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)

To investigate the mechanisms of proteolysis within the glioma, and tissue reactions against glioblastoma, immunohistochemical detection both outside and inside of the tumor was performed using seven brains with glioblastoma that were obtained from autopsies. Immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-1,-2,-9, membrane-type matrix metalloproteinase (MT-MMP), interleukin (IL)1-beta, and IL-6. The data were translated into color graphics and the localization of these proteins was analyzed. In glial cells around the tumor, GFAP, VEGF, MMP-2, and MT-MMP were strongly expressed. Moreover, IL1-beta was also expressed strongly in the glial cells at the periphery of the tumor. IL-6 was recognized outside of the tumor, but was expressed only in the swollen astrocytes and normal pyramidal cells. These data suggest that in the periphery of the tumor, tissue reconstruction processes take place with concomitant degradation of the matrix by MMP-2 and MT-MMP, as well as vascular remodeling promoted by VEGF. The fact that IL1-beta, but not IL-6, was expressed strongly in the glial cells around the tumor, may indicate that these proteins expressed outside of the tumor are not utilized for tumor growth, but may be used to guard the tumor against invasions, such as immune response.
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PMID:Immunohistochemical analysis of reactive astrocytes around glioblastoma: an immunohistochemical study of postmortem glioblastoma cases. 1193 42

We have previously reported on the anti-invasive and angiosuppressive effects of SI-27, an anti-matrix metalloproteinase (MMP) agent. The molecular mechanism of its anti-MMP action, however, has not yet been determined. The purpose of this study was to investigate the effects of SI-27 on MMP- 1, -2, -3, -9, and TIMP-1, -2 secreted by human glioma cell lines (U87MG, U251MG, U373MG, and Y98G). When cells were exposed to non-cytotoxic concentrations of SI-27 (preliminarily determined by the MTT assay), expressions of mRNAs for the enzymes was not inhibited. For an MMP activity assay, we employed the fact that active MMPs could cleave modified pro-urokinase to form active urokinase, which then acted on S-2444 peptide to create a chromogenic product. Secretion of all pro-MMPs from glioma cells was not significantly reduced by SI-27. However, activation of pro-MMPs was significantly inhibited in a dose-dependent manner ((IC50 values for MMP-2; U87MG, 3.5 microg/ml; U25 IMG, 4.2 microg/ml; U373MG, 4.8 microg/ml; Y98G, 4.0 degreesg/ml); (IC50 values for MMP-9; 251MG, 7.2 microg/ml, U373MG, 2.8 microg/ml). In addition, active MMPs were not inhibited by SI-27. These findings were supported by zymographic analysis and by collagenolysis assay data. TIMP-1 and -2 were also not inactivated by SI-27. These findings suggest that SI-27 targets the activation process of pro-MMP. S-2444, a specific chromogenic peptide, was useful for quantitative analysis of the activity of MMP subtypes in this study.
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PMID:Suppression of matrix metalloproteinase activity by SI-27: detection by a new activity assay with S-2444, a specific chromogenic peptide. 1216 Jan 35

Glioma, the most common form of brain tumor, has been shown mostly by in vitro studies to utilize matrix metalloproteinase (MMP) for invasive growth through degradation of the extracellular matrix. In order to examine the in vivo role of MMP, we established a rodent model of glioma progression using C6 rat glioma cells and analyzed the effect of tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 rather than TIMP-1 caused significant reduction of the tumor size accompanied by the presence of degenerated blood vessels and ischemic necrosis. Because TIMP-2 inhibits MMP-2 preferentially, we then examined glioma growth in MMP-2-deficient mice and observed essentially identical consequences. While MMP-2 activity was present in the tumor and adjacent tissues of the wild-type mice, no MMP-2 activity was detected even in the tumor of the null mice, although C6 cells are known to express MMP-2. These observations suggest that glioma induces MMP-2 and utilizes its activity in the host tissue to support angiogenesis and to maintain angioarchitecture.
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PMID:In vivo glioma growth requires host-derived matrix metalloproteinase 2 for maintenance of angioarchitecture. 1222 Sep 55

Glioblastoma is a severe type of primary brain tumor and its invasion is strongly correlated with the secretion of matrix metalloproteinases (MMPs). To investigate a role of PTEN, a tumor suppressor gene, in the regulation of hyaluronic acid (HA)-induced invasion of glioma cells, we examined the secretion of MMP-9 in various glioma cells with or without a functional PTEN gene. The secretion of MMP-9 in glioma cells lacking functional PTEN (U87MG, U251MG, and U373MG) was induced by HA, although not in wildtype (wt)-PTEN-harboring cells (LN229, LN18, and LN428). In addition, stable expression of wt-PTEN into U87MG cells significantly decreased the secretion of HA-induced MMP-9 and basal levels of MMP-2, inhibiting the activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, whereas the secretion levels of the tissue inhibitor of metalloproteinase-1 and -2 were increased, finally resulting in the inhibition of invasion by HA in vitro. Ectopic expressions of adenoviral (Ad)-wt-PTEN and -lipid phosphatase-deficient (G129E)-PTEN, but not both protein and -lipid phosphatase-deficient (C124S)-PTEN, reduced MMP-9 secretion and invasion by HA. These results were also confirmed by expressions of Ad-wt-PTEN and Ad-G129E-PTEN in other glioblastoma cells lacking functional PTEN, U251MG, and U373MG. These findings strongly suggest the possibility that PTEN may block HA-induced MMP-9 secretion and invasion through its protein phosphatase activity.
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PMID:PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. 1241 63

Fusogenic membrane glycoproteins (FMG) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas. FMG expression constructs caused massive syncytia formation followed by cytotoxic cell death in glioma cell lines, and antitumor activity has been shown in glioma xenografts. FMG-induced fusion in glioma cells can involve heterologous cell lines including normal astrocytes and fibroblasts, therefore making targeting important. Here we report on the use of matrix metalloproteinase (MMP) cleavable linkers to target cytotoxicity of FMGs against gliomas. Expression constructs were made expressing the hyperfusogenic version of the Gibbon Ape Leukemia Virus envelope glycoprotein (GALV) linked to a blocking ligand (the C-terminal extracellular domain of CD40 ligand) via either an MMP cleavable linker (GALV M40), a factor Xa protease cleavable linker (GALV X40), or a noncleavable linker (GALV N40). Unmodified GALV expressing constructs were used as positive controls. The glioma cell lines U87, U118, and U251 previously characterized by zymography and MMP-2 activity assay as high, medium, and low MMP expressors, respectively; normal human astrocytes and the MMP-poor cell line TE671 were transfected with the GALV, GALV N40, GALV X40, and GALV M40 constructs. In contrast to unmodified GALV constructs, transfection with GALV X40 and GALV N40 constructs blocked fusion and cytotoxic cell death. Fusion occurred, however, after transfection with constructs containing MMP cleavable linkers to an extent dependent on MMP expression in the specific cell line. Use of the broad-spectrum MMP inhibitors, 1,10-phenanthroline and N-hydroxy-piperazine-carboxamide completely abolished the ability of MMP constructs to induce fusion. In cell mixing experiments, mixing of MMP-poor cell lines transfected with GALV M40 constructs with the MMP overexpressing untransfected U87 glioma cells led to partial restoration of fusion. Use of U87 supernatant did result in a similar effect. Establishment of stable tranfectants expressing the membrane-type MMPs, MT-1 MMP and MT-2 MMP did restore fusion in the MMP-poor cell line TE671 after transfection with GALV M40, thus indicating that both membrane-type MMPs and soluble MMPs activate the MMP cleavable constructs. In addition, the GALV M40 construct retained its cytotoxic activity against U87 cells in vivo, although less effectively as compared to unmodified GALV. Our data indicate that GALV-induced cytotoxicity in glioma cell lines can be blocked by display of the CD40 ligand. Incorporation of an MMP cleavable linker can selectively restore cytotoxicity in MMP expressing glioma cell lines both in vitro and in vivo, while sparing normal human astrocytes. Given the high frequency of MMP overexpression in gliomas, this represents a promising targeting strategy.
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PMID:Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease-substrate interaction. 1270 11

The systemic administration of endogenous inhibitors significantly reduced the growth of human glioma in vivo, but required the production of a large amount of biologically active protein. In this study we reduced the amount of protein needed and optimized the therapeutical response by delivering the endogenous inhibitors locally into the brain by osmotic minipumps. Human hemopexin fragment of MMP-2 or COOH-terminal fragment of platelet factor-4 were delivered locally and continuously into the brain of mice implanted intracranially with glioma cells, by osmotic minipumps connected to an intracranial catheter. Local delivery of human hemopexin fragment of MMP-2 and COOH-terminal fragment of platelet factor-4 significantly inhibited the growth of well-established malignant glioma in nude and BALB/C mice. When the inhibitors were given at the same concentration, the efficacy of the local delivery was much higher than that reached with the systemic administration, both when the inhibitor was administered daily or continuously by s.c. minipumps. Moreover, the local delivery reduced the amount of protein needed to reach a significant therapeutic response. Intracerebral delivery maintained a long-term control of glioma growth and inhibited glioma recurrence in a surgical resection model. Treatment showed no side effects. Histochemical analysis of tumors showed that the tumor growth inhibition was the result of a decrease in tumor vasculature and a change in tumor vessel morphology. Our data demonstrate that local intracerebral delivery of endogenous inhibitors effectively inhibits malignant glioma growth and reduces the amount of protein needed to reach a therapeutical response.
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PMID:Local intracerebral delivery of endogenous inhibitors by osmotic minipumps effectively suppresses glioma growth in vivo. 1275 Feb 72

Testican family proteins are putative extracellular heparan/chondroitin sulfate proteoglycans of unknown function. We identified recently N-Tes, which is a product of testican 3 splicing variant gene, as an inhibitor of membrane-type matrix metalloproteinases (MT-MMPs). The inhibitory function is common among testican family members except for testican 2, which was shown to uniquely abolish inhibition of MT1-MMP- or MT3-MMP-mediated pro-MMP-2 activation by other testican family members. Testican 2 inactivates N-Tes by binding to the COOH-terminal extracellular calcium-binding domain of N-Tes through its NH(2)-terminal unique domain as demonstrated by coimmunoprecipitation analysis, and, thus, testican 2 was unable to inactivate a N-Tes deletion mutant lacking the extracellular calcium-binding domain (N-Tes-Delta 122). Migration of U251 cells on collagen, which was dependent on MT1-MMP activity under serum-free condition, was inhibited by N-Tes or N-Tes-Delta 122 deposited on collagen. Testican 2 was not incorporated into collagen by itself, and was deposited only in the presence of N-Tes, suggesting that testican 2 binds to N-Tes deposited on collagen. Binding of testican 2 to N-Tes deposited on collagen allowed migration of cells expressing MT1-MMP. Unlike wild-type N-Tes, N-Tes-Delta 122 did not bind to testican 2, and, thus, expression of testican 2 did not recover cell migration blocked by N-Tes-Delta 122. In situ hybridization showed that neurons are a major source of all of the testican family members in the normal brain. The quantitative reverse transcription-PCR analysis demonstrated that all of the testican family members are expressed prominently in normal brain, and their expression levels decrease as tumor grade increases. The expression level of testican 2 was the highest among testican family members regardless of histological grade of astrocytic tumors. These results suggest that abundant distribution of testican 2 may contribute to glioma invasion by inactivating other testican family members including N-Tes, which all inhibit MT-MMPs. We propose that N-Tes-Delta 122, which is resistant to testican 2, may have therapeutic potential as a barrier against glioma invasion.
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PMID:Testican 2 abrogates inhibition of membrane-type matrix metalloproteinases by other testican family proteins. 1281 Jun 72

Tumor invasiveness is an intrinsic feature of most glial tumors that accounts for their malignant and locally destructive nature. We evaluated the subcutaneous (sc) tumorigenicity and in vivo invasiveness of 9 astrocytoma cell lines together with their respective metalloprotease activity in order to establish their biologic behavior and malignant potential. Invasiveness was assessed with an in vivo invasion assay using tracheal xenotransplants subcutaneously implanted into Scid mice. This assay permitted us to evaluate the penetration of tumor cells into the transplanted deepithelialized tracheas previously inoculated with either normal primary glial cells or with astrocytoma-derived cell lines. Although only 2 cell lines were tumorigenic after sc inoculation, 5 out of 9 tumor cell lines were tumorigenic in the tracheal graft system. The astrocytoma cell lines showed varying levels of penetration into the tracheal wall. The tumor lines GOS3, M059K, CCFSTTG1 and A172, as well as primary normal astrocytes, were nontumorigenic and noninvasive in this experimental model. LN405, SW1088 and SW1783 cells that were not tumorigenic as sc xenotransplants, on the other hand, grew well in the tracheal graft system showing low levels of in vivo invasiveness. U87MG and U118MG cells were tumorigenic as sc xenotransplants and showed high levels of invasiveness. In parallel to these in vivo studies, the constitutive levels of secreted gelatinases and stromelysins (MMP-3 and MMP-11) were investigated using conditioned media submitted to gelatin or casein-substrate zymography and Western blot analysis. Neither the gelatinases (MMP-2 and MMP-9) nor MMP-11 showed a direct correlation with the levels of in vivo tumor cell invasiveness. Conversely, secretion of MMP-3 correlated closely with tumorigenicity and invasiveness. In vitro tumor cell invasiveness was significantly reduced after incubation with the metalloproteinase inhibitor GM6001. This positive correlation between MMP-3 and the depth of tracheal wall penetration led us to conclude that the invasive properties of brain tumor cells may be due to the direct or indirect proteolytic effects of MMP-3 on extracellular matrix (ECM) macromolecules and that this enzyme might be a potential target for future therapies.
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PMID:Stromelysin-1/matrix metalloproteinase-3 (MMP-3) expression accounts for invasive properties of human astrocytoma cell lines. 1286 26

In gliomas, a high frequency of homozygous p16 gene deletions have been demonstrated, which are believed to be linked with malignant progression. The aim of this study was to assess the role of p16 in growth, invasion, and senescence. The human glioma cell lines U87 MG and U373 MG were transduced with Ad-p16, and cell viability was assessed by trypan blue staining. To examine the mechanism of cell growth inhibition, cell cycle analyses and annexin assays were performed. The invasive potential of Ad-p16 transduced cells was evaluated using a Matrigel invasion assay, and trimolecular complex (MMP-2/MT1-MMP/TIMP-2) synthesis was proven by zymography and Western blotting. To establish the link between p16 and cell senescence, we stained for Senescence-Associated beta-galactosidase activity. A cell proliferation assay demonstrated that Ad-p16 treatment significantly inhibits cell growth. Moreover, this cell growth inhibition was induced by cell cycle arrest, not by apoptosis. In vitro treatment of malignant glioma cells with Ad-p16 significantly decreased their invasive potential by Matrigel invasion assay. However, we were unable to demonstrate any differences in the constitutive productions and secretions of MMP-2, MT1-MMP, and TIMP-2, among the mock-treated, Ad-lacZ-transduced, and Ad-p16-transduced cells. p16 expression caused an enlargement of all cells, and these were morphologically similar to senescent cells. Staining for Senescence-Associated beta-galactosidase activity showed that the enlarged cells stained positively. Taken together these data strongly suggest that the anti-cancer effect of p16 is modulated by p16-mediated cell cycle arrest and by the induction of senescence.
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PMID:Adenoviral p16/CDKN2 gene transfer to malignant glioma: role of p16 in growth, invasion, and senescence. 1288 67

Local invasion of tumour cells is characteristic of brain tumour progression. It is associated with increased motility and a potential to hydrolyse macromolecular components of the extracellular matrix. The peptidases that have been most investigated, and are induced during this process, are reviewed: the plasminogen activators (PAs), matrix metalloproteinases (MMPs) and lysosomal cysteine peptidases called cathepsins (Cats). Increased levels of urokinase-type PA (uPA) are observed mainly at the invasive margins of a tumour, whereas the data on the expression of tissue-type PA (tPA) are still controversial. It has been shown that the endogenous inhibitor of PAs, PAI-1, is localised in both tumour and tumour-associated endothelial cells. Among MMPs, the expression of the gelatinases, MMP2 and MMP9, strongly correlates with glioma progression. Membrane bound MT-MMPs, in particular MT1- and MT2-MMP, seem to play a major role in activating MMP-2. Several members of the ADAMTS family have also been detected in brain tumours, the most relevant being ADAMTS4, due to its cleavage of CNS specific proteins. Lysosomal cathepsin B is highly expressed in malignant glial cells and in endothelial cells of vascularised glioblastomas and is a predictor of a shorter survival. In addition to invasion, cathepsin L may play a role in decreased susceptibility of anaplastic glioma cells to apoptosis. Finally, cathepsin B was proposed as a marker for malignancy in the more aggressive type of meningiomas. Each of these peptidases may act alone, or in concert with the others, to support malignant behaviour of brain tumour cells; the development of new inhibitors of invasion, therefore, should contribute to the control of local spread of a tumour.
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PMID:Proteases in brain tumour progression. 1450 15


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