Abstract
The EWS/FLI-1 fusion gene is characteristic of most cases of Ewing's sarcoma and has been shown to be crucial for tumor transformation and cell growth. In this study we demonstrate a drastic down-regulation of the EWS/FLI-1 protein, and a growth arrest, following serum depletion of Ewing's sarcoma cells. This indicates that growth factor circuits may be involved in regulation of the fusion gene product. Of four different growth factors tested, basic fibroblast growth factor (bFGF) was found to be of particular significance. In fact, upon treatment of serum-depleted cells with bFGF, expression of the EWS/FLI-1 protein and growth of the Ewing's sarcoma cells were restored. In addition, a bFGF-neutralizing antibody, which was confirmed to inhibit FGF receptor (FGFR) phosphorylation, caused down-regulation of EWS/FLI-1. Experiments using specific cell cycle blockers (thymidine and colcemide) suggest that EWS/FLI-1 is directly linked to bFGF stimulation, and not indirectly to cell proliferation. We also demonstrated expression of FGFRs in several tumor samples of Ewing's sarcoma. Taken together, our data suggest that expression of FGFR is a common feature of Ewing's sarcoma and, in particular, that the bFGF pathway may be important for the maintenance of a malignant phenotype of Ewing's sarcoma cells through up-regulating the EWS/FLI-1 protein. Oncogene (2000) 19, 4298 - 4301
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / pathology
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Antibodies, Monoclonal / pharmacology
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology*
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Cell Cycle / drug effects
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Cell Division / drug effects
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Chromosomes, Human, Pair 11 / genetics
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Chromosomes, Human, Pair 11 / ultrastructure
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Chromosomes, Human, Pair 22 / genetics
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Chromosomes, Human, Pair 22 / ultrastructure
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Culture Media, Serum-Free
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Demecolcine / pharmacology
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Drug Synergism
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Epidermal Growth Factor / pharmacology
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Fibroblast Growth Factor 2 / antagonists & inhibitors
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Fibroblast Growth Factor 2 / immunology
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Fibroblast Growth Factor 2 / physiology*
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Fibroblasts / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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Insulin-Like Growth Factor I / pharmacology
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Male
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Oncogene Proteins, Fusion / biosynthesis*
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Oncogene Proteins, Fusion / genetics
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Platelet-Derived Growth Factor / pharmacology
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Prostatic Neoplasms / pathology
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Proto-Oncogene Protein c-fli-1
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RNA-Binding Protein EWS
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Receptors, Fibroblast Growth Factor / drug effects
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Receptors, Fibroblast Growth Factor / physiology
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Sarcoma, Ewing / metabolism
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Sarcoma, Ewing / pathology*
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Thymidine / pharmacology
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Translocation, Genetic
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
Substances
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Antibodies, Monoclonal
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Culture Media, Serum-Free
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EWS-FLI fusion protein
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Platelet-Derived Growth Factor
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Proto-Oncogene Protein c-fli-1
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RNA-Binding Protein EWS
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Receptors, Fibroblast Growth Factor
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Transcription Factors
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Fibroblast Growth Factor 2
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Epidermal Growth Factor
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Insulin-Like Growth Factor I
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Thymidine
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Demecolcine