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)

Glioblastoma multiforme (GBM), the most common malignant brain tumor of adults, is relatively rare in children. In a GBM affecting a 16-year-old boy, the tumor spread across the corpus callosum (butterfly glioma). This type of bilateral hemispheric growth has previously been thought to result from spread along the white matter tracts. Two samples obtained from opposite sides of the same tumor were analyzed comprehensively for loss of heterozygosity (LOH) and microsatellite instability (MSI). Amplification of EGFR and MDM2 was studied by means of multiplex polymerase chain reaction. Exons 5, 6, 7, and 8 of TP53 were screened for mutations by sequencing. In neither specimen were molecular alterations found in the EGFR, MDM2, or TP53 genes. The specimen obtained from the right hemisphere exhibited a high level of MSI and LOH in chromosome arms 5q, 9p, and 13q. The specimen from the left hemisphere exhibited LOH in chromosome arms 3p, 5q, 9p, 9q, 10p, 10q, and 13q. Here we propose four plausible hypothetical scenarios underlying the tumorigenesis of this GBM.
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PMID:Diverse molecular pattern in a bihemispheric glioblastoma (butterfly glioma) in a 16-year-old boy. 1785 67

Studies support involvement of the erbB/HER (human epidermal growth factor receptor) family, comprising the c-erbB-1/2/3/4 receptor proteins, in the tumourigenesis of human gliomas, raising their potential role in diagnostic and therapeutic approaches to these tumours. Reliable detection systems for these molecules in glioma tissue are therefore needed. Formalin-fixed and paraffin-embedded sections from twenty-one human glioblastomas were investigated by standard immunohistochemical procedures for expression of c-erbB-1/2/3/4 receptor proteins using commercial antibodies. All the antibodies used worked satisfactorily on paraffin-sections. For EGFR (epidermal growth factor receptor) two antibodies reactive against the external and internal domain were used. The first revealed positive immunoreactivity in 13 of 21 tumours (62 %), whereas all were positive with the latter. All glioblastomas were negative for the mutated variant of EGFR (i.e. EGFRvIII). Nine of 21 tumours (43 %) were immunoreactive for c-erbB-2, 19 of 20 tumours (95 %) for c-erbB-3, and 21 of 21 for c-erbB-4. Kaplan-Meier plots as a function of growth factor receptor expression did not show any significant association with survival among the glioblastoma patients. In conclusion, immunohistochemistry is well suited for detection of erb receptor proteins in glioblastoma tissue and demonstrated abundant and simultaneous immunoreactivity of these receptors.
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PMID:Coexpression of c-erbB 1-4 receptor proteins in human glioblastomas. An immunohistochemical study. 1798 95

Glioblastoma is the most malignant and frequent of the glial tumors. A minor fraction of glioblastoma may contain areas showing oligodendroglioma-like tumor cell differentiation. Several authors have described such tumors as glioblastoma with oligodendroglial component (GBMO). GBMO may represent the ultimate level of malignancy in the oligodendroglial lineage. The oligodendroglial component and combined loss of chromosomal arm 1p and 19q in glioblastoma indicate increased survival. In our study, we analyzed 1p and 19q status in a series of 12 glioblastoma and 8 oligodendroglial tumors using fluorescence in situ hybridization (FISH) on paraffin-embedded tissues. In each case, hybridization status was classified as deletion, imbalance, polysomy, amplification, or normal pattern. Other genetic alterations such as CDKN2A (p16), RB, and EGFR were also assessed. On histological review, 2 of 12 glioblastoma (16.7%) were classified as GBMO. Chromosome 1p/19q deletion was detected in 3 of 12 glioblastomas (25%). In contrast, all 8 oligodendroglial tumors showed 1p/19q deletion. All GBMO had 19q deletion with imbalance, whereas 1 of 10 ordinary glioblastoma (10%) demonstrated 19q deletion with imbalance. All but 1 ordinary glioblastoma (90%) showed CDKN2A (p16) deletion, but no GBMO displayed this alteration. Our results indicate that GBMO may be a distinct subtype of glioblastoma harboring a characteristic molecular profile. FISH on paraffin-embedded specimens is a useful method for subclassification of glioblastoma.
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PMID:FISH 1p/19q deletion/imbalance for molecular subclassification of glioblastoma. 1809 37

The c-Jun NH2-terminal kinase (JNK), which belongs to mitogen-activated protein kinase family, plays a major role in apoptosis in various cell types. JNK activation, however, also contributes to proliferation, survival, and tumorigenesis in some tumors, including gliomas. In this study, we used an immunohistochemical approach to examine the activation status of JNK of 226 gliomas in a high-density tissue microarray comprising all WHO codified WHO diffuse glioma subtypes and grades. The results were correlated with grade and EGFR expression status. Constitutively activated JNK (pJNK) was detected in 90.5%, 62.9% and 17.5% of WHO grade IV, III and II gliomas, respectively (p < 0.001). pJNK expression was not detected in the astrocytes or oligodendrocytes of any of 10 normal cerebral and cerebellar brain tissue samples. Among the 76 diffuse gliomas that exhibited EGFR expression, 63 (82.9%) were positive for pJNK. In contrast, only 50% (36/72) of the gliomas that were negative for EGFR were positive for pJNK (p < 0.0001). Overexpression of EGFR vIII in U87 cells or EGF treatment of U87-EGFR stable cells led to marked increase in JNK activation compared to parental U87 cells. Our data thus provide strong support for the hypothesis that JNK activation plays a role in the tumorigenesis and/or progression of diffuse gliomas, and suggests that EGFR is involved in constitutive JNK activation in diffuse gliomas. The ability to inhibit JNK activation might confer increased sensitivity to therapeutic modalities targeting this pathway.
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PMID:Constitutive activation of c-Jun N-terminal kinase correlates with histologic grade and EGFR expression in diffuse gliomas. 1824 8

In the present study, we tested the hypothesis that a mild cerebral tissue injury promotes subsequent glioma invasion via activation of the ADAM17-EGFR-PI3K-Akt pathway. Mild injury was induced by photodynamic therapy (PDT), which employs tissue-penetrating laser light exposure following systemic administration of a tumor-localizing photosensitizer. Athymic nude mice were treated with sublethal PDT (80 J/cm2 with 2 mg/kg Photofrin). Hypoxic stress and ADAM17-EGFR-PI3K-Akt were measured using Western blot and immunostaining. Additional groups with/without pro-sublethal PDT were subsequently implanted with U87 glioma tumor cell. Tumor invasion and ADAM17-EGFR-PI3K-Akt pathway in tumor area were measured. After a sublethal dose of PDT, HIF-1alpha expression was increased by a factor of three in PDT-treated normal brain tissue compared to contralateral control brain tissue. PDT-treated brain tissue exhibited a significant increase in ADAM17, p-EGFR, p-Akt expression compared to non-treated tissue. ADAM17 positive area significantly increased from 1.78% to 10.89%. The percentage of p-EGFR and p-Akt positive cells significantly increased from 9.50% and 14.50% to 21.31% and 32.29%, respectively, PDT treatment significantly increased subsequent implanted U87 glioma cell invasion by 3.68-fold and increased ADAM17, EGFR, p-EGFR, Akt, p-Akt expression by 178%, 43.9%, 152.7%, 89.6%,and 164.2%, respectively, compared to control group. Our data showed that a sublethal sensitization of cerebral tissue with PDT significantly increased U87 cell invasion in nude mice, and that glioma cell invasion is highly correlated with activation of the ADAM17-EGFR-PI3K-Akt pathway (r=0.928, 0.775, 0.870, 0.872, and 0.883, respectively), most likely via HIF-1alpha.
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PMID:Sensitization of cerebral tissue in nude mice with photodynamic therapy induces ADAM17/TACE and promotes glioma cell invasion. 1835

Receptor tyrosine kinases (RTK) are therapeutic targets for the treatment of malignancy. However, tumor cells develop resistance to targeted therapies through the activation of parallel signaling cascades. Recent evidence has shown that redundant or compensatory survival signals responsible for resistance are initiated by nontargeted glycoprotein RTKs coexpressed by the cell. We hypothesized that disrupting specific functions of the posttranslational machinery of the secretory pathway would be an effective strategy to target both primary and redundant RTK signaling. Using the N-linked glycosylation inhibitor, tunicamycin, we show that expression levels of several RTKS (EGFR, ErbB2, ErbB3, and IGF-IR) are exquisitely sensitive to inhibition of N-linked glycosylation. Disrupting this synthetic process reduces both cellular protein levels and receptor activity in tumor cells through retention of the receptors in the endoplasmic reticulum/Golgi compartments. Using U251 glioma and BXPC3 pancreatic adenocarcinoma cell lines, two cell lines resistant to epidermal growth factor receptor-targeted therapies, we show that inhibiting N-linked glycosylation markedly reduces RTK signaling through Akt and radiosensitizes tumor cells. In comparison, experiments in nontransformed cells showed neither a reduction in RTK-dependent signaling nor an enhancement in radiosensitivity, suggesting the potential for a therapeutic ratio between tumors and normal tissues. This study provides evidence that enzymatic steps regulating N-linked glycosylation are novel targets for developing approaches to sensitize tumor cells to cytotoxic therapies.
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PMID:Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. 1848 64

Transgenic rats expressing v-erbB (viral form of the EGF receptor) under transcriptional regulation by the S100beta promoter develop brain tumors (Ohgaki et al. J Neuropathol Experimental Neurol 65: 1111-1117, 2006). In the present study, we carried out detailed immunohistochemical and ultrastructural characterization of the brain tumors that developed in these rats. Of 49 homozygous transgenic rats between 16 and 94 weeks of age (mean, 59 weeks), 31 rats were autopsied because they showed severe neurological symptoms and/or became moribund. Among these, 30 rats had brain tumors, which were classified histologically as malignant glioma, anaplastic oligodendroglioma, and low-grade oligodendroglioma. Six transgenic rats developed two different histologic types of brain tumor, which were considered to be of multiclonal origin, because of the lack of histological transitions. All brain tumors contained neoplastic cells immunoreactive for S100 and GFAP. Diffuse immunoreactivity for Olig2 and Nkx2.2 was observed in neoplastic cells in all seven anaplastic oligodendrogliomas and in all three low-grade oligodendrogliomas analyzed, but in none of 26 malignant gliomas. Electron microscopy, carried out on four malignant gliomas and four anaplastic oligodendrogliomas, revealed the presence of intermediate filament bundles devoid of side arms, indicating glial differentiation. There was no evidence of cilia, microvilli, neurosecretory granules, synaptic structures or neurofilaments, excluding the possibility of ependymal or neuronal tumors. The present study thus provides additional evidence that the brain tumors developing in S100beta-v-erbB transgenic rats are of glial origin, with or without oligodendroglial differentiation. Reproducible development of three distinct histologic types of brain tumor in unique localizations may be explained by activation of the v-erbB transgene driven by the S100beta promoter in specific precursor cells during development of the brain. Thus, S100beta-v-erbB transgenic rats may be useful to study the histogenesis and molecular mechanisms of development of glial tumors due to disruption of the EGFR pathway.
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PMID:Immunohistochemical and ultrastructural characterization of brain tumors in S100beta-v-erbB transgenic rats. 1849 86

This study assessed the prognostic value of several markers involved in gliomagenesis, and compared it with that of other clinical and imaging markers already used. Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes, oncogenes, MGMT and hTERT expressions, losses of heterozygosity, as well as relevant clinical and imaging information were recorded. This prospective study was based on all adult gliomas. Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort. The endpoint was overall survival, estimated by the Kaplan-Meier method. Univariate analysis was followed by multivariate analysis according to a Cox model. p14(ARF), p16(INK4A) and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only. This study confirms the prognostic value of several markers. However, the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making.
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PMID:Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study. 1850 88

Gliomas are the most frequent tumors of the central nervous system. The WHO classification, based on the presumed cell origin, distinguishes astrocytic, oligodendrocytic and mixed gliomas. A grading system is based on the presence of the following criteria: increased cellular density, nuclear atypias, mitosis, vascular proliferation and necrosis. The main histological subtype of grade I gliomas are pilocytic astrocytomas, which are benign. Diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas are low-grade (II) or high-grade (III and IV) tumors. Glioblastomas correspond to grade IV astrocytomas. C. Daumas-Duport et al. have proposed another classification based on histology and imaging data, which distinguishes oligodendrogliomas and mixed gliomas of grade A (without endothelial proliferation and/or contrast enhancement), oligodendrogliomas and mixed gliomas of grade B (with endothelial proliferation or contrast enhancement), glioblastomas and glioneuronal malignant tumors. Both classifications lack reproducibility. Many studies have searched for a molecular classification. Recurrent abnormalities in gliomas have been found. They encompassed recurrent chromosomal alterations, such as lost of chromosome 10, gain of chromosome 7, deletion of chromosome 1p and 19q, but also activation of the Akt pathway (amplification of EGFR), dysregulation of the cell cycle (deletion of p16, p53). These studies have enabled the description of two molecular subtypes for glioblastomas. De novo glioblastomas, which occur in young patients without of a prior history of brain tumor and harbor frequent amplification of EGFR, deletion of p16 and mutation of PTEN while mutation of p53 is infrequent. Secondary glioblastomas occur in the context of a preexisting low-grade glioma and are characterized by more frequent mutation of p53. On the other side, combined complete deletion of 1p and 19q as the result of the translocation t(1;19)(q10;p10) is highly specific of oligodendrogliomas. However, histological and molecular classifications do not always correspond as many alterations are shared by high-grade tumors, whatever their histological type. Besides, few molecular alterations have a prognostic value. Among them combined 1p19q loss is associated with a better prognosis and response to treatment for oligodendrogliomas. Another promising marker is MGMT, a DNA repairing enzyme. If inactivated (by methylation of the promoter of the gene) a better sensitivity is observed with nitrosoure agents. However, some concerns exist for the method of detection of this abnormality. Quality control for molecular techniques is also required before using them for therapeutic strategy. In the future, studies of gene expression profiles by cDNA-microarray as well as works in the field of neural progenitor cells will probably provide new insights in gliomagenesis.
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PMID:[Histological and molecular classification of gliomas]. 1856 48

Pleomorphic xanthoastrocytoma (PXA) is a rare superficial glioma that predominates in the young and has good prognosis. A long history of repeated seizures is commonly associated with PXA, which is frequently observed in neuroimaging scans as a solid-cystic, contrast-enhancing lesion. We report a case in which PXA diagnosis was favored by its histological features, such as pleomorphic multinucleated giant cells, with disproportionately few mitoses and necrotic areas. An eye-catching feature was widespread, pale-staining, circumscribed deposits in the cytoplasm of tumor cells, which turned out to be glycogen upon histochemical and electron-microscopical examination. The stored material was strongly PAS-positive and digested by diastase, and had a finely granular ultrastructural appearance. No evidence of lipid droplets was found on oil-red-O staining. The tumor was immunoreactive for glial fibrillary acidic protein and vimentin. Many cells were positive for CD34 on the external membrane, a feature which has been described in chronic CNS lesions associated with epilepsy. Intracytoplasmic immunostaining for EGFR was observed in most tumor cells, which might have favored neoplastic proliferation. Nuclear immunolabeling for p53 protein was rare and does not support a major role for p53 mutation in PXA tumorigenesis. Intracellular accumulation of glycogen in glial tumors is uncommon and may originate from abnormalities in carbohydrate metabolic pathways.
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PMID:Temporal pleomorphic xanthoastrocytoma with glycogen accumulation--case report. 1866 39


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