UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular mechanisms involved in tumor progression from a low-grade astrocytoma to the most malignant glioblastoma multiforme (GBM) have been hampered due to lack of suitable experimental models. We have established a model of tumor progression comprising of two cell lines derived from the same astrocytoma tumor with a set of features corresponding to low-grade glioma (as in HNGC-1) and high-grade GBM (as in HNGC-2). The HNGC-1 cell line is slow-growing, contact-inhibited, nontumorigenic, and noninvasive, whereas HNGC-2 is a rapidly proliferating, anchorage-independent, highly tumorigenic, and invasive cell line. The proliferation of cell lines is independent of the addition of exogenous growth factors. Interestingly, the HNGC-2 cell line displays a near-haploid karyotype except for a disomy of chromosome 2. The two cell lines express the neuronal precursor and progenitor markers vimentin, nestin, MAP-2, and NFP160, as well as glial differentiation protein S100beta. The HNGC-1 cell line also expresses markers of mature neurons like Tuj1 and GFAP, an astrocytic differentiation marker, hence contributing toward a more morphologically differentiated phenotype with a propensity for neural differentiation in vitro. Additionally, overexpression of epidermal growth factor receptor and c-erbB2, and loss of fibronectin were observed only in the HNGC-2 cell line, implicating the significance of these pathways in tumor progression. This in vitro model system assumes importance in unraveling the cellular and molecular mechanisms in differentiation, transformation, and gliomagenesis.
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PMID:A unique model system for tumor progression in GBM comprising two developed human neuro-epithelial cell lines with differential transforming potential and coexpressing neuronal and glial markers. 1496 45

Children affected with the inherited tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to the development of low-grade astrocytic optic pathway tumors (optic pathway glioma [OPG]). Previously, we developed a model of NF1-associated astrocytoma (GFAPCre; Nf1(flox/mut) mice) in which mice develop optic nerve and chiasm glioma. To define the molecular pathogenesis of OPG, we used this mouse model to study the natural history of OPG formation using immunohistological and radiographic approaches. We observed that whereas astrocyte hyperplasia is present in the optic nerves associated with gross optic nerve thickening at 3 weeks of age, overt neoplastic changes were not seen until 2 months of age. Astrocyte proliferation was maximal between 3 weeks and 2 months of age, suggesting that the most rapid period of growth occurs early. Mouse OPG tumors were detected by magnetic resonance imaging at 2 months of age and exhibited contrast enhancement, as seen in human OPG. In addition, the mouse OPG tumors exhibited expression of proteins associated with astroglial progenitors, including nestin and brain lipid binding protein. Last, we observed neovascularization and microglial cell infiltration by 3 weeks of age before overt neoplastic transformation, suggesting that these cellular changes participate in the early stages of tumor formation.
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PMID:Natural history of neurofibromatosis 1-associated optic nerve glioma in mice. 1562 33

To investigate adult neural stem cell (NSC) biology in relation to glioma, the C6 glioma cell line was tagged with green fluorescent protein (GFP) and inoculated into the brain of adult rats. The in vivo biological response of the brain to glioma was studied using immunohistochemical analysis of the subventricular zone (SVZ), peritumoral areas, and glioma. Nestin immunoreactive cells were found infiltrating glioma, but the distribution of abnormal immunoreactivity was restricted to the dorsal and medial border of the tumor relative to the ipsilateral ventricle. The SVZ was found to be hypertrophic, hypercellular, and up-regulated nestin expression. Furthermore, a dense contiguous population of nestin immunoreactive cells could be found streaming from ipsilateral dorsal tip of the SVZ, tracking along the ventral margin of the corpus callosum, and fanning out to encompass and infiltrate the proximal tumor border. Although most cells were either nestin or glial fibrillary acidic protein (GFAP) immunoreactive in the SVZ and along the ventral margin of the corpus callosum, the number of cells co-expressing both markers increased proportionally as the tumor was approached so that the predominant cell population along the proximal tumor border was GFAP immunoreactive. Finally, we demonstrated that a significant proportion of cells found in areas of abnormal immunoreactivity were proliferating, especially in peritumoral areas. In summary, there is an induction of neuropoietic activity in a rat intracranial glioma model that results in an infiltration and accumulation of abnormal nestin and GFAP expressing cells with proliferative potential along the dorsal and medial border of intracranial C6 glioma.
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PMID:Up-regulation of neuropoiesis generating glial progenitors that infiltrate rat intracranial glioma. 1573 12

Oncolytic herpes simplex virus-1 (HSV-1) mutants possessing mutations in the ICP34.5 and ICP6 genes have proven safe through clinical trials. However, ICP34.5-null viruses may grow poorly in cells due to their inability to prevent host-cell shut-off of protein synthesis caused by hyperphosphorylation of eukaryotic initiation factor 2alpha. To increase tumor selectivity, glioma-selective expression of ICP34.5 in the context of oncolysis may be useful. Malignant gliomas remain an incurable disease. One molecular marker of malignant gliomas is expression of the intermediate filament nestin. Expression of nestin mRNA was confirmed in 6 of 6 human glioma lines and in 3 of 4 primary glioma cells. Normal human astrocytes were negative. A novel glioma-selective HSV-1 mutant (rQNestin34.5) was thus engineered by expressing ICP34.5 under control of a synthetic nestin promoter. Replication, cellular propagation, and cytotoxicity of rQNestin34.5 were significantly enhanced in cultured and primary human glioma cell lines compared with control virus. However, replication, cellular propagation, and cytotoxicity of rQNestin34.5 in normal human astrocytes remained quantitatively similar to that of control virus. In glioma cell lines infected with rQNestin34.5, the level of phospho-eukaryotic initiation factor 2alpha was lower than that of cells infected by control rHsvQ1, confirming selective ICP34.5 expression in glioma cells. In vivo, rQNestin34.5 showed significantly more potent inhibition of tumor growth compared with control virus. Treatment in the brain tumor model was instituted on animal's display of neurologic symptoms, which usually led to rapid demise. rQNestin34.5 treatment doubled the life span of these animals. These results show that rQNestin34.5 could be a potent agent for the treatment of malignant glioma.
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PMID:An oncolytic HSV-1 mutant expressing ICP34.5 under control of a nestin promoter increases survival of animals even when symptomatic from a brain tumor. 1580 84

The myelodysplasia/myeloid leukemia factor 1-interacting protein MLF1IP is a novel gene which encodes for a putative transcriptional repressor. It is localized to human chromosome 4q35.1 and is expressed in both the nuclei and cytoplasm of cells. Northern and Western blot analyses have revealed MLF1IP to be present at very low amounts in normal brain tissues, whereas a number of human and rat glioblastoma (GBM) cell lines demonstrated a high level expression of the MLF1IP protein. Immunohistochemical analysis of rat F98 and C6 GBM tumor models showed that MLF1IP was highly expressed in the tumor core where it was co-localized with MLF1 and nestin. Moreover, MLF1IP expression was elevated in the contralateral brain where no tumor cells were detected. These observations, together with previous data demonstrating a role for MLF1IP in erythroleukemias, suggest a possible function for this protein in glioma pathogenesis and potentially in other types of malignancies.
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PMID:Regulation of myeloid leukemia factor-1 interacting protein (MLF1IP) expression in glioblastoma. 1589 39

Chemotherapy in itself is suspected to cause the development or selection of drug-resistant tumor cells, which have more aggressive phenotypes. The authors investigated the differential changes of gene expression in the 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant subline of the C6 rat glioma (C6AR2), which was established from C6 rat glioma cells by exposure to ACNU in vitro. The resistance to ACNU of C6AR2 was confirmed by MTS assay. The increased expression of O6-methylguanine-DNA methyltransferase in C6AR2 cells was shown using RT-PCR. C6AR2 cells displayed a higher proliferative activity relative to C6 cells. Analysis with cDNA array showed that 19 genes were transcriptionally up-regulated and 16 genes down-regulated in C6AR2 cells compared to C6 cells. They belonged to various functional classes of genes beside the drug-resistant system. Among them, the down-regulation of several genes in C6AR2 cells, including c-kit, pleiotrophin, platelet-derived growth factor receptor-alpha, peripheral myelin protein-22 and NG2 chondroitin sulfate proteoglycan, which are expressed originally in developmental glial lineages, were verified using semi-quantitative RT-PCR. In addition, the gene expression of astroglial intermediate filament proteins, including GFAP, vimentin and nestin, were decreased in C6AR2 cells relative to C6 cells in semi-quantitative RT-PCR and immunocytochemistry. These findings may represent an undifferentiated state of ACNU-resistant glioma cells and a more aggressive phenotype in recurrent tumors following chemotherapy.
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PMID:Gene expression profiles of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant C6 rat glioma cells. 1664 21

To better study early events in glioma genesis, markers that reliably denote landmarks in glioma development are needed. In the present study, we used microarray analysis to compare the gene expression patterns of magnetic resonance imaging (MRI)-localized N-ethyl-N-nitrosourea (ENU)-induced tumors in rat brains with those of uninvolved contralateral side and normal brains. Our analysis identified osteopontin (OPN) as the most up-regulated gene in glioma. Using immunohistochemistry we then confirmed OPN expression in every tumor examined (n = 17), including those with diameters as small as 300 mum. By contrast, no OPN immunostaining was seen in normal brain or in brains removed from ENU-exposed rats before the development of glioma. Further studies confirmed that OPN was co-localized exclusively in intratumoral glial fibrillary acidic protein-expressing cells and was notably absent from nestin-expressing ones. In conjunction with this, we confirmed that both normal neurosphere cells and ENU-im-mortalized subventricular zone/striatal cells produced negligible amounts of OPN compared to the established rat glioma cell line C6. Furthermore, inducing OPN expression in an immortalized cell line increased cell proliferation. Based on these findings, we conclude that OPN overexpression in ENU-induced gliomas occurs within a specific subset of intratumoral glial fibrillary acidic protein-positive cells and becomes evident at the stage of tumor progression.
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PMID:Osteopontin expression in intratumoral astrocytes marks tumor progression in gliomas induced by prenatal exposure to N-ethyl-N-nitrosourea. 1665 33

Some intermediate filament (IF) proteins expressed in the development of glia include nestin, vimentin, and glial fibrillary acidic protein (GFAP). However, GFAP is the major intermediate filament protein of mature astrocytes. To determine the organization of GFAP in glial cells, rat GFAP cDNA tagged with enhanced green fluorescent protein (EGFP) was transfected into the rat C6 glioma cell line. After selection, two stable C6-EGFP-GFAP cell lines were established. Stable C6-EGFP-GFAP cell lines with or without heat shock treatment were analyzed by immunocytochemistry, electron microscopy, and Western blot analysis. In the transient transfection study, EGFP-GFAP transiently expressed in C6 cells formed punctate aggregations in the cytoplasm right after transfection, but gradually a filamentous structure of EGFP-GFAP was observed. The protein level of nestin in the C6-EGFP-GFAP stable clone was similar to that in the pEGFP-C1 transfected C6 stable clones and non-transfected C6 cells, whereas the level of vimentin was reduced in Western blotting. Interestingly, the expression level of small heat shock protein alphaB-crystallin in C6-EGFP-GFAP cells was also enhanced after transfection. Immunostaining patterns of C6-EGFP-GFAP cells showed that GFAP was dispersed as a fine filamentous structure. However, after heat shock treatment, GFAP formed IF bundles in C6-EGFP-GFAP cells. In the meantime, alphaB-crystallin also colocalized with IF bundles of GFAP in C6-EGFP-GFAP cells. The heat-induced GFAP reorganization we found suggested that small heat shock protein alphaB-crystallin may play a functional role regulating the cytoarchitecture of GFAP.
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PMID:Redistribution of GFAP and alphaB-crystallin after thermal stress in C6 glioma cell line. 1672 37

Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen, a widely used Chinese herbal medicine. It has antioxidant properties, cytotoxic activities against multiple human cancer cells, inducing apoptosis and differentiation of some human cancer cells. The purpose of this study is to confirm its anticancer activity on human glioma cells, and to elucidate mechanism of its activity. Human glioma cells were tested in vitro for cytotoxicity, colony formation inhibition, BrdU incorporation after treatment with tanshinone IIA. Its effect of apoptosis induction was detected through EB/AO staining, cell cycle analysis and the expressions of ADPRTL1 and CYP1A1 genes, the differentiation induction effect was investigated through morphology, mRNA and protein expressions of GFAP and nestin genes by RT-PCR and immunocytochemistry. Tanshinone IIA demonstrated a dose- and time-dependent inhibitory effect on cell growth, IC(50) was 100 ng/ml, and it significantly inhibited colony formation and BrdU incorporation of human glioma cells. After treatment with 25-100 ng/ml of tanshinone IIA, the apoptotic cells increased significantly (P < 0.01), the cells in G(0)/G(1) phase increased (P < 0.01), and decreased in S phase, ADPRTL1 and CYP1A1 mRNA expression increased 1-2 folds. The cells treated with 100 ng/ml tanshinone IIA demonstrated astrocytes or neuron-like morphology, GFAP mRNA and protein expressions increased, nestin mRNA and protein expressions decreased significantly. The findings in this study suggested that tanshinone IIA exhibited strong effects on growth inhibition and induction of apoptosis and differentiation in human glioma cells. It might serve as a novel promising differentiation-inducing and/or therapeutic agent for human gliomas, and need to be investigated further.
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PMID:Growth inhibition and induction of apoptosis and differentiation of tanshinone IIA in human glioma cells. 1695 20

Doublecortin (DCX) is a microtubule-associated protein expressed in migrating neuroblasts. DCX expression is increased in subventricular zone (SVZ) cells migrating to the boundary of an ischemic lesion after induction of middle cerebral artery occlusion (MCAO) in adult rats and mice. We tested the hypothesis that DCX, in addition to being a marker of migrating neuroblasts, serves to protect neuroblasts from conditions of stress, such as oxygen and glucose deprivation (OGD). Using gene transfer technology, we overexpressed DCX in rat SVZ and U-87 human glioma cells. The cells remained viable against severe OGD, up to 32 h exhibiting 1% apoptosis compared with 100% apoptosis in control. In addition, these genetically modified cells upregulated expression of E-, VE- and N-cadherin, molecules that promote endothelial survival signals via the VE-cadherin/vascular endothelial growth factor receptor-2/phosphoinositide 3-kinase (PI3-K)/AKT/beta-catenin pathway and inactivate the proapoptotic factor Bad. DCX overexpression also significantly increased cell migration in SVZ tissue explants and U-87 cells and significantly upregulated microtubule-associated protein-2 (MAP2) and nestin protein levels in SVZ and U-87 cells compared with wild-type control cells. Knocking down DCX expression in DCX overexpressing SVZ and U-87 cells with DCX small interfering RNA (siRNA), confirmed the specificity of DCX on cell survival against OGD, and the DCX induced upregulation of E-, VE- and N-cadherin, MAP2 and nestin. In NIH3T3 cells, DCX overexpression had no effect on cell survival against OGD, and indicating that the protective effects of DCX was restricted to brain cells e.g. SVZ and U-87 cells. Our data suggest a novel and an important role for DCX as a protective agent for migrating neuroblasts and tumor cells.
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PMID:Ectopic expression of doublecortin protects adult rat progenitor cells and human glioma cells from severe oxygen and glucose deprivation. 1696 12

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