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 ability of glioma cells to migrate great distances from a primary tumor mass is the primary cause of tumor recurrence. The urokinase-type plasminogen activator (uPA) is a serine protease that can initiate proteolytic cascades, which result in remodeling of extracellular matrix and basement membrane, allowing cells to move across and through these barriers. The binding between uPA and its receptor uPAR also mediates several signaling events that seem to contribute to the evolution of a migratory phenotype. In this study, we determined how the downregulation of uPA affects the signaling pathways leading to cell migration. Stably transfecting human glioblastoma cells with antisense uPA decreased the amount of cell-bound uPA and disrupted actin cytoskeleton formation and cell migration. The phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathway has been suggested to mediate migration in various cancer cells. The antisense-uPA clones also had less phosphorylated PI3k and Akt than control cells, a finding associated with decreased cell migration, G2/M-phase arrest, and decreased clonogenic survival. Decreased activation of PI3k and the antiapoptotic factor Akt was not sufficient to induce apoptosis in the antisense-uPA clones, but staurosporine sensitized them to apoptosis to a greater extent than control cells. These results indicate that PI3k/Akt pathway is involved in the signaling cascade required to induce cell migration and that uPA has a direct role in regulating migration.
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PMID:Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells. 1254 60

Research on invasion and metastasis of glioma in vivo was performed by implanting C6 glioma cells transfected with enhanced green fluorescent protein (EGFP) gene into the brain of SD rats. Firstly, C6 glioma cells were transfected with a plasmid vector (pEGFP-N3) containing the EGFP gene. Stable EGFP-expressing clones were isolated and examination for these cells by flow cytometry and electron microscope was done. Secondly, EGFP-expressing cells were stereotactically injected into the brain parenchyma of SD rats to establish xenotransplanted tumor. Four weeks later rats were killed and continuous brain sections were examined using fluorescence microscopy after adjacent sections were examined by immunohistochemistry or routine hematoxylin and eosin staining for the visualization and detection of tumor cell invasion. Xenotransplanted tumor was primarily cultured to determine the storage of EGFP gene in vivo. The results showed that EGFP-transfected C6 glioma cells maintained stable high-level EGFP expression in the central nervous system during their growth in vivo. EGFP fluorescence clearly demarcated the primary tumor margin and readily allowed for the visualization of distant micrometastasis and invasion on the single-cell level. Small locally invasive foci, including those immediately adjacent to the leading invasive edge of the tumor, were virtually undetectable by routine hematoxylin and eosin staining and immunohistochemistry. These results suggested that EGFP-transfected C6 cells can be visualized by fluorescence microscopy after intracranial implantation. This model is an excellent experimental animal model in research on invasion and metastasis of brain glioma in vivo.
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PMID:Experiment and observation on invasion of brain glioma in vivo. 1260 81

Tyrosinase-related protein (TRP)-2 is an immunogenic antigen in melanoma. The authors sought to investigate whether TRP-2 could be a potential target for patients with malignant glioma. RT-PCR analysis demonstrated that TRP-2 was present in 51.2% of primary tumor cell lines derived from patients with glioblastoma multiforme (GBM). The percentage of TRP-2-6b, TRP-2-INT2, TRP-2-LT, and TRP-2-8b isoform expression in all tested GBM cells was 13.9%, 34.9%, 41.9%, and 39.5%, respectively. TRP-2 protein expression was detected in GBM cells and tumor tissues by Western blot and immunohistochemistry. In addition, an HLA-A2-restricted cytotoxic T cell clone that recognizes the TRP-2(180-188) peptide (SVYDFFVWL) specifically lysed the TRP-2 positive GBM cells in a HLA-A2 restricted manner. In addition, the level of TRP-2 mRNA expression, as determined by real-time quantitative RT-PCR, correlated with the level of CTL recognition as measured by IFN-gamma secretion (R = 0.90; p < 0.01). To further test the immunogenicity of TRP-2 in glioma, PBMCs from a healthy donor were primed in vitro using autologous dendritic cells (DCs) pulsed with irradiated GBM cells. These in vitro generated T cells specifically lysed T2 cells pulsed with TRP-2(180-188) peptide and TRP-2 positive GBM cell lines. Most importantly, TRP-2(180-188) specific CTL frequency in four patients' PBMC who were both HLA-A2 and TRP-2 positive was significantly (p < 0.01) increased, respectively, after vaccinations with DCs pulsed with autologous tumor lysate. The authors' studies demonstrate that TRP-2 could be a useful antigen target for monitoring or developing immunotherapeutic strategies for glioma patients.
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PMID:Molecular and functional analysis of tyrosinase-related protein (TRP)-2 as a cytotoxic T lymphocyte target in patients with malignant glioma. 1284 92

Heparanase is an endo-beta-glucuronidase responsible for the cleavage of heparan sulfate, participating in extracellular matrix degradation and remodeling. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase up-regulation was detected in essentially all human tumors examined, correlating, in some cases, with poor postoperative survival and increased tumor vascularity. The role of heparanase in primary tumor progression is, however, poorly understood. Here, we overexpressed the human heparanase gene in a human glioma cell line, U87. We found that heparanase overexpression induces cell invasion, as might be expected. Surprisingly, elevated heparanase expression levels correlated with decreased proliferation rates and increased cell spreading and formation of a tight monolayer rather than large cell aggregates. This phenotypic appearance was accompanied by beta1-integrin activation, FAK and Akt phosphorylation, and Rac activation. In a xenograft tumor model, relatively moderate heparanase expression levels significantly enhanced tumor development and tumor vascularity, whereas high heparanase expression levels inhibited tumor growth. These results indicate that heparanase activates signal transduction pathways and, depending on its expression levels, may modulate tumor progression.
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PMID:Heparanase affects adhesive and tumorigenic potential of human glioma cells. 1463 98

Central nervous system malignant neoplasias, in particular, glioblastoma multiforme (GBM) have defied all current therapeutic modalities. New therapies involving tumor targeting approach are being explored. This approach relies on the identification of unique or over-expressed cell surface receptors or antigens on tumor cells. In that regard, we have identified receptor for an immune regulatory cytokine, interleukin-13 (IL-13), which is over-expressed on human malignant glioma cell lines and primary tumor cell cultures. To target IL-13 receptors (IL-13R) for cancer therapy, we have developed a recombinant fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL13-PE38QQR or IL-13 cytotoxin). The IL-13 cytotoxin was found to be highly selective and potent in killing human GBM cells in vitro while normal cells including immune cells, endothelial cells and normal brain cells were generally spared the cytotoxic effect of IL-13 cytotoxin. This is because these cells either expressed none or expressed low levels of IL-13R. Consistent with in vitro cytotoxic activity, IL-13 cytotoxin mediated remarkable anti-tumor activity to human glioma in animal xenograft models. The direct injection of IL-13 cytotoxin into subcutaneous human GBM tumors grown in nude mice produced complete and durable regression of established tumors. Intravenous and intraperitoneal administration of IL-13 cytotoxin also reduced tumor burden significantly with fewer complete responders. All animals tolerated therapy well with minimal toxicity to vital organs. Pre-clinical safety and toxicity studies were performed in mice, rats and monkeys. Systemic administration of IL-13 cytotoxin appeared to be well tolerated at high doses (up to 50 microg/kg). Intrabrain parenchyma administration of IL-13 cytotoxin at doses up to 100 microg/ml was very well tolerated without any evidence of gross or microscopic necrosis, whereas at 500 microg/ml dose, localized necrosis was observed in normal rat brain. Based on these encouraging pre-clinical studies, three Phase I/II clinical trials in adults with malignant glioma have been initiated. The first clinical trial involves convection-enhanced delivery (CED) of IL-13 cytotoxin into recurrent malignant glioma. This route of IL-13 cytotoxin administration appears to be fairly well tolerated with no neurotoxicity. The second clinical trial involves infusion of IL-13 cytotoxin by CED following tumor resection. The initial stage of the second study assessed histologic effect of drug administered prior to resection. In third one, IL-13 cytotoxin is infused by CED followed by tumor resection. All three clinical trials are currently ongoing.
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PMID:Interleukin-13 receptor-directed cytotoxin for malignant glioma therapy: from bench to bedside. 1464 84

Many malignant glioma cells express death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL-induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase-8-initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild-type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to downregulate caspase-8 inhibitor c-FLIP(S) (the short form of cellular Fas-associated death domain-fike interleukin-1-converting enzyme-inhibitory protein) and up-regulate Bak, a pro-apoptotic Bcl-2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.
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PMID:TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways. 1465 59

We investigated the variability in infectivity of cells in primary brain tumor samples from different patients using an HSV-1 amplicon vector. We studied the infectivity of HSV-1 amplicon vectors in tumor samples derived from neurosurgical resections of 20 patients. Cells were infected with a definite amount of HSV-1 amplicon vector HSV-GFP. Transduction efficiency in primary tumor cell cultures was compared to an established human glioma line. Moreover, duration of transgene expression was monitored in different tumor cell types. All primary cell cultures were infectable with HSV-GFP with variable transduction efficiencies ranging between 3.0 and 42.4% from reference human Gli36 Delta EGFR glioma cells. Transduction efficiency was significantly greater in anaplastic gliomas and meningiomas (26.7+/-17.4%) compared to more malignant tumor types (glioblastomas, metastases; 11.2+/-8.5%; P=0.05). To further investigate the possible underlying mechanism of this variability, nectin-1/HevC expression was analyzed and was found to contribute, at least in part, to this variability in infectability. The tumor cells expressed the exogenous gene for 7 to 61 days with significant shorter expression in glioblastomas (18+/-13 d) compared to anaplastic gliomas (42+/-24 d; P<0.05). Interindividual variability of infectivity by HSV-1 virions might explain, at least in part, why some patients enrolled in gene therapy for glioblastoma in the past exhibited a sustained response to HSV-1-based gene- and virus therapy. Infectivity of primary tumor samples from respective patients should be tested to enable the development of efficient and safe herpes vector-based gene and virus therapy for clinical application.
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PMID:Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors. 1567 97

A key feature in the malignant behavior of glioblastoma is the tendency to invade host brain tissue surrounding the primary tumor site. Several members of the matrix metalloproteinase family are thought to contribute to this invasive capacity. A single nucleotide polymorphism has been described in the matrix metalloproteinase-1 (MMP-1) promoter that consists of either the presence or absence of a guanine nucleotide at position -1607. The presence of the guanine base creates a functional binding site for members of the ETS family of transcription factors and has been shown to increase MMP-1 transcription. The purpose of our study was to characterize this polymorphism in human glioblastoma. Promoter genotyping was performed on brain tumor tissue obtained from 81 patients and compared to 57 healthy individuals. The 2G/2G genotype is more prevalent in glioblastoma tissue compared to healthy individuals (p = 0.01). mRNA and protein expression were measured in a subset of brain tumor and normal brain tissue samples. MMP-1 protein levels are significantly higher in glioblastoma tissue compared to normal brain (p = 0.001). Electromobility shift assays and promoter assays were performed to assess binding capability and transcriptional activity, respectively. Proteins present in glioma cell lines can specifically bind the 2G promoter probe. MMP-1 transcription is significantly higher in cells transfected with the 2G promoter when compared to cells transfected with the 1G promoter (p<0.02). This polymorphism may provide a mechanism for increased expression of MMP-1 in malignant gliomas via elevation of MMP-1 mRNA transcription and may underlie the invasive phenotype.
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PMID:Association of a single nucleotide polymorphism in the matrix metalloproteinase-1 promoter with glioblastoma. 1595 63

Glioma, and in particular high-grade astrocytoma termed glioblastoma multiforme (GBM), is the most common primary tumor of the brain. Primarily because of its diffuse nature, there is no effective treatment for GBM, and relatively little is known about the processes by which it develops. Therefore, in order to design novel therapies and treatments for GBM, research has recently intensified to identify the cellular and molecular mechanisms leading to GBM formation. Modeling of astrocytomas by genetic manipulation of mice suggests that deregulation of the pathways that control gliogenesis during normal brain development, such as the differentiation of neural stem cells (NSCs) into astrocytes, might contribute to GBM formation. These pathways include growth factor-induced signal transduction routes and processes that control cell cycle progression, such as the p16-CDK4-RB and the ARF-MDM2-p53 pathways. The expression of several of the components of these signaling cascades has been found altered in GBM, and recent data indicate that combinations of mutations in these pathways may contribute to GBM formation, although the exact mechanisms are still to be uncovered. Use of novel techniques including large-scale genomics and proteomics in combination with relevant mouse models will most likely provide novel insights into the molecular mechanisms underlying glioma formation and will hopefully lead to development of treatment modalities for GBM.
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PMID:Molecular mechanisms in gliomagenesis. 1609 98

Gliomas are the most common intrinsic brain tumors. The degree of vascularization corresponds to malignancy and is related to prognosis. In order to retrieve information about tumor behavior in situ, the use of primary tissue material for experiments is advantageous. With increasing evidence for the importance of microenvironment and vascularization in tumor biology, we concentrated on the isolation of endothelial cells (EC) from primary tumor material to investigate the role of endothelium within tumor tissue. We developed a method for isolation and purification of tumor-derived endothelial cells. EC were isolated and cultivated from normal brain using tissue digestion and Percoll density gradient centrifugation resulting in a <95% of EC culture. For isolation of EC from gliomas of different malignancy grades a combination of tissue digestion, Percoll gradient centrifugation and magnetic bead sorting by anti-CD31, -VE-Cadherin and -CD 105 was employed. This approach provided a purity of <98%. Cells were classified and characterized by testing expression of CD105, CD31, VE-Cadherin, vWF, UEA-1 and measuring DiI-Ac-LDL-uptake. To exclude contamination, staining and negative selection with anti-SMA, -GFAP, and -CD68 was performed. Tumors were histopathologically diagnosed according to WHO classification. We isolated EC from normal brain (NBEC, n = 11), low-grade gliomas WHO II (LGEC, n = 22), and high-grade gliomas WHO III & IV (HGEC, n = 11). There were no clear differences in EC morphology between the different tumor grades. However, a significantly higher proliferation rate of HGEC compared to LGEC was observed as well as distinctive antigen expression. Already in early passages isolated EC showed a rapid change in antigen expression indicating a phenotypic shift under culture conditions. We could establish a protocol for reliable and reproducible isolation and culture of EC from gliomas with different WHO grading. In first phenotypical and functional analyses, NBEC, LGEC and HGEC show remarkable differences. EC from all tumors could be grown in culture. However, passage related changes of EC phenotype demand very early passages to work with.
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PMID:Isolation and culture of microvascular endothelial cells from gliomas of different WHO grades. 1615 23


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