Fas-Negative Osteosarcoma Tumor Cells Are Selected during Metastasis to the Lungs: The Role of the Fas Pathway in the Metastatic Process of Osteosarcoma

Koshkina, Nadezhda V.; Khanna, Chand; Mendoza, Arnulfo; Guan, Hui; DeLauter, Lindsey; Kleinerman, Eugenie S.

doi:10.1158/1541-7786.mcr-07-0007

Cited by 60 publications

(49 citation statements)

References 33 publications

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“…K7=FDN lung nodules were Fasþ when analyzed by immunohistochemistry. (35) These data confirmed that, in the absence of a functional Fas pathway, Fasþ cells can grow in the lung and induce lung metastases.…”

Section: The Fas/fas Ligand Pathway and Osteosarcomasupporting

confidence: 64%

“…To determine the importance of an intact Fas signaling pathway to the metastatic potential of OS cells, we transfected nonmetastastic K7 cells with Fas-associated death-domain, dominant-negative plasmid (K7=FDN). (35,36) K7=FDN cells were resistant to FasL in vitro, were retained in the lung longer than control cells, and induced large lung metastases. Control transfected (K7neo1-1) and parental (K7) cells did not form lung metastases following i.v.…”

Section: The Fas/fas Ligand Pathway and Osteosarcomamentioning

confidence: 91%

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Aerosol Therapy for the Treatment of Osteosarcoma Lung Metastases: Targeting the Fas/FasL Pathway and Rationale for the Use of Gemcitabine

Gordon

Kleinerman

2010

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Lung metastases are the main cause of death in patients with osteosarcoma (OS). Salvage chemotherapy has been largely unsuccessful in improving the long-term survival of these patients. Understanding the mechanisms that play a role in the metastatic process may identify new therapeutic strategies. We have demonstrated that the cell surface Fas expression, the Fas=FasL signaling pathway, and the constitutive expression of FasL in the lung microenvironment play a critical role in the metastatic potential of OS cells. Here we review the status of Fas expression in two sets of OS cells, human SAOS and LM7 and murine K7 and K7M2, which differ in their ability to metastasize to the lungs. We demonstrated that Fas expression inversely correlated with metastatic potential. Evaluation of Fas expression in a set of lung metastases from patients demonstrated low or no Fas expression consistent with our hypothesis that Fasþ osteosarcoma cells cannot form metastases. The absence of FasL in the lung allows Fasþ osteosarcoma cells to form metastases indicating that the microenvironment is an important contributor to the metastatic potential of osteosarcoma cells. Disruption of the signal transduction pathway using Fas-associated death domain dominant negative (FDN) also allowed Fasþ cells to form lung metastases. Aerosol Gemcitabine (GCB) upregulated Fas expression and induced tumor regression in wild-type Balb=c mice but not Fas L-deficient mice. In conclusion, Fas constitutes an early defense mechanism that allows Fasþ tumor cells to undergo apoptosis when in contact with constitutive FasL in the lung. FasÀ cells or cells with a corrupted Fas pathway evade this defense mechanism and form lung metastases. The aerosol delivery of chemotherapeutic agents that upregulate Fas expression may benefit patients with established pulmonary metastases.

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Section: The Fas/fas Ligand Pathway and Osteosarcomasupporting

confidence: 64%

Section: The Fas/fas Ligand Pathway and Osteosarcomamentioning

confidence: 91%

Aerosol Therapy for the Treatment of Osteosarcoma Lung Metastases: Targeting the Fas/FasL Pathway and Rationale for the Use of Gemcitabine

Gordon

Kleinerman

2010

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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“…Tumors resist Fas-mediated signaling, by means of 1) down-regulation of Fas expression, 2) synthesis of secreted forms of Fas, 3) synthesis of Fas that lacks signal transduction capabilities, and 4) mutations in downstream effectors of Fas (Abrams, 2005). In addition, mutations in Fas-mediated signaling (Shin et al, 2002) and the lack of Fas-FasL interaction (Owen-Schaub et al, 1998;Koshkina et al, 2007) have been implicated in the ability of tumors to metastasize. Another way tumors could control the immune system is by way of FasL expression on tumor cells, which may induce apoptosis in Fas-expressing immune cells, although this latter model is controversial (Abrams, 2005).…”

Section: Cancer-related Mechanismsmentioning

confidence: 99%

Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

Boutros

Chevet²,

Metrakos³

2008

Pharmacol Rev

509

448

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“…Fas plays an important role in tumour cell apoptosis and tumorigenesis and in several clinical studies a decrease of Fas expression correlated with poor prognosis [39]. Furthermore, inhibition of Fas signalling promoted lung metastases growth in a murine osteosarcoma model and was considered as a potential therapeutic target for the treatment of osteosarcoma [40].…”

Section: Low Expression Of Fas By Osteoblastic Osteosarcomamentioning

confidence: 99%

Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma

Kubista

Klinglmueller

Bilban

et al. 2010

International Orthopaedics (SICOT)

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Osteosarcoma is the most common primary malignant bone tumour. Currently osteosarcoma classification is based on histological appearance. It was the aim of this study to use a more systematic approach to osteosarcoma classification based on gene expression analysis and to identify subtype specific differentially expressed genes. We analysed the global gene expression profiles of ten osteosarcoma samples using Affymetrix U133A arrays (five osteoblastic and five non-osteoblastic osteosarcoma patients). Differential gene expression analysis yielded 75 genes up-regulated and 97 genes down-regulated in osteoblastic versus non-osteoblastic osteosarcoma samples, respectively. These included genes involved in cell growth, chemotherapy resistance, angiogenesis, steroid-and neuropeptide hormone receptor activity, acute-phase response and serotonin receptor activity and members of the Wnt/ß-catenin pathway and many others. Furthermore, we validated the highly differential expression of six genes including angiopoietin 1, IGFBP3, ferredoxin 1, BMP, decorin, and fibulin 1 in osteoblastic osteosarcoma relative to non-osteoblastic osteosarcoma. Our results show the utility of gene expression analysis to study osteosarcoma subtypes, and we identified several genes that may play a role as potential therapeutic targets in the future.

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Fas-Negative Osteosarcoma Tumor Cells Are Selected during Metastasis to the Lungs: The Role of the Fas Pathway in the Metastatic Process of Osteosarcoma

Cited by 60 publications

References 33 publications

Aerosol Therapy for the Treatment of Osteosarcoma Lung Metastases: Targeting the Fas/FasL Pathway and Rationale for the Use of Gemcitabine

Aerosol Therapy for the Treatment of Osteosarcoma Lung Metastases: Targeting the Fas/FasL Pathway and Rationale for the Use of Gemcitabine

Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma

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