Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of plasmin(ogen) in mammary tumor development and progression, plasminogen-deficient mice were crossed with transgenic mice expressing Polyoma middle T antigen under the control of the mouse mammary tumor virus long terminal repeat. Virgin females carrying the Polyoma middle T antigen uniformly developed multiple, bilateral mammary tumors, regardless of the presence or absence of circulating plasminogen. Both the age at which these tumors became palpable and subsequent tumor growth were indistinguishable between plasminogen-deficient mice and plasminogen-expressing littermates. However, plasminogen was found to greatly modify the metastatic potential in this model system; lung metastasis in plasminogen-deficient mice was significantly reduced as compared to littermate controls with respect to frequency of occurrence, total number of metastases, and total metastatic tumor burden. Plasminogen activators, as well as other key factors that govern the conversion of plasminogen to plasmin, were expressed within the mammary tumors, suggesting that the plasminogen/plasmin system may promote metastasis by contributing to tumor-associated extracellular proteolysis. The data provide direct evidence that plasmin(ogen) is a tumor progression factor in PymT-induced mammary cancer, and support the hypothesis that hemostatic factors play an important role in tumor biology.
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PMID:Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice. 967 88

Since tumor growth factor beta (TGF-beta) and its receptor are ubiquitously expressed and because latent TGF-beta cannot bind to the cell surface receptor, the ability of a cell to activate latent TGF-beta upon secretion represents an important regulatory mechanism of TGF-beta action. In vivo, the protease plasmin is considered to be one of the main enzymes operative in the proteolytic cleavage of the latency-associated peptide moiety from TGF-beta, which converts it into the biologically active form. The TGF-beta response was characterized in alveolar macrophages during pulmonary inflammation (d 3) and fibrosis (d 120) induced by a single intratracheal instillation of silica particles (5 mg/mouse). To appreciate the role of urokinase-type plasminogen activator (uPA) in the activation of TGF-beta, the production of total, active and latent TGF-beta by explanted alveolar macrophages was compared in uPA-deficient (uPA-/-) mice and their normal counterparts (uPA+/+). At d 3 and 120 after silica treatment, a significant increase in cell-associated PA activity was found in uPA+/+ mice compared to that of saline controls. As expected, this response was almost totally absent in uPA-/- mice. Alveolar macrophages from uPA+/+ controls were found to release TGF-beta mainly expressed in a biologically active form. In response to silica treatment, inflammatory cells were found to upregulate, especially at the fibrotic stage, their secretion of total and bioactive TGF-beta. No significant difference was found between uPA-/- and uPA+/+ silica-treated animals for the expression of total, active, or latent TGF-beta. Although it has previously been reported that macrophage surface activation of TGF-beta is dependent on both plasmin generation and uPA cell surface receptor, no evidence was found to support this hypothesis in the present study.
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PMID:Role of urokinase in the activation of macrophage-associated TGF-beta in silica-induced lung fibrosis. 982 59

Various proteases and their inhibitors have been shown to be important in tumor invasion. Angiogenesis is further a prerequisite for the growth and progression of solid tumors. Since these systems are functionally linked, in situ hybridization and in situ zymography were used to investigate the spatial and temporal expression of factors representative of the plasmin/plasminogen system and of an angiogenic factor in the BT4C glioma model. This tumor is invasive with a high grade of neovascularization. Tissue-type plasminogen activator urokinase-type plasminogen activator and plasminogen activator inhibitor-1 mRNA were expressed in glioma cells during the entire tumor growth. Early in the tumor development the expression was found throughout the small tumor (approximately 10 mm3) while later in the time course the expression was found predominantly in the invasive tumor border of the tumor. The in situ zymography demonstrated that the plasminogen activators were translated into functional proteins. Vascular endothelial growth factor mRNA was expressed following a similar spatial and temporal pattern with an early expression in the entire small tumor while later, in larger tumors, it was exclusively expressed in the invasive tumor edge. In normal brain, the ventricular ependyma, meninges, as well as scattered neurons expressed tissue-type plasminogen activator mRNA. Vascular endothelial growth factor mRNA was observed in the choroid plexus, and in scattered cells in normal brain tissue. Our finding may suggest a functional co-operation of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1 and vascular endothelial growth factor during glioma progression. This model could be of value when evaluating different treatment modalities aimed at blocking the migrating capacity and growth of glial tumors.
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PMID:Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression. 1057 9

Many studies have highlighted the role played by matrix metalloproteinases MMP-2 and -9, by serine proteases uPA and plasmin in tumor cell invasion. This study investigates the impact of the MMP-inhibitor Batimastat and/or the serine protease inhibitor Aprotinin on the in vitro proteolytic activity and in vivo invasive behavior the of esophageal (OC1) and ovarian (OVCAR-3) carcinoma cells. In presence and absence of inhibitors, proteolytic activity of the tumor cells was determined by caseinolytic and collagenolytic in vitro assays and tumor cell invasion by intraperitoneal inoculation of the tumor cells into nude mice. In vitro, Aprotinin, tested alone or in combination with Batimastat, efficiently inhibited degradation of collagen IV and casein by the tumor cells. Batimastat alone had no effect on caseinolytic activities and only partially blocked collagen-type-IV-degradation by the tumor cells. In vivo, Aprotinin tested alone or in combination with Batimastat did not prevent tumor cell invasion. Treatment of tumor bearing mice with Batimastat significantly inhibited tumor growth but promoted tumor cell invasion into the liver. Our findings demonstrate that the inhibition pattern of cellular proteolytic activity achieved in vitro by a serine protease and an MMP inhibitor may lead to predictions that are not necessarily verified in vivo and may even have adverse effects.
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PMID:Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo. 1062 17

Previously, a specific angiogenesis inhibitor, angiostatin, discovered in urine and serum of tumor-bearing mice, was reported to potently block tumor growth and metastasis in animal models. Detection of angiostatin and its precursor proteins in urine from cancer patients has not been reported. Now, we report the development of an antibody-based analysis system that allows us to detect angiostatin and plasminogen/plasmin (Pgn/plasmin) in the urine of cancer patients. The detection system is a combination of a novel lysine-ELISA assay and Western immunoblot analysis using a specific antibody to human angiostatin and Pgn/plasmin. High levels of Pgn/plasmin were detected in the urine from various cancer patients, whereas healthy individuals showed relatively low levels of urine Pgn/plasmin. Of interest, angiostatin is detectable in urine samples of patients with various cancers, including acute lymphoblastic leukemia, suggesting that angiogenesis may play an important role in the development and progression of leukemia. Our data for the first time show that angiostatin and Pgn/plasmin are present at relatively high levels in the urine of human cancer patients. Detection of urine angiostatin in cancer patients helps us not only to understand the role of this angiogenesis inhibitor in cancer development and progression but also allows us to develop tools of cancer diagnosis and prognosis. Thus angiostatin has both therapeutic and diagnostic implications in cancer disease.
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PMID:Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients. 1076 60

Angiogenesis, the development of new blood vessels from an existing vascular bed, is essential for the growth and spread of malignant tumors. Several endogenous angiogenesis inhibitors have been discovered and shown to suppress endothelial cell function in vitro and tumor growth in vivo. Several of these are proteolytic fragments of larger, endogenous proteins. Here we show that a Mr 50,000 polypeptide derived from the plasmin cleavage of fibrinogen, fibrinogen E-fragment, inhibits endothelial cell migration and tubule formation induced by both proangiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in vitro.
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PMID:Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro. 1098 75

A methanol extract (500 mg/kg x 2/day) of the heartwood of Cassia garrettiana inhibited the tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. We isolated the two active substances from the methanol extract of C. garrettiana: compound 1 was identified as Cassigarol A and the determination of the structure of compound 2 is now in progress. We examined the effect of the active substance (compound 1, Cassigarol A) on tumor growth and lung metastasis in LLC-bearing and primary tumor-removed mice and found that Cassigarol A (50 mg and 100 mg/kg x 2/day) inhibited the tumor growth and metastasis to the lung. In addition, Cassigarol A inhibited the plasmin activity and the formation of capillary-like networks of human umbilical vein endothelial cells (HUVECs) at concentrations of 10 to 100 microM. Therefore, it is suggested that the antitumor and antimetastatic activities of Cassigarol A might be due to the inhibition of plasmin activity and formation of tubes (angiogenesis) from HUVECs.
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PMID:Inhibitory effects of active substances isolated from Cassia garrettiana heartwood on tumor growth and lung metastasis in Lewis lung carcinoma-bearing mice (Part 1). 1106 99

Detailed studies of tumor cell-associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.
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PMID:Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. 1107 21

Angiogenesis, the process by which new blood vessels form from preexisting vasculature, underlies a number of biologic processes including embryologic development, inflammation, wound healing, hypoxic retinal vascular proliferation, tumor growth, and atherosclerosis. The fibrinolytic system represents a cascade of serine protease activation events that culminate in the generation of plasmin. Although in-vitro studies suggest several possible roles that plasmin might play in angiogenesis, angiogenesis and fibrinolytic activity do not always correlate in in-vivo systems. During cutaneous and corneal wound healing, for example, angiogenesis proceeds normally in plasminogen-deficient animals. Similarly, the growth of most neoplasms is unimpaired in the absence of plasminogen. On the other hand, hypoxia-driven vascular proliferation may require plasmin-like activity, and angiogenesis within the atherosclerotic plaque seems to be associated with increased expression of fibrinolytic proteins. Recently, several nonplasmin fibrinolysins that may support the invasive phenotype of endothelial cells under specific circumstances have been identified. Thus, the contribution of individual fibrinolysins appears to be context-specific, just as the profile of endothelial cell gene expression depends upon the surrounding tissue milieu.
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PMID:New concepts in fibrinolysis and angiogenesis. 1112 73

The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.
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PMID:The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. 1126 68


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