Abstract
The malignant bone tumors that are categorized as chondrosarcomas display a high potential for metastasis in late-stage disease. Higher-grade chondrosarcomas contain higher levels of expression of platelet-derived growth factor (PDGF) and its receptor. The phosphorylation of sphingosine by sphingosine kinase enzymes SphK1 and SphK2 generates sphingosine-1-phosphate (S1P), which inhibits human chondrosarcoma cell migration, while SphK1 overexpression suppresses lung metastasis of chondrosarcoma. We sought to determine whether S1P mediates levels of PDGF-A expression and angiogenesis in chondrosarcoma. Surprisingly, our investigations found that treatment of chondrosarcoma cells with S1P and transfecting them with SphK1 cDNA increased PDGF-A expression and induced angiogenesis of endothelial progenitor cells (EPCs). Ras, Raf, MEK, ERK and AP-1 inhibitors and their small interfering RNAs (siRNAs) inhibited S1P-induced PDGF-A expression and EPC angiogenesis. Our results indicate that S1P promotes the expression of PDGF-A in chondrosarcoma via the Ras/Raf/MEK/ERK/AP-1 signaling cascade and stimulates EPC angiogenesis.
Highlights
The malignant bone tumors that constitute chondrosarcomas are not easy to diagnose or treat [1, 2], being characterized by poor responsiveness to conventional chemotherapy and radiotherapy [3], and high-grade chondrosarcoma has a poor prognosis with low survival rates despite wide surgical resection, which is considered to be the cornerstone of treatment [4].Metastasis is the primary cause of cancer mortality [5,6,7]
To confirm the role of S1P in endothelial progenitor cells (EPCs) angiogenesis, the cells were transfected with sphingosine kinase 1 (SphK1) cDNA
Growth rates of many low- and moderate-grade chondrosarcomas are relatively slow; approximately 15% of all deaths due to metastasis occur more than 5 years after diagnosis [34]
Summary
The malignant bone tumors that constitute chondrosarcomas are not easy to diagnose or treat [1, 2], being characterized by poor responsiveness to conventional chemotherapy and radiotherapy [3], and high-grade chondrosarcoma has a poor prognosis with low survival rates despite wide surgical resection, which is considered to be the cornerstone of treatment [4].Metastasis is the primary cause of cancer mortality [5,6,7]. Angiogenesis is vital for the development of cancer and metastasis [8,9,10]; the chief proangiogenic factor in these processes is vascular endothelial growth factor-A (VEGF-A) [11, 12]. Another crucial mediator of tumor angiogenesis and metastasis is the platelet-derived growth factor receptor (PDGFR); a positive correlation has been observed between levels of PDGFR-α expression and the aggressiveness of chondrosarcoma [13], so it is important to examine the molecular mechanisms underlying PDGF expression in human chondrosarcoma cells.
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