Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular receptor for urokinase-type plasminogen activator (uPAR) in glioblastoma cell lines has been identified and found to be similar to the uPAR expressed by other tumor cell lines. Increased levels of uPAR have been found in primary malignant brain tumor tissues, especially highly malignant glioblastoma, and, to a lesser degree, in malignant astrocytomas, suggesting that this receptor might be involved in efficient activation of pro-uPA and confinement of uPA activity on the cell surface of invading brain tumors. The cell surface uPARs in gliomas could constitute an optimum environment for the generation and activity of plasmin, which is known to play a crucial role in the dissolution of the extracellular matrix during tumor cell invasion. In situ hybridization studies have shown that uPAR mRNA is expressed abundantly in tumor cells and is consistently present at the invasive edges of malignant gliomas. These results imply that uPAR is involved in plasmin-catalyzed proteolysis during glioma invasion and that interference with the uPA:uPAR interactions could constitute a novel approach for developing therapeutic strategies to counteract invasion of brain tumors.
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PMID:Proteolysis and invasiveness of brain tumors: role of urokinase-type plasminogen activator receptor. 774 67

Extracellular proteinases may be selectively targeted to cell surfaces by specific receptors or binding sites. In previous studies, we have characterized cellular binding sites for plasminogen and plasmin on rat C6 glioma cells. In this investigation, we studied the response of C6 cells to alpha-thrombin and plasmin by measuring the rapid kinetics of free intracellular Ca2+ concentrations ([Ca2+]i). Thrombin produced a strong, concentration-dependent rise in [Ca2+]i with an onset within 3 s and peak levels achieved in less than 10 s. A similar response was also evoked by an SFLLRN-containing thrombin-agonist peptide. C6 cells did not respond to plasmin (25 nM-1.5 microM). By contrast, pretreatment of C6 cells with 100 nM plasmin significantly inhibited the [Ca2+]i response to thrombin and the thrombin-agonist peptide. The peak [Ca2+]i response to thrombin, in cells pretreated with plasmin, was reduced by approx. 50%. The effect of plasmin on the cellular response to thrombin was selective, as pretreatment of the cells with plasmin did not affect the [Ca2+]i response to platelet-activating factor. Di-isopropylphosphorylplasmin and plasminogen did not inhibit the cellular response to thrombin, indicating that plasmin activity is required and that occupancy of cellular plasmin(ogen)-binding sites alone is insufficient. These studies demonstrate that plasmin does not directly induce a response in C6 cells, but may affect cellular function by specifically modulating the thrombin response.
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PMID:Plasmin modulates the thrombin-evoked calcium response in C6 glioma cells. 828 96

Anisoylated Lys-plasminogen streptokinase activator complex (APSAC) was purified from Eminase by chromatography on Superose-12. Purified APSAC did not significantly deacylate within 4 h at 4 degrees C in solution as determined by hydrolysis of D-Val-L-leu-L-lys-p-nitroanilide HCl (S-2251). At 37 degrees C, maximum amidase activity developed in 120 min; epsilon-amino-n-caproic acid (EACA) did not affect the apparent rate of APSAC deacylation but stabilized the streptokinase-plasmin(ogen) complex (SkPl) which formed. APSAC bound to C6 glioma cells and human umbilical vein endothelial cells (HUVECs) in culture. Binding as completely inhibited by EACA suggesting an essential role for the plasminogen kringle domains. Cell-associated APSAC deacylated to form active SkPl which hydrolyzed S-2251 and D-Val-Leu-Lys-7-amino-4-methyl coumarin. The rate of APSAC deacylation was increased when the APSAC was cell-associated. APSAC that was initially bound to C6 cells or HUVECs also activated 125I-plasminogen. This activity may have reflected cell-associated APSAC or APSAC but dissociated into solution. Plasmin was recovered bound to cells and in solution. These studies demonstrate that APSAC associates with cell-surfaces and retains activity. In the circulation, cell-surfaces may provide a significant pharmacologic compartment for intravenously administered APSAC.
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PMID:Binding of anisoylated Lys-plasminogen streptokinase activator complex to cells in culture. 838 80

Protease nexin 1 (PN1), a serine protease inhibitor that inactivates thrombin, urokinase, and plasmin, is produced abundantly in cultures of human fibroblasts and rat and human glioma cells. The major sites of PN1 synthesis in vivo and the specific physiological function(s) of this serpin are unknown. Using Northern blot analysis and a full-length PN1 cDNA probe we demonstrated the presence of PN1 mRNA in human term placentas. In situ hybridization of placental tissue with a PN1 riboprobe showed that PN1 mRNA is present throughout the placenta and is also abundant in the placental membranes. Immunohistochemical analysis with an anti-PN1 antibody showed co-localization of PN1 and its mRNA within the placenta.
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PMID:Protease nexin 1 is expressed in the human placenta. 845 23

We have previously demonstrated a low-affinity (0.8 microM, non-covalent complex formation between high-molecular-mass kininogen (HK) and plasminogen (Plg) which prevented Plg interaction with glioma and endothelial cells. We have now extended our previous observations by exploring the potential complex formation between Plg and low-molecular-mass kininogen (LK) and between LK and HK with Plg cleaved with human neutrophil elastase (HNE). Plg cleavage by HNE (PlgHNE) yielded kringles 1-3, kringle 4 and mini-plasminogen. PlgHNE was subjected to SDS/PAGE under non-reducing conditions, followed by western blotting, and incubated with either 125I-HK or 125I-LK. Autoradiograms revealed that 125I-HK bound to miniplasminogen and to kringles 1-3 but not to kringle 4 and the presence of 10 mM 6-aminohexanoic acid (Ahx) disrupted only the interaction with kringles 1-3. In contrast, 125I-LK bound to miniplasminogen but not to kringles 1-3 or 4 and Ahx had no effect at all. The complex formation of either HK (0.67 microM) or LK (3 microM) with Plg (1.5 microM) did not affect its conversion to plasmin by tissue plasminogen activator (t-PA) (10 U/ml) in the presence of a tissue plasminogen stimulator (0.14 microM). However, the rate of conversion of plasminogen to plasmin by t-PA was affected when platelets were added to the reaction mixture. Since HK (0.83 microM) has been shown to inhibit plasmin-induced platelet aggregation, we investigated whether this inhibitory property is found within the heavy chain shared by HK and LK. We found that LK inhibited plasmin-induced platelet aggregation, but a 4-fold molar excess was required when compared to HK. Compared to plasmin, 3-5-fold molar excess of miniplasmin is required to induce platelet aggregation, indicating the important role of kringles 1-3 for plasmin interactions with these cells. These results indicate that HK and LK-mediated inhibition of plasmin-induced platelet aggregation is likely due to complex formation with kringle 5 without interfering with plasmin's active site. We found an additional interaction between HK and kringles 1-3 enhancing the inhibitory effect, presumably by interfering with plasmin's interaction with platelets. This HK and LK-associated modulation of plasmin-induced platelet aggregation may serve as a template to develop synthetic peptides as novel therapeutic agents to prevent some of the plasmin-associated thrombocytopenia seen during thrombolytic therapy.
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PMID:High-molecular-mass and low-molecular-mass kininogens block plasmin-induced platelet aggregation by forming a complex with kringle 5 of plasminogen/plasmin. 942 7

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

In this study, the authors have demonstrated the effect of lithium, a typical mood stabilizer, on thrombin-evoked Ca2+ mobilization in C6 cells to elucidate the action mechanisms of the drug. Thrombin-induced Ca2 mobilization was reduced 24 hr after 1 or 10 mM lithium chloride (LiCl) pretreatment. The Ca2+ rise was reduced in a time-dependent manner, and the significant inhibition was observed 9 hr pretreatment with 10 mM LiCl. On the other hand, pretreatment of the cells with 10 mM LiCl for 24 hr did not alter the amount of Galphaq/11 significantly. Pretreatment with 10 mM LiCl for 24 hr failed to reduce the 5-HT-induced Ca2+ mobilization or to affect the desensitization of the 5-HT signal. Finally, thrombin-elicited Ca2+ rise was markedly inhibited in the presence of 0.05 U/ml plasmin, however, the Ca2+ rise was not further attenuated in the presence of plasmin in C6 cells pretreated with LiCl for 24 hr. These results indicate that pretreatment with LiCl attenuated thrombin-evoked intracellular Ca2+ mobilization in plasmin sensitive manner in C6 rat glioma cells. Thus, it is important to investigate the effect of lithium on thrombin-induced cellular responses to clarify the action mechanism of lithium in relation to some abnormality in thrombin-evoked Ca2+ rise observed in bipolar disorders.
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PMID:Lithium chloride inhibits thrombin-induced intracellular calcium mobilization in C6 rat glioma cells. 1065 85

As a means of defining functionally important regions of the L1 neuronal cell adhesion molecule, neurite outgrowth from cerebellar neurons was compared on monolayers of L1-negative B28 glioma cells, B28 cells transfected with wild-type human L1, and B28 cells transfected with variant forms of L1. Neurite outgrowth on L1-positive B28 cells is greatly enhanced over that seen on parental B28 cells. Neurite outgrowth on B28 cells expressing L1 variants that lack either the first or the fifth fibronectin type III repeat is comparable to that seen on monolayers expressing wild-type L1. In contrast, B28 cells expressing L1 without the third fibronectin type III repeat do not support neurite outgrowth above the background level seen on parental B28 cells. This suggests that the third fibronectin type III repeat plays a key role in the ability of L1 to promote neurite extension. This is consistent with reports that the third fibronectin type III repeat mediates L1 homomultimerization and integrin binding and that plasmin cleavage within this domain interferes with L1 function by abolishing these molecular interactions.
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PMID:The third fibronectin type III repeat is required for L1 to serve as an optimal substratum for neurite extension. 1086 97

Characteristics of human malignant glioma are excessive proliferation, infiltrative growth, angiogenesis and suppression of anti-tumor immune surveillance. Transforming growth factor-beta (TGF-beta), a versatile cytokine, is intimately involved in the regulation of these processes. Here, we discuss the interactions of TGF-beta with growth factors, such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet derived growth factor (PDGF), metalloproteinases (MMP-2, MMP-9) and their inhibitor, plasmin activator inhibitor-1 (PAI-1), and immune cells, like natural killer cells, T-cells and microglia. The differential effects of TGF-beta in glioma biology are outlined with emphasis on the induction of a survival advantage for glioma cells by enforced cell growth, migration, invasion, angiogenesis and immune paralysis. By virtue of its growth regulatory and immunomodulatory properties, TGF-beta promises to become a novel target for the experimental therapy of human malignant glioma.
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PMID:Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. 1117 Feb 99

Protease inhibitors regulate a variety of physiological and pathological processes including angiogenesis, embryo implantation, intravascular fibrinolysis, wound healing, and tumor invasion. Tissue factor pathway inhibitor (TFPI) 2 is a Mr 32,000 Kunitz-type serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase-type plasminogen activator, tissue plasminogen activator, or thrombin. In this study, we determined the relative amounts of TFPI-2 in low-, intermediate-, and high-grade human glioma cell lines and tumor tissue samples. TFPI-2 protein and mRNA levels (measured by Western and Northern blotting) were highest in low-grade glioma cells (Hs683), lower in anaplastic astrocytoma cells (SW1088 and SW1783), and undetectable in high-grade glioma cells (SNB19). Analysis of TFPI-2 protein in human normal brain and in glioma tumor tissues for TFPI-2 revealed the highest levels in normal brain, lesser amounts in low-grade gliomas and anaplastic astrocytomas, and undetectable amounts in glioblastomas. In situ hybridization of TFPI-2 mRNA with normal brain tissues revealed the greatest positivity in neurons, with moderate positivity in both glial and endothelial cells and moderate, little, or no TFPI-2 mRNA in low-grade glioma, anaplastic astrocytoma, and glioblastoma tumor tissue samples, respectively. We also found that recombinant TFPI-2 inhibited the invasiveness of SNB19 glioblastoma cells in a Matrigel assay in a dose-dependent manner. Collectively, these results suggest that TFPI-2 has a regulatory role in the invasiveness of gliomas in vitro and in vivo.
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PMID:Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. 1129 50


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