Article

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: 1.88). 07/2004; 13(6):759-66. DOI: 10.3892/ijmm.13.6.759
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Ewa Skrzypczak-Jankun, Jul 14, 2015
0 Followers
 · 
109 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 2.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasminogen activator inhibitor type-1 (PAI-1) is considered one of the key regulators of tumor invasion, metastasis, as well as cancer-related angiogenesis. The literature suggests that PAI-1 plays a dual role in these processes because it inhibits plasmin-originated proteolysis and binds to vitronectin or integrins. Stimulation or inhibition of angiogenesis largely depends on which of these elements PAI-1 interacts. Wild PAI-1 converts quickly into its latent, inactive form and loses its anti-proteolytic activity, but still binds to vitronectin and integrins. Thus we constructed PAI-1s with extended half-life to prolong their anti-proteolytic activity. We have analyzed the effects of sprout formation inhibition by PAI-1s on two functionally different endothelial cell (EC) systems, human umbilical vein endothelial cells (HUVEC), expressing moderate amounts of urokinase (uPA), and human lung microvascular endothelial cells (HLMVEC), expressing high amounts of this enzyme. We have used wild-type PAI-1 (wPAI-1) (t(1/2) = 1.6 h) and PAI-1 cysteine mutants (CysPAI-1) characterized by their prolonged half-life time (hDbetaT) (t(1/2) = 63.6 h and t(1/2) = 7,000 h). We have observed a significant inhibitory dose-dependent effect exerted by the CysPAI-1s on sprout formation by HUVEC and HLMVEC cells. The inhibition rate was considerably stronger in lung capillary cell cultures and significantly more pronounced for CysPAI-1 mutants with longer anti-uPA activity (betaT). wPAI-1 with a short anti-proteolytic half-life has induced sprout formation in HUVEC, but not in HLMVEC cultures. This difference in behavior was most likely related to the presence of excessive amounts of uPA in HLMVEC cells and the known mechanism of clearing PAI-1/uPA/uPAR complexes from the cell surface. A less efficient system of HUVEC cells might give wPAI-1 the chance to interact with non-proteolytic pathways of angiogenesis stimulation. We conclude that while the anti-proteolytic properties of PAI-1 constructs are preserved, these proteins inhibit angiogenesis and inhibitory activity dominates over any stimulatory effects of PAI-1.
    Oncology Reports 01/2005; 12(6):1155-62. DOI:10.3892/or.12.6.1155 · 2.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the human endometrium, stromal cells mediate the proliferative response of epithelial cells to the steroid hormones estrogen and progesterone. These stromal-epithelial interactions are readily studied in vitro by coculture of both cell types. A major impediment to such studies is the rapid senescence of normal stromal cells. To circumvent this problem, we tested whether human endometrial stromal cells immortalized by expressing a transduced human telomerase reverse transcriptase (TERT) subunit retained the ability to mediate hormonal control of epithelial proliferation in the coculture assay. We found that the telomerized stromal cells were very similar to the parental strain from which they were derived according to criteria of proliferation, karyotype, cellular localization of cytoskeletal markers and nuclear staining, and basal gene expression based on microarray analysis. We also showed that expression of estrogen and progesterone receptors, as assessed by immunodetection, was similar in both telomerized and parental stromal cells. Importantly, the telomerized stromal cells were shown in coculture assay to be as effective as normal stromal cells in regulating the proliferation of endometrial epithelial cells in response to estrogen or progesterone. The availability of these long-lived stromal cells may advance studies addressing the mechanistic, regulatory, and cell structural basis of stromal-epithelial interactions and hormonal responses in normal, preneoplastic, and neoplastic human endometrial tissue.
    Biology of Reproduction 08/2005; 73(1):106-14. DOI:10.1095/biolreprod.104.035063 · 3.45 Impact Factor
Show more