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International Journal of Molecular... Feb 2021Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere... (Review)
Review
Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere extracellular-matrix-degrading enzymes, fibrinolytic factors interfere with many processes during primary cancer growth and metastasis. Their many receptors give them access to cellular functions that tumor cells have widely exploited to promote tumor cell survival, growth, and metastatic abilities. They give cancer cells tools to ensure their own survival by interfering with the signaling pathways involved in senescence, anoikis, and autophagy. They can also directly promote primary tumor growth and metastasis, and endow tumor cells with mechanisms to evade myelosuppression, thus acquiring drug resistance. In this review, recent studies on the role fibrinolytic factors play in metastasis and controlling cell-death-associated processes are presented, along with studies that describe how cancer cells have exploited plasminogen receptors to escape myelosuppression.
Topics: Anoikis; Autophagy; Cell Survival; Cellular Senescence; Drug Resistance, Neoplasm; Exosomes; Extracellular Matrix; Humans; Neoplasm Metastasis; Neoplasms; Plasminogen; Plasminogen Inactivators; Signal Transduction
PubMed: 33669052
DOI: 10.3390/ijms22052304 -
Cancer Metastasis Reviews Sep 2019The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an... (Review)
Review
The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an abundant scientific literature that has pointed to a pro-angiogenic role, a growth and migration stimulatory function, and an anti-apoptotic activity, all directed toward promoting tumor growth, cancer cell survival, and metastasis. With uPA, PAI-1 is among the most reliable biomarkers and prognosticators in many cancer types. More recently, a novel pro-tumorigenic function of PAI-1 in cancer-related inflammation has been demonstrated. These multifaceted activities of PAI-1 in cancer progression are explained by the complex structure of PAI-1 and its multiple functions that go beyond its anti-fibrinolytic and anti-plasminogen activation activities. However, despite the multiple evidences supporting a pro-tumorigenic role of PAI-1 in cancer, and the development of several inhibitors, targeting PAI-1, has remained elusive. In this article, the various mechanisms responsible for the pro-tumorigenic functions of PAI-1 are reviewed with emphasis on its more recently described contribution to cancer inflammation. The challenges of targeting PAI-1 in cancer therapy are then discussed.
Topics: Animals; Biomarkers, Tumor; Disease Progression; Humans; Models, Molecular; Neoplasms; Plasminogen Activator Inhibitor 1; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic
PubMed: 31734763
DOI: 10.1007/s10555-019-09806-4 -
Journal of Cellular Physiology Feb 2012Fibrosis is defined as a fibroproliferative or abnormal fibroblast activation-related disease. Deregulation of wound healing leads to hyperactivation of fibroblasts and... (Review)
Review
Fibrosis is defined as a fibroproliferative or abnormal fibroblast activation-related disease. Deregulation of wound healing leads to hyperactivation of fibroblasts and excessive accumulation of extracellular matrix (ECM) proteins in the wound area, the pathological manifestation of fibrosis. The accumulation of excessive levels of collagen in the ECM depends on two factors: an increased rate of collagen synthesis and or decreased rate of collagen degradation by cellular proteolytic activities. The urokinase/tissue type plasminogen activator (uPA/tPA) and plasmin play significant roles in the cellular proteolytic degradation of ECM proteins and the maintenance of tissue homeostasis. The activities of uPA/tPA/plasmin and plasmin-dependent MMPs rely mostly on the activity of a potent inhibitor of uPA/tPA, plasminogen activator inhibitor-1 (PAI-1). Under normal physiologic conditions, PAI-1 controls the activities of uPA/tPA/plasmin/MMP proteolytic activities and thus maintains the tissue homeostasis. During wound healing, elevated levels of PAI-1 inhibit uPA/tPA/plasmin and plasmin-dependent MMP activities, and, thus, help expedite wound healing. In contrast to this scenario, under pathologic conditions, excessive PAI-1 contributes to excessive accumulation of collagen and other ECM protein in the wound area, and thus preserves scarring. While the level of PAI-1 is significantly elevated in fibrotic tissues, lack of PAI-1 protects different organs from fibrosis in response to injury-related profibrotic signals. Thus, PAI-1 is implicated in the pathology of fibrosis in different organs including the heart, lung, kidney, liver, and skin. Paradoxically, PAI-1 deficiency promotes spontaneous cardiac-selective fibrosis. In this review, we discuss the significance of PAI-1 in the pathogenesis of fibrosis in multiple organs.
Topics: Fibrosis; Gene Expression Regulation; Humans; Plasminogen Activator Inhibitor 1
PubMed: 21465481
DOI: 10.1002/jcp.22783 -
Cellular and Molecular Life Sciences :... Mar 2011The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and... (Review)
Review
The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α(2)-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α(2)-antiplasmin, the plasmin-antiplasmin system is also regulated by the general protease inhibitor α(2)-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamily.
Topics: Antifibrinolytic Agents; Binding Sites; Blood Coagulation; Fibrinolysis; Humans; Models, Biological; Models, Molecular; Plasminogen; Plasminogen Activators; Plasminogen Inactivators; Protein Structure, Tertiary; Serine Proteases; Serine Proteinase Inhibitors; alpha-Macroglobulins
PubMed: 21136135
DOI: 10.1007/s00018-010-0566-5 -
American Journal of Respiratory and... Mar 2023
Topics: Humans; Plasminogen Activator Inhibitor 1; Pleural Diseases; Pleural Effusion; Exudates and Transudates
PubMed: 36269762
DOI: 10.1164/rccm.202210-1925ED -
Cell Chemical Biology Dec 2021Aberrant protein citrullination is associated with many pathologies; however, the specific effects of this modification remain unknown. We have previously demonstrated...
Aberrant protein citrullination is associated with many pathologies; however, the specific effects of this modification remain unknown. We have previously demonstrated that serine protease inhibitors (SERPINs) are highly citrullinated in rheumatoid arthritis (RA) patients. These citrullinated SERPINs include antithrombin, antiplasmin, and t-PAI, which regulate the coagulation and fibrinolysis cascades. Notably, citrullination eliminates their inhibitory activity. Here, we demonstrate that citrullination of antithrombin and t-PAI impairs their binding to their cognate proteases. By contrast, citrullination converts antiplasmin into a substrate. We recapitulate the effects of SERPIN citrullination using in vitro plasma clotting and fibrinolysis assays. Moreover, we show that citrullinated antithrombin and antiplasmin are increased and decreased in a deep vein thrombosis (DVT) model, accounting for how SERPIN citrullination shifts the equilibrium toward thrombus formation. These data provide a direct link between increased citrullination and the risk of thrombosis in autoimmunity and indicate that aberrant SERPIN citrullination promotes pathological thrombus formation.
Topics: Animals; Antifibrinolytic Agents; Antithrombins; Disease Models, Animal; Female; Male; Mice; Mice, Inbred C57BL; Peptide Hydrolases; Plasminogen Inactivators; Serine Proteinase Inhibitors; Venous Thrombosis
PubMed: 34352225
DOI: 10.1016/j.chembiol.2021.07.009 -
FEBS Letters Feb 1994Recent findings have elucidated the mechanism for clearance from the extracellular space of the two types of plasminogen activators, urokinase-type plasminogen activator... (Review)
Review
Recent findings have elucidated the mechanism for clearance from the extracellular space of the two types of plasminogen activators, urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA), and their type-1 inhibitor (PAI-1). Activator/PAI-1 complexes and uncomplexed t-PA bind to the multi-ligand receptors alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR) and epithelial glycoprotein 330 (gp330). These receptors mediate endocytosis and degradation of u-PA/PAI-1 complex bound to the glycosyl phosphatidyl inositol-anchored urokinase receptor (u-PAR) on cell surfaces, and participate, in cooperation with other receptors, in hepatic clearance of activator/PAI-1 complexes and uncomplexed t-PA from blood plasma. The alpha 2MR- and gp330-mediated endocytosis of a ligand (u-PA/PAI-1 complex) initially bound to another receptor (u-PAR) is a novel kind of interaction between membrane receptors. Binding to alpha 2MR and gp330 is a novel kind of molecular recognition of serine proteinases and serpins.
Topics: Amino Acid Sequence; Animals; Endocytosis; Heymann Nephritis Antigenic Complex; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Membrane Glycoproteins; Molecular Sequence Data; Plasminogen Activators; Plasminogen Inactivators; Receptors, Immunologic
PubMed: 8307187
DOI: 10.1016/0014-5793(94)80276-9 -
American Journal of Hematology Sep 2008Variation in bleeding in the perioperative period is a complex and multifactorial event associated with immediate and delayed consequences for the patient and health... (Review)
Review
Variation in bleeding in the perioperative period is a complex and multifactorial event associated with immediate and delayed consequences for the patient and health care resources. Little is known about the complex genetic influences on perioperative bleeding. With the discovery of multiple variations in the human genome and ever-growing databases of well-phenotyped surgical patients, better identification of patients at risk of bleeding is becoming a reality. In this review, polymorphisms in the platelet receptor genes, plasminogen activator inhibitor, and angiotensin genes among others will be discussed. We will explore the nature, effects, and implications of the genetics that influence perioperative bleeding above and beyond surgical bleeding, particularly in cardiac surgery.
Topics: Angiotensins; Blood Coagulation Factors; Blood Coagulation Tests; Blood Loss, Surgical; Blood Proteins; Cardiac Surgical Procedures; Genetic Predisposition to Disease; Genetic Variation; Genotype; Hemorrhagic Disorders; Hemostasis; Humans; Plasminogen Inactivators; Platelet Activation; Polymorphism, Genetic; Postoperative Hemorrhage; Risk Factors
PubMed: 18508320
DOI: 10.1002/ajh.21205 -
Blood Feb 1987
Review
Topics: Amyloid beta-Protein Precursor; Carrier Proteins; Glycoproteins; Humans; Plasminogen Activators; Plasminogen Inactivators; Protease Inhibitors; Protease Nexins; Receptors, Cell Surface
PubMed: 3099859
DOI: No ID Found -
Annals of Palliative Medicine Oct 2021Endothelium injury and coagulation dysfunction play an important role in the pathogenesis of sepsis. Soluble thrombomodulin (sTM), tissue plasminogen activator-inhibitor... (Observational Study)
Observational Study
Identification of soluble thrombomodulin and tissue plasminogen activator-inhibitor complex as biomarkers for prognosis and early evaluation of septic shock and sepsis-induced disseminated intravascular coagulation.
BACKGROUND
Endothelium injury and coagulation dysfunction play an important role in the pathogenesis of sepsis. Soluble thrombomodulin (sTM), tissue plasminogen activator-inhibitor complex (t-PAIC), thrombin-antithrombin complex (TAT) and α2-plasmin inhibitor-plasmin complex (PIC) are biomarkers of endothelium injury and coagulation dysfunction. This study aimed to explore the prognostic values and diagnostic performance for septic shock and sepsis-induced disseminated intravascular coagulation (DIC) of endothelial biomarkers.
METHODS
We conducted an observational study on patients with sepsis admitted to intensive care unit (ICU) at a teaching hospital from January 2016 to December 2018. Levels of sTM, t-PAIC, TAT and PIC were measured at admission day and day 5-7 after admission and detected by qualitative chemiluminescence enzyme immunoassay performed on HISCL automated analyzers.
RESULTS
A total of 179 septic patients and 125 non-septic ICU controls were enrolled. The level of sTM was higher in septic patients compared to ICU controls (OR =1.093, 95% CI: 1.045-1.151, P<0.001). Moreover, higher levels of sTM and t-PAIC were independent predictors of poor 60-day prognosis for septic patients (HR =1.012, 95% CI: 1.003-1.022, P=0.012; HR =1.014, P=0.009). Level of sTM was also higher in patients with septic shock as revealed by multivariate analysis (OR =1.049, 95% CI: 1.020-1.078, P=0.001), as well as in patients with sepsis-induced DIC (OR =1.109, 95% CI: 1.065-1.158, P<0.001). sTM was considered as a sensitive biomarker for the early prediction of septic shock and sepsis-induced DIC, with AUC up to 0.765 (0.687-0.842) and 0.864 (0.794-0.935) of receiver operating characteristic curve.
CONCLUSIONS
Most patients developed coagulopathy which was closely linked to endothelial injury in initial phase of sepsis, which was demonstrated by abnormalities in endothelial biomarkers and their strong association with poor 60-day prognosis and development of septic shock and sepsis-induced DIC.
Topics: Biomarkers; Disseminated Intravascular Coagulation; Humans; Plasminogen Inactivators; Prognosis; Sepsis; Shock, Septic; Thrombomodulin; Tissue Plasminogen Activator
PubMed: 34551574
DOI: 10.21037/apm-21-2222