Plasminogen activator inhibitor type-1: Its structure, biological activity and role in tumorigenesis (Review)

Department of Laboratory Diagnostics and Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
International Journal of Molecular Medicine (Impact Factor: 2.09). 07/2004; 13(6):759-66. DOI: 10.3892/ijmm.13.6.759
Source: PubMed


Plasminogen activator inhibitor type-1 (PAI-1), is a unique member of serpin superfamily, the primary regulator of plasminogen activation and therefore essential factor regulating physiological thrombotic/fibrinolytic balance in vivo. Via interactions with integrins and extracellular matrix components it orchestrates also cell adhesion and migration. Therefore, PAI-1 is considered one of the key regulators of tumor invasion and metastasis, as well as cancer-related angiogenesis. This review summarizes recent findings on the structure and functional activity of the plasminogen activator inhibitor type-1, and current opinions on its role in tumorigenesis.

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    • "are the spesific point mutations that have been reported as a risk factors for the development of venous thrombosis for Factor V gene (Zaatari et al., 2006). The plasminogen activator inhibitor-1 gene (PAI-1) is an essential regulator of plasminogen activation and has been linked to the pathogenesis of lung carcinomas (Pavey et al., 1996; Chorostowska-Wynimko et al., 2004). The angiotensinconverting enzyme (ACE) is a zinc metallopeptidase that plays an important role in the blood pressure and inflammation. "
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    ABSTRACT: Background: A large variety of familiar and non-familiar lung carcinomas (LC) are caused by long term exposure to chemical carcinogens that are present in tobacco smoke. We aimed to investigate the prevalence of 5 thrombophilic germ-line mutations in patients with lung carcinomas. Materials and methods: A total of 52 LC patients and 212 healthy controls from same population were analyzed for FV Leiden, factor V H1299R (R2), PAI-1, MTHFR C677T, MTHFR A1298C, ACE I/D, and Apo E genes and compared. Results: Overall, heterozygous and/or homozygous point mutations in FV Leiden Apo E2, PAI-1 and MTHFR C677T genes were associated with LC in the current cohort. There was no meaningful association between LC and ACE I/D gene markers. Conclusions: The current results showed that LC is related to combined thrombophilic gene mutations and individuals with homozygosity of 4G in PAI-1 and MTHFR C677T genes and heterozygosity of FV Leiden, Apo E4 genes have a germ-line risk for LC tumorigenesis.
    Asian Pacific journal of cancer prevention: APJCP 09/2013; 14(9):5449-54. DOI:10.7314/APJCP.2013.14.9.5449 · 2.51 Impact Factor
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    • "PAI-1 is part of the Plasminogen Activator (PA) system that includes also urokinase Plasminogen Activator (uPA) and its receptor (uPAR). In addition to catalyzing the degradation of the extracellular matrix and modulating cell adhesion [13], [14], various components of the PA system also influence cell migration [15], [16], [17]. Binding of PAI-1 to Vitronectin (VN) stabilizes PAI-1 in its active conformation. "
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    ABSTRACT: The microenvironment of a tumor can influence both the morphology and the behavior of cancer cells which, in turn, can rapidly adapt to environmental changes. Increasing evidence points to the involvement of amoeboid cell migration and thus of cell blebbing in the metastatic process; however, the cues that promote amoeboid cell behavior in physiological and pathological conditions have not yet been clearly identified. Plasminogen Activator Inhibitor type-1 (PAI-1) is found in high amount in the microenvironment of aggressive tumors and is considered as an independent marker of bad prognosis. Here we show by immunoblotting, activity assay and immunofluorescence that, in SW620 human colorectal cancer cells, matrix-associated PAI-1 plays a role in the cell behavior needed for amoeboid migration by maintaining cell blebbing, localizing PDK1 and ROCK1 at the cell membrane and maintaining the RhoA/ROCK1/MLC-P pathway activation. The results obtained by modeling PAI-1 deposition around tumors indicate that matrix-bound PAI-1 is heterogeneously distributed at the tumor periphery and that, at certain spots, the elevated concentrations of matrix-bound PAI-1 needed for cancer cells to undergo the mesenchymal-amoeboid transition can be observed. Matrix-bound PAI-1, as a matricellular protein, could thus represent one of the physiopathological requirements to support metastatic formation.
    PLoS ONE 02/2012; 7(2):e32204. DOI:10.1371/journal.pone.0032204 · 3.23 Impact Factor
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    • "The fibrinolytic system also plays an important role in tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is one of the key regulators of tumor invasion, metastasis and cancer related angiogenesis (Falanga and Rickles, 1999; Chorostowska-Wynimko et al., 2004). Whole blood thromboelastography (TEG Haemoscope) evaluates primary hemostasis, secondary hemostasis, the fibrinolytic system, and clot strength. "
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    ABSTRACT: Hemostatic abnormalities were investigated in 32 dogs with carcinoma and 19 age-matched healthy dogs. Thromboelastography, hemostasis profile (i.e. prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen concentration), platelet count (PLT), thrombin-antithrombin complexes (TAT), and plasminogen activator inhibitor-1 (PAI-1) activity were evaluated. Dogs with carcinomas had faster thrombus generation (TEG(TG), a mathematic value obtained from the first derivate of the thromboelastographic tracing; 834.8±91.1 vs. 707.8±75.8mm/min; mean±SD), increased fibrinogen concentration (276 vs. 151mg/dL), and PLT (425 vs. 324U×10(9)/L), but had decreased PAI-1 activity (15.7 vs. 26.2IU/mL).The most common hemostatic abnormalities found in carcinoma dogs were hypercoagulability (TEG(TG)>mean+2 SD of healthy dogs) and thrombocytosis (PLT>424×10(9)U/L) in 46% of cases, and hyperfibrinogenemia (fibrinogen >384mg/dL) in 32% of cases. Disseminated intravascular coagulation was uncommon and the extent of disease was not correlated with hypercoagulability. TEG(TG) showed good correlation with fibrinogen (r=0.80) and hyperfibrinogenemia seems to be a main factor of the hypercoagulable state in carcinoma dogs. In conclusion, TEG(TG) is a valid parameter to diagnose hypercoagulability.
    The Veterinary Journal 03/2011; 190(2):e78-83. DOI:10.1016/j.tvjl.2011.02.025 · 1.76 Impact Factor
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