Abstract
Osteosarcoma is a highly malignant tumor that contains a small subpopulation of tumor-propagating cells (also known as tumor-initiating cells) characterized by drug resistance and high metastatic potential. The molecular mechanism by which tumor-propagating cells promote tumor growth is poorly understood. Here, we report that the transcription factor forkhead box C2 (FOXC2) is frequently expressed in human osteosarcomas and is important in maintaining osteosarcoma cells in a stem-like state. In osteosarcoma cell lines, we show that anoikis conditions stimulate FOXC2 expression. Downregulation of FOXC2 decreases anchorage-independent growth and invasion in vitro and lung metastasis in vivo, while overexpression of FOXC2 increases tumor propagation in vivo. In osteosarcoma cell lines, we demonstrate that high levels of FOXC2 are associated with and required for the expression of osteosarcoma tumor-propagating cell markers. In FOXC2 knockdown cell lines, we show that CXCR4, a downstream target of FOXC2, can restore osteosarcoma cell invasiveness and metastasis to the lung.
Highlights
Osteosarcomas are aggressive bone malignancies derived from osteoblast progenitor cells of mesenchymal origin [1]
We show that anoikis conditions stimulate forkhead box C2 (FOXC2) expression
We demonstrate that high levels of FOXC2 are associated with and required for the expression of osteosarcoma tumor-propagating cell markers
Summary
Osteosarcomas are aggressive bone malignancies derived from osteoblast progenitor cells of mesenchymal origin [1]. These primary bone tumors, which frequently arise during period of rapid bone growth, most commonly affect children and young adults and are the second highest cause of cancer-related death in children and adolescents [2]. It has been suggested that the lack of improvement in survival may be due to the inability to effectively target tumor-propagating cells in osteosarcoma [4]. Identifying molecular pathways that regulate the maintenance and expansion of tumorpropagating cells is critical to designing effective targeted therapy against these cells [7]
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