RESUMO
Urokinase plasminogen activator receptor (uPAR) has been identified some 15 years ago and the anticipation was that its presence on the cell surface will provide a focus for anchoring uPA and possibly protect the enzyme from native inhibitors. The studies of the last decade have shown that uPA localized to the surface of cells by uPAR is indeed an important factor in the process of cancer cell invasion and metastasis. We developed a chick embryo model in which we showed that uPAR is crucial in invasion of stroma and in intravasation (breaching of the blood vessels walls). More recently and unexpectedly, uPAR--a protein anchored in the outer leaf-let of the plasma membrane, has been shown to initiate signal transduction events and affect cell migration. We have shown that uPAR co-associates with fibronectin binding integrin, alpha 5 beta 1, activates them and that this interaction leads to a greatly increased level of active ERK. When the association between uPAR and integrin or integrin and fibronectin are interrupted either by reduction of surface uPAR expression, or by other means, human carcinoma cells enter a state of protracted dormancy. We show that very high levels of active ERK are required to keep cancer cells proliferating in vivo.
Assuntos
Invasividade Neoplásica , Neoplasias/fisiopatologia , Ativadores de Plasminogênio/fisiologia , Receptores de Superfície Celular/fisiologia , Ativador de Plasminogênio Tipo Uroquinase/fisiologia , Animais , Embrião de Galinha , Humanos , Metástase Neoplásica , Neoplasias/metabolismo , Transdução de Sinais , Fatores de TempoRESUMO
Urokinase plasminogen activator receptor (uPAR) has been identified some 15 years ago and the anticipation was that is presence on the cell surface will provide a focus for anchoring uPA and possibly protect the enzyme from native inhibitors. The studies of the last decade have shown that uPA localized to the surface of cells by uPAR is indeed an important factor in the process of cancer cell invasion and metastasis. We developed a chick embryo model in which we showed that uPAR is crucial in invasion of stroma and in intravasation (breaching of the blood vessels walls). More recently and unexpectedly, uPAR-a protein anchored in the outer leaflet of the plasma membrane, has been shown to initiate signal transduction events and affect cell migration. We have shown that uPAR co-associates with fibronectin binding integrin, alpha5beta1, activates them and that this interaction leads to a greatly increased level of active ERK. When the association between uPAR and integrin or integrin and fibronectin are interrupted either by reduction of surface uPAR expression, or by other means, human carcinoma cells enter a state of protracted dormancy. We show that very high levels of active ERK are required to keep cancer cells proliferating in vivo. (AU)
Assuntos
Animais , Embrião de Galinha , RESEARCH SUPPORT, U.S. GOVT, P.H.S. , RESEARCH SUPPORT, NON-U.S. GOVT , Ativadores de Plasminogênio/fisiologia , Ativador de Plasminogênio Tipo Uroquinase/fisiologia , Receptores de Superfície Celular/fisiologia , Neoplasias/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Fatores de Tempo , Transdução de SinaisRESUMO
Urokinase plasminogen activator receptor (uPAR) has been identified some 15 years ago and the anticipation was that is presence on the cell surface will provide a focus for anchoring uPA and possibly protect the enzyme from native inhibitors. The studies of the last decade have shown that uPA localized to the surface of cells by uPAR is indeed an important factor in the process of cancer cell invasion and metastasis. We developed a chick embryo model in which we showed that uPAR is crucial in invasion of stroma and in intravasation (breaching of the blood vessels walls). More recently and unexpectedly, uPAR-a protein anchored in the outer leaflet of the plasma membrane, has been shown to initiate signal transduction events and affect cell migration. We have shown that uPAR co-associates with fibronectin binding integrin, alpha5beta1, activates them and that this interaction leads to a greatly increased level of active ERK. When the association between uPAR and integrin or integrin and fibronectin are interrupted either by reduction of surface uPAR expression, or by other means, human carcinoma cells enter a state of protracted dormancy. We show that very high levels of active ERK are required to keep cancer cells proliferating in vivo.
Assuntos
Animais , Embrião de Galinha , Invasividade Neoplásica , Neoplasias/metabolismo , Ativadores de Plasminogênio/fisiologia , Receptores de Superfície Celular/fisiologia , Ativador de Plasminogênio Tipo Uroquinase/fisiologia , Metástase Neoplásica , Transdução de Sinais , Fatores de TempoAssuntos
Animais , Humanos , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Ativadores de Plasminogênio/fisiologia , Matriz Extracelular/fisiologia , Fibrinólise , Células Neoplásicas Circulantes , Proteínas de Neoplasias/sangue , Neoplasias Experimentais/sangue , Neoplasias Experimentais/patologia , Prognóstico , Ativadores de Plasminogênio/sangue , Biomarcadores Tumorais/sangue , Ativador de Plasminogênio Tipo Uroquinase/uso terapêuticoAssuntos
Animais , Humanos , RESEARCH SUPPORT, NON-U.S. GOVT , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Ativadores de Plasminogênio/fisiologia , Matriz Extracelular/fisiologia , Fibrinólise , Células Neoplásicas Circulantes , Proteínas de Neoplasias/sangue , Neoplasias Experimentais/sangue , Neoplasias Experimentais/patologia , Ativadores de Plasminogênio/sangue , Prognóstico , Biomarcadores Tumorais/sangue , Ativador de Plasminogênio Tipo Uroquinase/uso terapêuticoAssuntos
Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Ativadores de Plasminogênio/fisiologia , Animais , Biomarcadores Tumorais/sangue , Matriz Extracelular/fisiologia , Fibrinólise , Humanos , Proteínas de Neoplasias/sangue , Neoplasias Experimentais/sangue , Neoplasias Experimentais/patologia , Células Neoplásicas Circulantes , Ativadores de Plasminogênio/sangue , Prognóstico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêuticoRESUMO
Vários estudos mostram que o sangue humano lisa espontaneamente enquanto o sangue de outras espécies animais necessitam de altas concentraçöes de ativadores. Nossos resultados mostram que o plasma de rato näo tratado é capaz de lisar a fibrina murina, mas näo a fibrina humana ou bovina. Porém, quando tratamos estes animais com adrenalina, um conhecido ativador do sistema fibrinolítico, o plasma destes animais é capaz de digerir a fibrina humana e bovina. Estes resultados mostram que o uso da fibrina adequada para cada espécie de animal estudado pode evitar resultados discrepantes nos diferentes laboratórios que estudam atividade fibrinolítica
Assuntos
Humanos , Animais , Masculino , Ratos , Ativadores de Plasminogênio/fisiologia , Bovinos , Epinefrina/fisiologia , Fibrinogênio/fisiologia , Fibrinólise/fisiologia , Fibrina/fisiologia , Plasminogênio/fisiologia , Ratos EndogâmicosRESUMO
The data that are being accumulated on the mechanisms by which pemphigus autoantibodies induce acantholysis in vivo conform that tissue injury in pemphigus is a complex phenomenon where several effector mechanisms may interact. Active research is being performed in many laboratories around the world, employing both in vitro and now in vivo models to further define this unique autoimmune disease.
Assuntos
Acantólise/imunologia , Doenças Autoimunes/imunologia , Modelos Animais de Doenças , Pênfigo/patologia , Acantólise/tratamento farmacológico , Acantólise/patologia , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Animais , Animais Recém-Nascidos , Antígenos de Superfície/imunologia , Autoanticorpos/imunologia , Autoanticorpos/toxicidade , Doenças Autoimunes/patologia , Brasil , Ativação do Complemento , Complemento C5/deficiência , Epiderme/imunologia , Haplorrinos , Imunoglobulina G/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Pênfigo/classificação , Pênfigo/imunologia , Ativadores de Plasminogênio/fisiologia , CoelhosRESUMO
The role of plasminogen activator in ovulation was investigated using the inhibitor, trans-aminomethylcyclohexane carboxylic acid (t-AMCHA). In the regular cycle rat, the plasminogen activator activity of the follicles increased from the diestrus to the estrus phase. In the latter phase, a proteolytic enzyme which was not inhibited by t-AMCHA appeared. After ovulation, the plasminogen activator activity decreased. When ovulation was induced in immature rats by pregnant mare serum gonadotrophin and human chorionic gonadotrophin, remarkable fibrinolytic activity appeared in the ovaries immediately before ovulation. When t-AMCHA was given in the ovulation-induced rats, the fibrinolytic activity of the ovaries was suppressed, the number of ovulated ova decreased and the timing of ovulation was delayed. When t-AMCHA solution was given to rats in the proestrus phase, ovulation was almost completely suppressed, but aprotinin solution exerted no effect on ovulation. These results suggest that plasminogen activator is a key enzyme in ovulation, and that the chain reaction from plasminogen activator to proteolytic enzyme (including collagenase) is of greater importance than that of plasminogen activator to plasmin.