Expression of c-FLIP in pulmonary metastases in osteosarcoma patients and human xenografts.

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(+) OS 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 contained 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: OS patient tissues, which included both primary and metastatic lesions, were evaluated for the expression of c-FLIP. In addition, tumors from human OS 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 OS to the lung. Inhibition of c-FLIP may be a future therapeutic target.