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)

During embryogenesis interactions between cells and extracellular matrix play a central role in the modulation of cell motility, growth, and differentiation. Modulation of matrix structure is therefore crucial during development; extracellular matrix ligands, their receptors, extracellular proteinases, and proteinase inhibitors all participate in the construction, maintenance, and remodeling of extracellular matrix by cells. The neural cell-adhesion molecule (NCAM)-negative rat glioma cell line BT4Cn secretes substantial amounts of metalloproteinases, as compared with its NCAM-positive mother cell line BT4C. We have transfected the BT4Cn cell line with cDNAs encoding the human NCAM-B and -C isoforms. We report here that the expression of transmembrane NCAM-B, but not of glycosyl-phosphatidylinositol-linked NCAM-C, induces a down-regulation of 92-kDa gelatinase (matrix metalloproteinase 9) and interstitial collagenase (matrix metalloproteinase 1), indicating that cellular expression of the recognition molecule NCAM regulates the metabolism of the surrounding matrix.
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PMID:Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down-regulates secretion of matrix metalloproteinases. 826 75

Matrix metalloproteinases play an important regulatory role in tissue morphogenesis, cell differentiation and motility, and tumor cell invasiveness. We have recently demonstrated elevated activity of the 92 kDa type IV collagenase (MMP-9) in human glioblastoma and in the present study examine the relative amounts of MMP-9 protein and mRNA in human gliomas and as well as the distribution of MMP-9 in human glioma tumors in vivo. Using an enzyme-linked immunosorbent assay for the quantitative determination of MMP-9 protein, we found that levels were significantly higher in malignant astrocytomas, especially in glioblastoma multiforme, than in normal brain tissues and low-grade gliomas. In addition, the amount of MMP-9 mRNA, as determined by northern blot analysis was higher in anaplastic astrocytomas and glioblastoma multiforme than in normal brain tissue and low-grade gliomas. Immunocytochemical staining for MMP-9 showed strong cytoplasmic immunoreactivity in the tumor cells and the proliferating endothelial cells of glioblastoma multiforme and anaplastic astrocytomas. The staining intensity was lowe in low-grade astrocytomas, and was undetectable or very low in normal brain astrocytes. The results indicate that expression of MMP-9 is dramatically upregulated in highly malignant gliomas and correlates with the highly malignant progression of human gliomas in vivo, and support a role for the MMP-9 in facilitating the invasiveness seen in malignant gliomas in vivo.
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PMID:Expression and localization of 92 kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas. 852 11

Matrix metalloproteinases (MMPs) are zinc-dependent peptidases and are amongst those enzymes responsible for extracellular matrix (ECM) degradation during tumour-cell migration. Gangliosides are a family of acidic membrane glycolipids thought to play a role during cell development, differentiation and oncogenic transformation. In this descriptive study, we investigated the effects of six exogenous gangliosides (GM1, GM3, GD1a, GD1b, GD3 and GT1b) on the secretion of MMP-2 (72 kDa gelatinase or gelatinase-A) and MMP-9 (92 kDa gelatinase or gelatinase-B). Cell-conditioned media from eight human glioma-derived cell-lines served as the source of MMPs and were investigated using SDS-PAGE zymography. Six of the cell lines showed upregulation of secretion of both enzymes by all six gangliosides. Of the remaining two cell lines, one showed inhibition of MMP secretion by all gangliosides and the other had a small but differential response to the range of gangliosides investigated. These results suggest that gangliosides may stimulate glioma cell invasiveness by promoting MMP expression.
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PMID:The effect of exogenous gangliosides on matrix metalloproteinase secretion by human glioma cells in vitro. 908 68

Matrix metalloproteinases (MMPs) are an homologous family of proteolytic enzymes capable of degrading components of the extracellular matrix (ECM) and thereby facilitating the invasion of tumour cells into normal tissues. The neural cell adhesion molecules (NCAMs) of neuronal and glial cells provide a Ca2+-independent mechanism for cell-cell and cell-ECM adhesion. NCAMs are downregulated to promote cell disaggregation during cell migration in the developing nervous system whereas MMPs facilitate migration. Recent studies have shown downregulation of MMP secretion in rat glioma cells transfected with an NCAM cDNA, implying an inverse correlation between NCAM and MMP expression. The purpose of this study was to establish whether such a correlation could be demonstrated in a panel of nine human glioma cell-lines, one metastatic carcinoma and one foetal astrocyte derived cell line. The secretion of two MMPs, 72 kDa gelatinase (MMP-2 or gelatinase-A) and 92 kDa gelatinase (MMP-9 or gelatinase-B), was investigated using SDS-PAGE zymography; NCAM-A was assayed by an immunochemiluminescent assay following SDS-PAGE of whole-cell extracts. An inverse correlation was found between the expression of NCAM-A and that of both MMPs studied although the patterns of expression showed no obvious correlation with histological type or grade of the parent tumours. Our results suggest that downregulation of NCAM-A may contribute to tumour invasiveness by promoting both cell disaggregation and protease secretion.
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PMID:An inverse correlation between expression of NCAM-A and the matrix-metalloproteinases gelatinase-A and gelatinase-B in human glioma cells in vitro. 917 60

Alterations in cytoskeleton and subsequent cell shape changes exert specific effects on the expression of various genes. Our previous results suggested that malignant human gliomas express elevated levels of matrix metalloproteinases compared with normal brain tissue and low grade gliomas. To understand the role of cell shape changes on matrix metalloproteinase expression in human glioma cells, we treated SNB19 cells with cytochalasin-D, an inhibitor of actin polymerization, and colchicine-B, a tubulin inhibitor, in the presence of phorbol 12-myristate 13-acetate. Cytochalasin-D treatment of SNB19 cells resulted in the loss of phorbol 12-myristate 13-acetate-induced matrix metalloproteinase-9 (also known as gelatinase-B) expression and coincided with inhibition of actin polymerization, resulting in cell rounding. Moreover, compared with monolayers, cells grown as spheroids or cell aggregates failed to express matrix metalloproteinase-9 in the presence of phorbol 12-myristate 13-acetate. Matrix metalloproteinase-9 expression was also inhibited by calphostin-C, a protein kinase inhibitor, suggesting the involvement of protein kinase C in matrix metalloproteinase-9 expression. Phorbol 12-myristate 13-acetate-induced invasion of SNB19 cells through Matrigel was inhibited by cytochalasin-D and calphostin-C. These results suggest that the actin polymerization transduces signals that modulate the expression of matrix metalloproteinase-9 expression and the subsequent invasion of human glioma cells.
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PMID:Induction of matrix metalloproteinase-9 requires a polymerized actin cytoskeleton in human malignant glioma cells. 959 90

Malignant gliomas maintain a poor prognosis and survival rate due to their marked local invasive growth and neovascularization. Matrix metalloproteinases (MMPs) have been implicated in glioma invasion and angiogenesis, but it is unknown whether they are produced by the tumor cells or surrounding stroma. Using in situ hybridization and immunohistochemistry, we found expression of mRNA for both gelatinase-A (MMP2) and gelatinase-B (MMP9) localized to tumor cells and vascular structures in glioma sections. Gelatinase-A protein expression was detected most prominently in tumor cells, with very little signal seen in vasculature. Gelatinase-B protein expression was prominent in vascular structures but was also expressed in tumor cells. Our data show that these proteases are produced by glioma cells and vascular structures and suggest that synthetic MMP inhibitors might be useful in this disease.
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PMID:Localization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas. 1130 34

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

Lipopolysaccharide (LPS) from Gram-negative bacterial has been identified as an important molecule involved in the inflammatory process through inducing nitric oxide (NO) production. However, the effect of LPS in carcinogenesis is still undefined. In the present study, the biological effect of LPS was examined in 12-o-tetradecanoylphorbol 13-acetate (TPA)-treated rat glioma cells C6. Results of MTT assay showed that LPS and TPA exhibited no significant cytotoxicity in glioma C6 cells. Interestingly, transformation foci were found in LPS/TPA-treated glioma C6 cells, but not in LPS- or TPA-treated cells. The transformation foci induced by LPS/TPA were also observed in the absence of serum. It indicates that induction of transformation foci formation by LPS and TPA is independent on the serum in glioma C6 cells. Induction of iNOS gene expression and NO production was examined in LPS/TPA-treated cells, but not obvious in LPS- or TPA-treated cells. NO donor sodium nitroprusside (SNP) induces transformation in glioma C6 cells in according with elevating NO production. In addition, LPS/TPA induces metalloproteinase 9 (MMP9) activity by gelatin activity assay in gel. Wogonin and quercetin but not rutin, inhibitors of iNOS gene expression and NO production induced by LPS, showed the significant inhibition on LPS/TPA-induced transformation foci formation, accompanied by inhibiting iNOS gene expression, NO production and MMP9 activity. Results of the present study provide scientific evidences to link the inflammatory responses and carcinogenesis, and suggest that NO derived from inflammation may contribute to the progression of carcinogenesis; natural products with anti-inflammatory effects such as wogonin and quercetin possess the ability to block transformation induced by LPS/TPA.
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PMID:Lipopolysaccharide enhancement of 12-o-tetradecanoylphorbol 13-acetate-mediated transformation in rat glioma C6, accompanied by induction of inducible nitric oxide synthase. 1470 May 23

The aim of this study was to explore the potential role of AKT2 in glioma cell invasion. Therefore, dominant-negative (DN-AKT2) and antisense AKT2 constructs (AS-AKT2) were transfected into rat C6 glioma cells with elevated endogenous AKT2 expression. In situ hybridization and Western blot analysis were used to identify AKT2 expression. Spheroid culturing was used to assess cell migration and invasion in Matrigel from spheroids. Cell motility and invasion were also evaluated by scratch and Transwell invasion assays, respectively. The secretion of matrix metalloproteinases (MMPs), MMP2 and MMP9, was determined by gelatin zymography. AKT2 expression was inhibited in C6 cells transfected with AS-AKT2 but did not significantly change in cells transfected with DN-AKT2. The cell migration distance from spheroids or the number of cells migrating into the acellular space created by scratching was reduced in cells transfected with DN-AKT2 or AS-AKT2 compared to the control cells. The invasive distance of cells from the spheroids in Matrigel sandwich and the number of invading cells through the Matrigel were also decreased in the DN-AKT2- and AS-AKT2-transfected cells. Gelatin zymography showed that the production of MMP2 and MMP9 was inhibited in transfected cells. In conclusion, AKT2 plays an important role in glioma cell motility and invasion. Therapy based on AKT inhibition may complement currently available treatment to control glioma cell invasion.
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PMID:Antisense and dominant-negative AKT2 cDNA inhibits glioma cell invasion. 1555 54

The progression of gliomas has been extensively studied at the genomic level using cDNA microarrays. However, systematic examinations at the protein translational and post-translational levels are far more limited. We constructed a glioma protein lysate array from 82 different primary glioma tissues, and surveyed the expression and phosphorylation of 46 different proteins involved in signaling pathways of cell proliferation, cell survival, apoptosis, angiogenesis, and cell invasion. An analysis algorithm was employed to robustly estimate the protein expressions in these samples. When ranked by their discriminating power to separate 37 glioblastomas (high-grade gliomas) from 45 lower-grade gliomas, the following 12 proteins were identified as the most powerful discriminators: IBalpha, EGFRpTyr845, AKTpThr308, phosphatidylinositol 3-kinase (PI3K), BadpSer136, insulin-like growth factor binding protein (IGFBP) 2, IGFBP5, matrix metalloproteinase 9 (MMP9), vascular endothelial growth factor (VEGF), phosphorylated retinoblastoma protein (pRB), Bcl-2, and c-Abl. Clustering analysis showed a close link between PI3K and AKTpThr308, IGFBP5 and IGFBP2, and IBalpha and EGFRpTyr845. Another cluster includes MMP9, Bcl-2, VEGF, and pRB. These clustering patterns may suggest functional relationships, which warrant further investigation. The marked association of phosphorylation of AKT at Thr308, but not Ser473, with glioblastoma suggests a specific event of PI3K pathway activation in glioma progression.
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PMID:Pathway alterations during glioma progression revealed by reverse phase protein lysate arrays. 1661 7


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