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)

Much data about genetic imbalances in tumors have been accumulated by comparative genomic hybridization (CGH). In order to distinguish between significantly and coincidentally involved regions in glioma by means of a meta-analysis, we summarized and analyzed the CGH results of 509 cases published in 26 reports between 1992 and 2001. The expansion of all aberrations to the 850-band level impressively visualized distinct patterns in astrocytoma, oligodendroglioma, and ependymoma as well as loci of frequent aberrations. For example, in astrocytoma the frequency of gains culminated at 7p12, 8q24.1, and 12q13-q15 (the loci of EGF-R, C-MYC and CDK4, respectively) and losses at 9p21 (the locus of p15 and p16) and 10q23.3 where PTEN resides. Most chromosomes were variably prone to copy number changes at different scales of aberrations. At the whole chromosome level the analysis showed +7, -10 in astrocytoma and +9, +18 in ependymoma, but +20q, -9p in astrocytoma and +1q, -22q in ependymoma at the p-q arm level. Furthermore, we could confirm the correlation between the average number of copy alterations per patient (average number of copy alterations [ANCA] index) and malignancy for astrocytoma in a refined graduation as well as for oligodendroglioma. As a new parameter, the average number of affected GTG-bands per patient (average number of affected GTG bands [ANAG] index) showed an even more striking correlation with the World Health Organization grade for gains and losses.
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PMID:Comparative genomic hybridization in glioma: a meta-analysis of 509 cases. 1212 99

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

Autocrine fibroblast growth factor (FGF) signaling mediates an uncontrollable growth of human gliomas. We investigated the intracellular signaling of FGF on cell survival activity. U251MG human glioma cells were infected with adenovirus vectors expressing dominant negative type I FGF receptor (DNFR), constitutive active Ras (RasL61), or dominant negative Ras (RasN17). DNFR reduced glioma cell accumulation with apoptosis and this reduction was alleviated with exogenous epidermal growth factor (EGF), which can activate Ras independent of FGFR but not with bFGF. RasL61 prevented but RasN17-enhanced DNFR-induced apoptosis. Reportedly, cell survival signaling through Akt was constitutively active in U251MG cells and this effect may be dependent on autocrine signaling and dysfunction of PTEN, a tumor suppressor gene limiting phosphatidylinositol 3-kinase (PI3K) activity. DNFR dose-dependently inhibited Akt activity and this inhibition was recovered by RasL61, whereas RasN17 inhibited Akt activity. Wortmannin (a PI3K inhibitor) inhibited Akt activity and mildly promoted apoptosis. RasL61 prevented the down-regulation of Akt activity and apoptosis induced by wortmannin, but RasN17 plus wortmannin strongly inhibited Akt activity and promoted marked apoptosis. Our data suggested that the cell survival activity of human gliomas is largely dependent on cross-talk between Ras and the PI3K-Akt pathway, and this cross-talk could be a potential target for molecular-based therapeutics.
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PMID:Autocrine signaling through Ras regulates cell survival activity in human glioma cells: potential cross-talk between Ras and the phosphatidylinositol 3-kinase-Akt pathway. 1243 Jul 14

Due to recent biological and technical advances, the list of potentially useful candidate genes is rapidly expanding in the study of brain tumors. However, traditional methods of screening individual genes in individual samples are slow and tedious, often with consumption of precious resources after only a few experiments. This study evaluates the feasibility of high-throughput molecular analysis using fluorescence in situ hybridization (FISH) on glioma tissue microarrays (TMA). A single microarray paraffin block was constructed using 65 WHO grade III and IV astrocytomas, sampled in duplicate with 0.6-mm-diameter punch cores. FISH was used to detect common alterations, such as EGFR amplification, chromosome 7, 9, and 10 aneusomies and deletions of 1p, 19q, PTEN, DMBT1, and p16. Of 585 hybridization sets, 508 (87%) yielded interpretable data, with hybridization failure in 33 (5.5%) and dislodged tissue in 44 sets (7.5%), respectively. Glioblastomas harbored significantly more alterations than anaplastic astrocytomas, with the overall frequencies of alterations similar to those reported using other techniques. The overall concordance rate between paired tumor core samples was 93%. We conclude that TMA-FISH is an efficient and reliable method for detecting molecular alterations in high-grade astrocytomas.
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PMID:High-throughput molecular profiling of high-grade astrocytomas: the utility of fluorescence in situ hybridization on tissue microarrays (TMA-FISH). 1248 70

Inactivation of the tumor suppressor gene PTEN and overexpression of VEGF are two of the most common events observed in high-grade malignant gliomas. The purpose of this study was to determine whether PTEN controls VEGF expression in gliomas under normoxic conditions. Transfer of PTEN to human glioma cells resulted in the transduction of a functional PTEN protein as evidenced by the upregulation of p27 and modification of the phosphorylation status of Akt. Under normoxic conditions, enzyme-linked immunosorbent assay and Northern blot analyses showed downregulation of VEGF in PTEN-treated cells. Moreover, conditioned media from PTEN-treated glioma cells significantly diminished the ability of endothelial cells to grow and migrate. Western blot assays demonstrated that, in a normoxic environment, PTEN downregulates HIF-1 alpha. Finally, promoter activity assays showed that the VEGF promoter region containing the HIF-1alpha binding site is necessary and sufficient for PTEN-mediated downregulation of VEGF. Experiments with PI3-K inhibitors and kinase assays suggested that PI3-K is mediating the effect of PTEN on VEGF, and not the p42/p48 or p38 MAP kinases. These results indicate that restoration of PTEN function in gliomas may induce therapeutic effect by downregulating VEGF. Furthermore, this close functional relationship between PTEN and VEGF suggests that a better understanding of the transduction signal regulated by PTEN might enhance the knowledge of the cause and physiology of vascular and inflammatory diseases.
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PMID:Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. 1250 54

In the present study we investigated two important signal transduction pathways in glioma biopsies. By Western analysis we found an overexpression of the epidermal growth factor receptor in 10 out of 27 (37%) glioblastoma multiforme (GBM), but not in astrocytomas WHO II/III which demonstrated only weak or absent expression. Only two GBM (8%) but none of the astrocytomas WHO II/III exhibited loss of PTEN expression. Activation of Akt/protein kinase B showed a close correlation with EGF receptor overexpression in human malignant gliomas since 6 out of 7 GBMs with high degrees of protein kinase B activation exhibited overexpression of the EGF receptor. In contrast, no significant differences in MAP kinase activation could be detected between individual GBMs. Our data show that EGF receptor overexpression seems to be responsible for activation of the protein kinase B whereas PTEN deletion seems to play a minor role in the dysregulation of this important pathway in human GBM in vivo.
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PMID:Activation of the anti-apoptotic Akt/protein kinase B pathway in human malignant gliomas in vivo. 1253 6

Approximately 30-40% of malignant glial tumors exhibit mutations in the tumor suppressor gene, PTEN/MMAC. Additionally, these tumors are associated with (a) mutations in epidermal growth factor receptor (EGFR), leading to a pro-oncogenic constitutive activation, as well as amplification of its gene, and/or (b) mutations in p53, disrupting normal cellular homeostatic processes. Whereas PTEN/MMAC has been shown to possess antiangiogenic action, constitutively active EGFR or p53 gene defects have been associated with proangiogenic action. In this article, we asked if PTEN/MMAC gene transfer into human glioma cells that possess inactivating mutations of the PTEN/MMAC gene but also express either constitutively active EGFR (U87DeltaEGFR cells) or possess an inactivating mutation of p53 (U251 cells) still display inhibited angiogenesis in orthotopic and ectopic models of gliomas. Human glioma xenografts treated with PTEN/MMAC gene transfer exhibited significantly decreased vascularity both in an orthotopic and in an ectopic model. Taken in combination, these results provide strong evidence of PTEN/MMAC's role in regulating glioma angiogenesis even in the presence of strong proangiogenic signals provided by constitutive EGFR activation or p53 inactivation.
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PMID:PTEN decreases in vivo vascularization of experimental gliomas in spite of proangiogenic stimuli. 1272 53

Human malignant gliomas arise from neural progenitor cells and/or dedifferentiated astrocytes. By now, they are genetically so well characterized that several murine glioma models have emerged that faithfully reiterate the typical histological features of the disease. In experimental animals, only one or two elements of the growth factor/Ras, PI3K/PTEN/PKB, p53/ARF/HDM2, and p16/Rb/cyclinD/CDK4 pathways are targeted. In human gliomas, many additional genes and pathways are targeted due to a most severe mutator phenotype that leads to the accumulation of countless epigenetic and genetic alterations. Changes that convey a growth advantage are selected for, leading to overgrowth of precursor cell populations with increasingly malignant tumor cell clones. While murine models represent a powerful tool for elucidating the role of genetic pathways, mechanisms of response and resistance to new therapeutic agents might be fundamentally different due to the high degree of genomic instability in the human disease. In fact, little is known about the molecular causes of genomic instability involved in gliomas, except for the rare Turcot's syndrome, O(6)-methylguanine-DNA methyltransferase, and the apurinic/apyrimidinic endonuclease Ape-1. Novel approaches that selectively exploit fundamental metabolic differences between tumor and normal cells have to consider these fundamental differences between human disease and presently available, highly sophisticated animal models.
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PMID:Genes and pathways driving glioblastomas in humans and murine disease models. 1278 72

Focal adhesion kinase (FAK) and hypoxia-inducible factor (HIF-1alpha) are both up-regulated in glioblastoma multiforme (GBMs), particularly in invasive zones. Because FAK may play an important role in the invasion of glioma cells into the surrounding brain, we sought an agent that causes down-regulation of FAK phosphorylation as a potential inhibitor of brain tumor invasion and growth. Geldanamycin (GA), a benzoquinone ansamycin antibiotic, binds to heat shock protein 90 (Hsp90) and interferes with its function. GA inhibits the proliferation of various non-glial cells and has anti-tumor activity. Moreover, GA blocks HIF-regulated transcription of VEGF and inhibits the VEGF-induced phosphorylation of FAK and migration of endothelial cells. Here, we tested the effect of GA on glioma cell migration in vitro and its potential to down-regulate HIF-1alpha induction. Our results demonstrate that GA (i) decreases U87MG, LN229, and U251MG glioma cell migration; (ii) reduces cell migration independent of p53 and PTEN status; (iii) prevents migration at non-toxic concentrations; (iv) reduces phosphorylation of FAK; and (v) inhibits cobalt chloride (CoCl(2))-mediated induction of HIF-1alpha in glioma cells. To the best of our knowledge, this is the first report showing that GA can inhibit phosphorylation of FAK concomitant with a decrease in cellular migration. One of the most clinically relevant aspects of this study is that GA interferes with the induction of HIF-1alpha that has been linked with glioma cell migration and angiogenesis. Given the fact that GA is a small lipophilic molecule capable of penetrating the blood brain barrier together with the data presented here provide a strong rationale for its use or its analogues in the treatment of highly invasive GBMs.
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PMID:Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. 1281 34

Previous work from our laboratory demonstrated that PTEN regulates tumor-induced angiogenesis and thrombospondin 1 expression in malignant glioma. Herein, we demonstrated the first evidence that the systemic administration of a phosphatidylinositol 3'-kinase (PI3K) inhibitor (LY294002) has antitumor and antiangiogenic activity in vivo. We show that PTEN reconstitution diminished phosphorylation of AKT, induced the transactivation of p53 (7.5-fold induction) and increased the expression of p53 target genes, p21(waf-1) and insulin-like growth factor binding protein 3 in glioma cells. PTEN and LY294002 induced p53 activity in human brain endothelial cells, suggesting that PTEN and PI3K pathways can suppress the progression of cancer through direct actions on tumor and endothelial cells. The capacity of PTEN and LY294002 to inhibit U87MG or U373MG glioma growth was tested in an ectopic skin and orthotopic brain tumor model. LY294002 inhibited glioma tumor growth in vivo, induced tumor regression, decreased the incidence of brain tumors, and blocked the tumor-induced angiogenic response of U87MG cells in vivo. These data provide evidence that both PTEN and PI3K inhibitors regulate p53 function and display in vivo antiangiogenic and antitumor activity. These results provide evidence that the two tumor suppressor genes, PTEN and p53, act together to block tumor progression in vivo. Our data provide the first preclinical evidence for the in vivo efficacy for LY294002 in the treatment of malignant gliomas.
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PMID:PTEN and phosphatidylinositol 3'-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. 1283 45


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