ABSTRACT
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.
Subject(s)
Animals , Chick Embryo , Neoplasm Invasiveness , Neoplasms/metabolism , Plasminogen Activators/physiology , Receptors, Cell Surface/physiology , Urokinase-Type Plasminogen Activator/physiology , Neoplasm Metastasis , Signal Transduction , Time FactorsSubject(s)
Animals , Humans , Neoplasm Invasiveness/physiopathology , Neoplasm Metastasis/physiopathology , Neoplasm Proteins/physiology , Plasminogen Activators/physiology , Extracellular Matrix/physiology , Fibrinolysis , Neoplastic Cells, Circulating , Neoplasm Proteins/blood , Neoplasms, Experimental/blood , Neoplasms, Experimental/pathology , Prognosis , Plasminogen Activators/blood , Biomarkers, Tumor/blood , Urokinase-Type Plasminogen Activator/therapeutic useABSTRACT
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