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Objective(s)
We have previously shown that Fas expression inversely correlates with the metastatic potential of osteosarcoma (OS) to the lung. FasL is constitutively expressed in the lung microenvironment and eliminates Fas+ osteosarcoma cells leaving Fas− cells to form metastases. Absence of FasL in the lung epithelium or blocking the Fas-signaling pathway interfered with this clearance mechanism allowing Fas+ cells to remain and form lung metastases. We also demonstrated that while the majority of patient OS lung metastases were Fas−, 10-20% of the lesions contain Fas+ cells, suggesting that these cells were not sensitive to FasL-induced apoptosis. The expression of c-FLIP, an inhibitor of the Fas pathway, has been associated with tumor development, progression, and resistance to chemotherapy. We therefore evaluated the expression of c-FLIP in OS patient tumor specimens and human xenograft lung metastases.
Methods
Osteosarcoma patient tissues, which included both primary and metastatic lesions, were evaluated for the expression of c-FLIP. In addition, tumors from human osteosarcoma xenografts were examined for c-FLIP expression.
Results
c-FLIP expression was significantly higher in the lung metastases than in the primary tumors.
Conclusion(s)
c-FLIP may play an important role in the metastatic potential of osteosarcoma to the lung. Inhibition of c-FLIP may be a future therapeutic target.
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