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1.
Br J Cancer ; 103(3): 370-81, 2010 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-20606682

RESUMEN

BACKGROUND: Ewing's sarcoma family of tumours (ESFT) is a malignant small round-cell tumour of the bone and soft tissues. It is characterised by a strong tendency to invade and form metastases. The microenvironment of the bone marrow is a large repository for many growth factors, including the basic fibroblast growth factor (bFGF). However, the role of bFGF in the invasive and metastatic phenotype of ESFT has not been investigated. METHODS: The motility and invasion of ESFT cells were assessed by a wound-healing assay, chemotaxis assay, and invasion assay. The expression and activation of FGF receptors (FGFRs) in ESFT cell lines and clinical samples were detected by RT-PCR, western blotting, and immunohistochemistry. The morphology of ESFT cells was investigated by phase-contrast microscopy and fluorescence staining for actin. Activation of Rac1 was analysed by a pull-down assay. RESULTS: bFGF strongly induced the motility and invasion of ESFT cells. Furthermore, FGFR1 was found to be expressed and activated in clinical samples of ESFT. Basic FGF-induced cell motility was mediated through the FGFR1-phosphatidylinositol 3-kinase (PI3K)-Rac1 pathway. Conditioned medium from bone marrow stromal cells induced the motility of ESFT cells by activating bFGF/FGFR1 signalling. CONCLUSION: The bFGF-FGFR1-PI3K-Rac1 pathway in the bone microenvironment may have a significant role in the invasion and metastasis of ESFT.


Asunto(s)
Médula Ósea/fisiología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Invasividad Neoplásica , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Proteína de Unión al GTP rac1/genética , Médula Ósea/fisiopatología , Línea Celular Tumoral , Movimiento Celular/fisiología , Citoesqueleto/patología , Activación Enzimática , Factor de Crecimiento Epidérmico/farmacología , Humanos , Osteosarcoma/genética , Osteosarcoma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Reacción en Cadena de la Polimerasa , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Proteínas Recombinantes/farmacología , Cicatrización de Heridas , Proteína de Unión al GTP rac1/metabolismo
2.
Ann Rheum Dis ; 67(9): 1299-304, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18063670

RESUMEN

OBJECTIVES: Recent animal studies have revealed critical roles of interleukin (IL)17, which is produced by a newly identified subset of helper T cells, Th17 cells, in the development of autoimmune diseases including arthritis. However, in human rheumatoid arthritis (RA), detailed characteristics and the prevalence of Th17 cells are unclear. METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 123 patients with RA and 28 healthy controls. Mononuclear cells were also prepared from synovial membrane or synovial fluid of 12 patients with RA. IL17 (IL17A) positive T cells were identified by a flow cytometer after ex vivo stimulation with phorbol myristate acetate and ionomycin. Disease activity was assessed with the 28-joint Disease Activity Score (DAS28). RESULTS: IL17 positive cells were detected in CD45RO+ CD4 T cells. Most IL17 positive T cells produced neither interferon (IFN)gamma nor IL4, but tumour necrosis factor (TNF)alpha similar to murine Th17 cells. The frequency of Th17 cells was neither increased in RA nor correlated with DAS28. Unexpectedly, the frequency of Th17 cells was significantly decreased in the joints compared with PBMC of the same patients with RA, whereas Th1 cells were more abundant in the joints than in PBMC. CONCLUSIONS: We could not obtain evidence that positively supports predominance of Th17 cells in RA. Further careful investigation is necessary before clinical application of IL17-targeting therapy.


Asunto(s)
Artritis Reumatoide/inmunología , Interleucina-17/biosíntesis , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Células Cultivadas , Femenino , Humanos , Interferón gamma/biosíntesis , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Membrana Sinovial/inmunología , Células TH1/inmunología
3.
J Biol Chem ; 275(49): 38912-20, 2000 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-10986284

RESUMEN

Angiostatin, a potent endogenous inhibitor of angiogenesis, is generated by cancer-mediated proteolysis of plasminogen. The culture medium of human prostate carcinoma cells, when incubated with plasminogen at a variety of pH values, generated angiostatic peptides and miniplasminogen. The enzyme(s) responsible for this reaction was purified and identified as procathepsin D. The purified procathepsin D, as well as cathepsin D, generated two angiostatic peptides having the same NH(2)-terminal amino acid sequences and comprising kringles 1-4 of plasminogen in the pH range of 3.0-6.8, most strongly at pH 4.0 in vitro. This reaction required the concomitant conversion of procathepsin D to catalytically active pseudocathepsin D. The conversion of pseudocathepsin D to the mature cathepsin D was not observed by the prolonged incubation. The affinity-purified angiostatic peptides inhibited angiogenesis both in vitro and in vivo. Importantly, procathepsin D secreted by human breast carcinoma cells showed a significantly lower angiostatin-generating activity than that by human prostate carcinoma cells. Since deglycosylated procathepsin D from both prostate and breast carcinoma cells exhibited a similar low angiostatin-generating activity, this discrepancy appeared to be attributed to the difference in carbohydrate structures of procathepsin D molecules between the two cell types. The seminal vesicle fluid from patients with prostate carcinoma contained the mature cathepsin D and procathepsin D, but not pseudocathepsin D, suggesting that pseudocathepsin D is not a normal intermediate of procathepsin D processing in vivo. The present study provides evidence for the first time that cathepsin D secreted by human prostate carcinoma cells is responsible for angiostatin generation, thereby causing the prevention of tumor growth and angiogenesis-dependent growth of metastases.


Asunto(s)
Catepsina D/metabolismo , Fragmentos de Péptidos/metabolismo , Plasminógeno/metabolismo , Neoplasias de la Próstata/enzimología , Serina Endopeptidasas/metabolismo , Angiostatinas , Antineoplásicos/farmacocinética , Neoplasias de la Mama , Femenino , Humanos , Concentración de Iones de Hidrógeno , Cinética , Masculino , Modelos Moleculares , Plasminógeno/química , Inhibidores de Proteasas/farmacología , Estructura Secundaria de Proteína , Serina Endopeptidasas/aislamiento & purificación , Células Tumorales Cultivadas
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