Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C6 rat glioblastoma cells are able to attach to and to spread on culture dishes which are coated with purified central nervous system myelin, in contrast to normal astrocytes, fibroblasts or neurons which adhere poorly and are unable to spread on this substrate. The metalloprotease blockers o-phenanthroline and a newly developed oligopeptide could specifically inhibit C6 cell spreading on central nervous system myelin, suggesting a crucial role for a metalloprotease. Here we characterize this metalloproteolytic activity of C6 cells using a peptide degradation assay with the iodinated tetrapeptide carbobenzoxy-Phe-Ala-Phe-125I-Tyr-amide as a substrate. Purified, salt-washed C6 plasma membranes cleaved the peptide between alanine and phenylalanine, an effect which is strongly inhibited by o-phenanthroline, but not by thiol-blocking agents or aspartic and serine protease inhibitors. The metalloendoprotease is highly sensitive to phosphoramidon but insensitive to thiorphan. The enzyme is tightly bound to the plasma membrane but not G protein-phosphatidylinositol linked. It can be solubilized in part by the detergents 3-(3-cholamidopropyldimethylamino)-1-propanesulfonate or Triton X-114. Gel filtration chromatography using the Triton X-114-solubilized proteins or the proteins removed by a short trypsin treatment revealed a molecular weight range for the C6 enzyme of 60,000-100,000. Polymerase chain reaction with primers corresponding to endopeptidase 24.11 or to the highly conserved motif of the "astacin family" showed that both enzymes were not detectable in the C6 glioblastoma cells.
 ...
PMID:Characterization of a membrane-bound metalloendoprotease of rat C6 glioblastoma cells. 803 33

Glioblastomas were examined for abnormalities in fibroblast growth factor receptor (FGFR) expression by polymerase chain reaction and immunocytochemical analysis. Polymerase chain reaction analysis demonstrated that FGFR1 mRNA levels were significantly higher in glioblastomas than in normal brain adjacent to the tumor or in untransformed human brain. These results were consistent with immunocytochemical localization of FGFR1 protein in glioblastomas: glioblastoma cells exhibited intense FGFR1 immunoreactivity in frozen sections of tumor and low to undetectable FGFR1 immunoreactivity in adjacent normal brain or in normal white matter obtained from patients without neoplastic disease. Endothelial cells of capillaries and larger vessels within the tumor were devoid of FGFR1 immunoreactivity. All glioblastomas evaluated in the present study expressed FGFR1 mRNA and FGFR1 immunoreactivity. Examination of the FGFR1 gene by Southern blot analysis indicated that overexpression of FGFR1 mRNA in glioblastomas did not result from gene amplification. These results indicate that glioblastoma cells, in contrast to endothelial cells within the tumor, display increased levels of FGFR1. Therefore, FGFR1 signal transduction may be associated with increased autocrine growth activity of tumor cells and is probably not related to the increased endothelial cell proliferation associated with these tumors.
 ...
PMID:Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme. 816 12

In malignant gliomas, the characteristically heterogeneous features and frequent diffuse spread within the brain have raised the question of whether malignant gliomas arise monoclonally from a single precursor cell or polyclonally from multiple transformed cells forming confluent clones. Although monoclonality has been shown in surgically resected tissues, these may not include the full spectrum of patterns seen on autopsy material. Little is known about the clonality of low-grade gliomas from which malignant gliomas may sometimes arise. We sought to investigate the clonality of low-grade and malignant gliomas by using and comparing surgical and autopsy material with a Polymerase chain reaction (PCR)-based assay for nonrandom X chromosome inactivation. For that, purpose, archival surgical and autopsy material from 15 female patients (group A) (age 4 to 73 years; median, 45) with malignant gliomas (12 glioblastomas, one gliosarcoma, one anaplastic oligoastrocytoma, one gliomatosis cerebri), surgical material only from 21 female patients (group S) (age 6 to 78 years; median, 60) with low-grade and malignant gliomas (four low-grade astrocytomas, three oligoastrocytomas, two anaplastic astrocytomas, one gemistocytic astrocytoma, four oligodendrogliomas, seven glioblastomas) were analyzed. In group A, representative areas (mean = 5/patient; median = 7) were microdissected from tissue sections and assayed by PCR amplification of a highly polymorphic microsatellite marker locus of the human androgen receptor gene (HUMARA) in the presence of alpha32P with and without predigestion with a methylation-sensitive restriction enzyme (HhaI). Products were resolved by denaturing gel electrophoresis and autoradiographed. In group S, selected tumor areas were used for the assay. Each patient's normal brain tissue was used for control. The band intensity of alleles were measured by densitometric scanning. In group A, 13 of 15 cases were informative (heterozygous). The same pattern of nonrandom X chromosome inactivation was present in all areas of solid dense and moderate tumor infiltration in eight including all components of the gliosarcoma. Two of eight also showed focal loss of heterozygosity (LOH). One of 13 presented global LOH. Two of 13 showed microsatellite instability, one of which in a patient with Turcot syndrome, the other in gliomatosis cerebri. Opposite skewing patterns were seen in distant areas of gliomatosis cerebri consistent with oligoclonal derivation. Clonality remained indeterminate in one glioblastoma and in the anaplastic oligoastrocytoma because of skewed lyonization in the normal control. In group S, 19 of 21 cases were informative. Fifteen of 19 were monoclonal (four low-grade astrocytomas, one anaplastic astrocytoma, one gemistocytic astrocytoma, two oligodendrogliomas, one oligoastrocytoma, six glioblastomas). Four of 19 were indeterminate. We conclude that (1) Low-grade and malignant gliomas are usually monoclonal tumors, and extensively infiltrating tumors must result from migration of tumor cells (2) Gliomatosis cerebri may initiate as an oligoclonal process or result from collision gliomas (3) Biphasic gliomas likely arise from a single precursor cell. (4) LOH at the HUMARA locus is probably related to partial or complete deletion of an X-chromosome, which occurs in malignant gliomas during clonal evolution.
 ...
PMID:Clonal analysis of gliomas. 934 24

The introduction of chromosome 10p into human glioblastoma or prostate cancer cells has been demonstrated to suppress their malignant phenotype, suggesting the presence of glioma or prostate tumor suppressor genes on 10p. As a resource for the fine mapping of these genes, a series of human-rodent hybrid cell lines containing single transferable fragments (STFs) of 10p were constructed. Normal chromosome 10 tagged with a neomycin-resistance gene on its short arm was fragmented by gamma-irradiation of 5-10krad, transferred into mouse L cells or Chinese hamster ovary cells by microcell-mediated chromosome transfer (MMCT), and then selected against G418. Thirty-three independent rodent-human hybrids carrying various-sized STFs were obtained. Polymerase chain reaction (PCR)-based genotyping revealed that these STFs contained the whole, or portions, of a 43-cM region on 10p14-pter and could be defined by 19 sequence-tagged-site (STS) markers. Using this panel of hybrids as donors for further MMCT, genes on the refined fragments could be transferred into other cells. This hybrid panel would therefore be a useful resource for the fine mapping of the genes on 10p14-pter to segments of about 2.4 cM by functional complementation.
 ...
PMID:Construction of human-rodent hybrid cells containing single transferable fragments of human chromosome 10p. 1118 48

Glioblastoma is the most frequent brain tumor and accounts for approximately 50--60% of all astrocytic tumors. Many chromosome alterations have been described in glioblastoma, but only for a few alterations were the genes identified and linked to genetic pathways in glioblastoma development. To contribute to the identification of novel genes involved in glioblastoma development we used a combined immunological and molecular screening approach. Here we report the identification and expression analysis of a novel gene from human chromosome 6q12 that is considered to be the third member of a family of PHD finger containing genes and is termed PHF3. PHF3 is ubiquitously expressed in normal tissues including brain, but its expression is significantly reduced or lost in glioblastoma, glioblastoma cell lines, anaplastic astrocytomas and astrocytomas. The PHF3 protein sequence contains several protein motifs frequently found in transcription factors. One of those motifs is a PHD finger, also termed LAP motif and known to bind large portions of DNA. Another region of the protein revealed a high homology to the transcription factor TFIIS, especially to a region that is necessary for the Polymerase II binding properties of TFIIS. Combining these results, PHF3 is a novel member of a large class of regulatory proteins containing a LAP motif, and loss of its expression in glioblastoma may contribute to glioma development.
 ...
PMID:PHF3 expression is frequently reduced in glioma. 1185 69

Despite binding to receptors distinct from those of type I interferons (IFNs), human interleukins-28A, -28B and -29 (IL-28A, IL-28B and IL-29; alternatively named IFN lambda-2 {IFN-lambda2}, IFN-lambda3 and IFN-lambda1, respectively, or collectively, type III IFNs), a small family of three structurally-related cytokines, are, like IFNs, known to induce antiviral activity. To further biologically characterize IL-28A and IL-29, we compared their activities with those of IFNs in a range of human cell lines. We found that they induced antiviral activity in fewer cell lines and more weakly than IFNs; also IL-28A was less active than IL-29. Additionally, we showed IL-28A and IL-29 induced reporter genes--protein MxA promoter linked to luciferase, or interferon stimulated response element (ISRE) linked to secreted alkaline phosphatase (SEAP)--more weakly than IFN. Antiproliferative activity was induced by IFNs in most cell lines, but only in one human glioblastoma cell line, LN319, was dose-dependent IL-29-growth inhibition demonstrable. Polymerase chain reaction (PCR) quantification of messenger (m) RNA of IL-28/29 receptor subunits, IL-28Ralpha and IL-10Rbeta, indicated variable expression levels; although their expression was highest in the responsive LN319 cell line, lower but significant expression of both mRNAs was found in relatively unresponsive cell lines. In conclusion, we found IL-28A and IL-29 act similarly to IFNs, but are less effective generally and have activity in a more limited range of cell lines.
 ...
PMID:Biological activity of interleukins-28 and -29: comparison with type I interferons. 1589 85

Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.
 ...
PMID:Genetic alterations in primary glioblastomas in Japan. 1641 Jul 44

The epidermal growth factor receptor (EGFR) is amplified in approximately 40% of glioblastomas making it a compelling molecular target for therapy. Before starting a therapy targeting the EGFR pathway, accurate determining of EGFR status is a prerequisite. We evaluated the reliability of the novel automated silver enhanced in situ hybridization for the detection of EGFR gene amplification in human glioblastomas. EGFR-amplification status was assessed in 93 cases of glioblastoma by silver enhanced in situ hybridization and compared with results of fluorescence in situ hybridization and immunohistochemistry. In a second cohort, silver enhanced in situ hybridization status was correlated with EGFR gene expression data. The EGFR gene was amplified in 25/90 tumours (28%) by silver enhanced in situ hybridization, and in 28/93 tumours (30%) by fluorescence in situ hybridization. The concordance rate for silver enhanced in situ hybridization and fluorescence in situ hybridization was 98%. Two glioblastomas were scored as being amplified by fluorescence in situ hybridization but not by silver enhanced in situ hybridization. Polymerase chain reaction-based EGFR-amplification data were highly correlated with EGFR silver enhanced in situ hybridization. Altogether, 81 of 91 cases (89%) showed positivity for EGFR expression by immunohistochemistry. Although EGFR protein over expression was associated with gene amplification (r=0.40, P<0.001), there were 29 of 91 cases that showed a high EGFR protein level and no EGFR amplification by fluorescence in situ hybridization. The high concordance rate of silver enhanced in situ hybridization and fluorescence in situ hybridization for the detection of EGFR amplification in paraffin-embedded glioblastomas samples demonstrates that silver enhanced in situ hybridization is a valid and attractive alternative to fluorescence in situ hybridization. Silver enhanced in situ hybridization combines the advantages of bright field microscopy with fully automated analysis in a cost-effective way thereby emphasizing its use for routine application in surgical pathology.
 ...
PMID:Comparison of automated silver enhanced in situ hybridization and fluorescence in situ hybridization for evaluation of epidermal growth factor receptor status in human glioblastomas. 1952 25