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

Abstract

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.

Protein Kinase B and Extracellular Signal-Regulated Kinase Inactivation is Associated with Regorafenib-Induced Inhibition of Osteosarcoma Progression In Vitro and In Vivo

“…Many anti-apoptotic proteins such as C-FLIP, MCL-1, and XIAP inhibit apoptosis through disruption of extrinsic/intrinsic apoptotic pathways in cancers [33]. C-FLIP inhibits FAS-mediated apoptosis through suppression of caspase-8 activation [34]. MCL-1 blocks intrinsic apoptotic signaling transduction through preventing the loss of mitochondrial membrane potential and cytochrome-c release from mitochondria [35].…”

Identification of critical genes and gene interaction networks that mediate osteosarcoma metastasis to the lungs

“…It has previously been reported that thatezrin, a member of the ezrin-radixin-moesin family, is highly expressed in metastatic OS cell lines, and is required for OS metastasis, due to its functional connection with the actin cytoskeleton ( 7 ). In addition, the expression of Fas has previously been associated with OS metastasis, and an inhibitor of the Fas pathway (c-FLIP) has been developed as a potential treatment for patients with lung metastasis ( 8 ). Nagao-Kitamoto et al ( 9 ) demonstrated that knockdown of GLI family zinc finger 2 (GLI2) using RNA interference was able to significantly attenuate the migration and invasion of OS cells; thus suggesting that inhibition of GLI2 may be a potential strategy for the treatment of patients with metastatic OS.…”

Moonlighting Proteins Are Important Players in Cancer Immunology

“…In addition to support resistance of cell death, c-FLIP triggers both epithelial-mesenchymal transition (EMT) and motility of cancer cells, thus promoting tumor invasive potential. Therefore, it is unsurprising that high levels of c-FLIP has been reported in several cancer settings such as colorectal cancer ( 46 ), cervical cancer ( 47 ), pancreatic cancer ( 48 ), lung cancer ( 49 ), breast cancer ( 50 ), Burkitt’s lymphoma ( 51 ), and non-Hodgkin’s Lymphoma ( 52 ) as well as that patients with tumors expressing high levels of FLIP tend to have a poorer prognosis ( 53 , 54 ). However, c-FLIP performs also unexpected functions during cancer progression.…”