field and recent advances in understanding sarcoma biology have led to the identification of several molecular determinants of different soft tissue and bone sarcoma subtypes. Monoclonal antibodies targeting insulin-like growth factor type 1 receptor have shown promise in phase I and II clinical trials for the treatment of paediatric sarcomas including osteosarcoma, Ewing sarcoma and rhabdomyosarcoma.[5,6] Sorafenib and pazopanib, small-molecule inhibitors of vascular endothelial growth factor receptor, have shown anticancer activity in leiomyosarcomas, angiosarcomas and synovial sarcomas.[7,8] In addition, the mechanistic target of rapamycin inhibitor, AP23573, has shown promising clinical efficacy in patients with advanced soft tissue sarcomas.[9,10] It is evident that improved sarcoma cure rates will likely be driven by new types of treatment that target specific deregulated proteins within these tumours
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