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)

Cell lines derived from 3 different types of human tumor (e.g., squamous carcinomas, melanomas and gliomas) were examined for production of plasminogen activator activity and for attachment and spreading on various extracellular matrix components in the presence or absence of plasminogen. All of the squamous carcinoma and melanoma lines produced high levels of plasminogen activator activity. In contrast, 4 of 6 glioma lines had undetectable activity. Cells from all 3 tumor types attached and spread on fibrinogen-coated or fibrin-coated plastic dishes in the absence of plasminogen. In the presence of exogenous plasminogen, the attachment and spreading of the cells which produced high levels of plasminogen activator activity was inhibited. The plasminogen activator-deficient cells were much less sensitive to exogenous plasminogen. In the presence of plasminogen, attachment and spreading on fibronectin-coated dishes was also partially inhibited. In contrast, plasminogen had no effect on the attachment and spreading of the cells on type-I or -IV collagen, laminin or thrombospondin. Previous studies have shown that tumor-cell adhesion to the extracellular matrix depends on the synthesis of receptors for extracellular matrix components or on the synthesis of extracellular matrix components themselves. The present study shows that, in addition, the production of enzymes which are capable of degrading these components also influences tumor-cell adhesion to extracellular matrix moieties.
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PMID:Plasminogen activator production by human tumor cells: effect on tumor cell-extracellular matrix interactions. 369 23

Brain cells and glioma cells in culture release a protein which induces neurite outgrowth in neuroblastoma cells. This neurite-promoting factor (NPF), which has been purified from serum-free glioma conditioned medium, has an apparent mol. wt. of 43 000. NPF inhibits urokinase as well as plasminogen activator-dependent caseinolysis or fibrinolysis. NPF and urokinase form an SDS-resistant complex. The fact that this glia-derived NPF is a potent protease inhibitor indicates that glial cells modulate the proteolytic activity associated with neuronal cells and suggests that this phenomenon is one of the biochemical events involved in the regulation of neurite growth.
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PMID:A glia-derived neurite-promoting factor with protease inhibitory activity. 406

The phenotypic expression of cells derived from human anaplastic astrocytomas, rat glioma, normal human adult and foetal brain tissue have been examined for differentiated and malignancy-associated properties. Glial fibrillary acidic protein (GFAP), high affinity glutamate and gamma-amino butyric acid (GABA) uptake and glutamine synthetase were used as indicators of astroglial differentiation. Plasminogen activator and tumour angiogenesis factor were the malignancy-associated markers. The normal adult brain-derived lines showed some differentiated astroglial features and expressed low levels of the malignancy-associated properties. The foetal cultures contained highly differentiated astroglia while the glioma lines showed considerable phenotypic heterogeneity from highly differentiated to undifferentiated. The least differentiated glioma cells exhibited the highest plasminogen activator activities. The density-dependent control of phenotypic expression was also investigated. High affinity GABA uptake, and GFAP in rat C6 glioma cultures, increased with increasing monolayer cell density, events probably mediated by an increase in the formation of cell-cell contacts at confluence. Plasminogen activator activity decreased with increasing cell density.
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PMID:Interrelationship between differentiation and malignancy-associated properties in glioma. 620 Jan 30

The production of plasminogen activator (PA) by two cloned cell lines, one from an ethylnitrosourea-induced glioma (A15A5) and the other from normal adult rat brain (ARBO C9), has been investigated. Three assays were used to detect and measure PA in harvest fluids, cells and cell lysates. Similar levels were detected in harvest fluids from both cell lines. However, the cell and lysate assays indicated much higher levels in the tumor line. When actively growing cells were compared A15A5 cells had approximately 16X more fibrinolytic activity than the control cells with a limit of detection in the order of 10(3) cells or 1 microgram protein (cell lysate). In contrast for the control cells PA could only be detected when upwards of 10(4) cells or 5-10 micrograms protein were assayed. Plaminogen activator in as few as 10(3) tumor cells could be detected in the presence of 10(4) non-tumor cells. Plasminogen activator in 26 micrograms protein of A15A5 cell lysate could also be detected in the presence of 44 micrograms protein from ARBO C9 lysates indicating no inhibitory activity in the control cell lysates. Levels of PA in both harvest fluids and cell lysates were determined as cultures progressed through the growth cycle. For cell lysates this showed a build-up of PA in the normal cell line as the cells approached and attained confluence. A much higher level was measured in the tumor cells soon after seeding and maintained to confluence. No differences in growth cycle-associated changes in secreted PA could be determined in harvest fluids: both cell lines showing similar levels at confluence.
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PMID:Differences in pattern and level of plasminogen activator production between a cloned cell line from an ethylnitrosourea-induced glioma and one from normal adult rat brain. 719 Sep 76

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer, pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n = 82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n = 50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA. Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.
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PMID:Prognostic significance of proteolytic enzymes in human brain tumors. 753 61

Because recent information suggests that the localized deposition of protease inhibitors is one mechanism by which cells regulate pericellular proteolysis during tissue invasion, the distribution of type 1 plasminogen activator inhibitor (PA1-1) associated with the invasive human glioma cell line U-251 was investigated. Direct and reverse fibrin zymography indicated the presence of urokinase-like plasminogen activator (u-PA) and PAI-1 in U-251 conditioned media and cell lysates. PA1-1 antigen was detected immunologically in cytoplasmic granules present within cellular processes of U-251 cells and these organelles could be isolated on Percoll density gradients in a high density band. In contrast, u-PA activity and another secreted protein, amyloid beta-protein precursor, were only present in the low density region of the gradients. Functional analysis of PAI-1 in the granules contained within the high density fractions revealed the presence of active PAI-1. Incubation of U-251 cells with the secretagogue, 8-bromoadenosine 3':5'-cyclic monophosphate, resulted in a 3-fold increase in the release of PAI-1 in the media conditioned by these cells. These data suggest that the human glioma cell line U-251 contains PAI-1 in a rapidly releasable form, which may provide another mechanism by which these tumors could regulate proteolytic activity in a localized manner.
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PMID:Human glioma U-251 cells contain type 1 plasminogen activator inhibitor in a rapidly releasable form. 881 93

Treatment of rat C6 glioma with high doses of 13 cis-retinoic acid (cRA) was responsible for death related to haemorrhagic necrosis localized to the tumor. Our aim was to explore this adverse effect of retinoid treatment. We show that cRA-treated C6 glioma at 25 mg/kg/day for 18 days exhibits in vivo an increase T-PA activity, which is responsible for a localized tumor fibrinolytic activity. Production of t-PA is supported by specific enhancement of gene expression, as was shown by the increase in t-PA mRNA (x 2.3). This production is a direct effect of cRA when treating the tumor, since tumor cells themselves do not produce enough t-PA and treatment of control rats does not increase the t-PA level. T-PA production by rat C6 glioma is in vivo related to the specific synthesis of t-PA by the C6 cell-line. The stimulation of C6 cell-line by cRA in vitro is dose-dependent and reached a maximum for 3 and 30 microM at the 72nd h. So cRA-treated C6 glioma cells produce t-PA which appears to be the major species associated with the fibrinolytic activity-induced intra-tumoral haemorrhage after exposure to retinoid treatment.
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PMID:Retinoids induced t-PA synthesis by C6 glioma cells--role in tumoral haemorrhagic necrosis. 881 86

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

We investigated the role of plasminogen activators (PAs) and their inhibitor (plasminogen activator inhibitor-1, PAI-1) in human brain tumours. The amounts of urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1), and the activity of u-PA and t-PA were determined by enzyme-linked immunosorbent assay (ELISA), and u-PA and PAI-1 were immunolocalized using monoclonal antibodies in human brain tumours and normal brain tissues. The tissues were surgically removed from 64 patients; normal brain tissue (5 cases), low-grade glioma (4 cases), high-grade glioma (17 cases), metastatic tumour (9 cases), meningioma (benign 12 cases, malignant 6 cases), acoustic schwannoma (11 cases). u-PA activity and u-PA and PAI-1 antigen levels were significantly elevated in malignant brain tumours (malignant meningiomas, high-grade gliomas, and metastatic tumours) and acoustic schwannomas but very low in benign meningiomas, low-grade gliomas and normal brain. There was no difference in t-PA antigen levels among normal and malignant tissues, however levels of t-PA activity were markedly decreased in metastastic tumours. All malignant brain tumour tissues showed positive immunostaining for u-PA and PAI-1, however, some tumour cells showed negative intensity while others showed strong intensity for these antibodies. This contrasts to the homogeneous staining pattern found in acoustic schwannoma. These findings indicate that malignancy in human brain tumours is associated with elevated levels of u-PA and PAI-1 and that an imbalance between these proteins in a micro-environment contributes (ascribes) to tumour cell invasion.
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PMID:Production of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) in human brain tumours. 968 30

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


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