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

Glioblastomas frequently carry genetic alterations resulting in an aberrant activation of the phosphoinositol-3-kinase (Pi3k)/protein kinase B (Akt) signalling pathway, including most notably phosphatase and tensin homolog (PTEN) mutation, epidermal growth factor receptor (EGFR) amplification and rearrangement, as well as carboxyl-terminal modulator protein (CTMP) hypermethylation [Knobbe et al., (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Institute, 96, 483-486]. Here, we investigated two further Pi3k/Akt pathway genes, namely PIK3CA (3q26.3) and phosphatidylinositol-3-kinase enhancer (PIKE) (CENTG1, 12q14), for genetic alteration and aberrant expression in a series of 97 primary glioblastomas. Single strand conformation polymorphism (SSCP) analysis of PIK3CA revealed somatic mutations in five tumours (5%). Twelve glioblastomas (12%) showed amplification of PIKE with invariable co-amplification of the adjacent CDK4 gene. All tumours with PIKE amplification as well as the vast majority of glioblastomas without amplification demonstrated increased expression of PIKE-A but not PIKE-S/L transcripts as compared with non-neoplastic brain tissue. Taken together, our data support an important role of PIK3CA and PIKE gene aberrations in the molecular pathogenesis of primary glioblastomas.
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PMID:Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. 1615 Jan 19

Glioblastoma is the most common primary tumor of the central nervous system, but the underlying genetic changes that give rise to these tumors are still poorly understood. We report a primary glioblastoma with an unusual age of presentation. The patient was a 22-year-old man with a survival of 16 months. Morphological findings showed an increase of cellularity with positive GFAP and EGFR expression, increase of proliferate index, vascular hyperplasia with glomeruloid structures and necrosis. Molecular analysis showed EGFR amplification. No mutations of the TP53 or amplification of MDM2 and CDK4 were detected. Neither homozygous deletion of the 9p21 locus genes nor aberrant methylation were found. The cytogenetic study showed a clonal karyotype. The metaphases presented, among other anomalies, a small ring chromosome and double-minutes chromosomes. Using FISH and CGH techniques, it was found that the ring chromosome was a partial trisomy of chromosome 7, and the region implicated corresponded to 7p13-q21. Partial trisomies in glioblastoma could play an important role in defining those regions where genes implicated in this tumor process may be found. We studied the possible correlation of these findings with the tumoral phenotype.
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PMID:Primary glioblastoma with EGFR amplification and a ring chromosome 7 in a young patient. 1686 1

High-grade gliomas comprise the most malignant type of primary brain tumor and are relatively frequent in adults. Recent studies have indicated that the loss of p16, an inhibitor of CDK4, promotes the acquisition of malignant characteristics in gliomas. A correlation between overexpression of urokinase-type plasminogen activator receptor (uPAR) and glioblastoma invasion has also been established. Moreover, uPAR/integrin binding has been shown to initiate or potentiate integrin signaling through focal adhesion kinase and/or src kinases. Our previous studies demonstrated that downregulation of uPAR expression and restoration of p16 regress glioma growth in nude mice and downregulate alphavbeta3 integrin receptor expression. Here, we show the effect of a bicistronic construct on alphavbeta5 integrin receptor expression, angiogenesis and the biochemical pathway that causes glioma cell death. The U251 glioblastoma and a glioblastoma xenograft cell line transduced with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 and antisense RNA of uPAR significantly inhibited human mammary epithelial cell capillary formation and vascular endothelial growth factor (VEGF) expression. Inactivation of anti-apoptotic molecules such as Akt, PARP, activation of caspases and accumulation of heteroduplex chromosomal DNA in pre-G1 phase of the cell cycle was demonstrated by Western blotting, caspase activity assay and FACS analysis. Nuclear DNA fragmentation upon induction of apoptosis was scored using the TUNEL assay. Significant downregulation of alphavbeta5 integrin receptor expression was also confirmed by FACS analysis, immunoprecipitation and RT-PCR. Taken together, the results demonstrate that the sense p16 and anti-sense uPAR bicistronic construct significantly inhibits angiogenesis, induces apoptosis by deregulation of the PI3K-Akt pathway and downregulates alphavbeta5 integrin receptor expression.
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PMID:Sense p16 and antisense uPAR bicistronic construct inhibits angiogenesis and induces glioma cell death. 1727 68

PIKE-A (phosphoinositide 3-kinases (PI 3)-kinase enhancer) is a ubiquitously expressed GTPase, which binds to and enhances protein kinase B (Akt) kinase activity in a guanine nucleotide-dependent manner. PIKE-A is one of the components of the CDK4 amplicon that is amplified in numerous human cancers. However, whether PIKE-A itself can mediate cell transformation, proliferation and migration remains unknown. Here, we show that PIKE-A is overexpressed in various human cancer samples, escalates U87MG glioblastoma invasion and provokes NIH3T3 cell transformation. Overexpression of wild-type (WT) PIKE-A enhances NIH3T3 and U87MG cell growth, which is further increased by cancer cell-derived PIKE-A active mutants. In contrast, both the dominant-negative mutant and the phosphoinositide lipids interaction-defective mutant antagonize cell proliferation. Moreover, PIKE-A and its active and inactive mutants similarly enhance or antagonize U87MG cell survival and invasion, and their ability to do so is coupled with the catalytic effect they have on Akt activation. Furthermore, PIKE-A WT and its active mutants significantly elicit NIH3T3 cell transformation. Thus, our findings support the concept that PIKE-A acts as a proto-oncogene, promoting cell transformation through Akt activation.
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PMID:PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion. 1729 40

Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anapalsic astrocytoma (secondary glioblastoma). The molecular alteration most frequent in these tumor-like types is the loss of heterozygosity on chromosome 10, in which several genes have been identified as tumors suppressor. The TP53/MDM2/P14arf and CDK4/RB1/ P16ink4 genetic pathways involved in cycle control are deregulated in the majority of gliomas as well as genes that promote the cellular division, EGFR. Finally the increase of growth and angiogenics factors is also involved in the development of glioblastomas. One of the objectives of molecular biology in tumors of glial ancestry is to try to find the genetic alterations that allow to approach better the classification of glioblastomas, its evolution prediction and treatment. The new pathmolecular classification of gliomas should improve the old one, especially being concerned about the oncogenesis and heterogeneity of these tumors. It is desirable that this classification had clinical applicability and integrates new molecular findings with some known histological features with pronostic value. In this paper we review the most frequent molecular mechanisms involved in the patogenesis of glioblastomas.
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PMID:[Biology molecular of glioblastomas]. 1800 11

Berberine is an isoquinoline plant alkaloid with a long history of being used for the treatment of many diseases in Chinese herbal medicine. Berberine has a wide range of biochemical and pharmacological effects, including antitumor activities, but its mechanism of action is not clearly understood. In this study, we investigated that the relationship between the antiproliferative activities of berberine and the apoptotic pathway associated with its molecular mechanism of action in human glioblastoma T98G cells. Berberine treatment of T98G cell lines inhibited cell proliferation and induced cell death in a dose (50-200 microg/ml) dependent manner with an IC50 value of 134 microg/ml, which was associated with an increase in G1 arrest. Western blot analysis showed that the berberine-induced G1 arrest was mediated through the increased expression of P27 and the decreased expression of cyclin-dependent kinase (CDK) 2, CDK4, cyclin D, and cyclin E proteins. Berberine treatment also markedly enhanced apoptosis in T98G cells through the induction of a higher ratio of the Bax/Bcl-2 proteins, the disruption of mitochondrial membrane potential, and the activation of procaspase-9, caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP). Berberine can inhibit T98G cell proliferation by inducing G1 arrest and apoptosis. These results demonstrate that the berberine-induced apoptosis of T98G cells is primarily mediated through the mitochondrial/caspases-dependent pathway.
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PMID:Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway. 1837 40

To further understand the biological significance of amplifications for glioma development and recurrencies, we characterized amplicon frequency and size in low-grade glioma and amplicon stability in vivo in recurring glioblastoma. We developed a 12q13-21 amplicon-specific genomic microarray and a bioinformatics amplification prediction tool to analyze amplicon frequency, size, and maintenance in 40 glioma samples including 16 glioblastoma, 10 anaplastic astrocytoma, 7 astrocytoma WHO grade 2, and 7 pilocytic astrocytoma. Whereas previous studies reported two amplified subregions, we found a more complex situation with many amplified subregions. Analyzing 40 glioma, we found that all analyzed glioblastoma and the majority of pilocytic astrocytoma, grade 2 astrocytoma, and anaplastic astrocytoma showed at least one amplified subregion, indicating a much higher amplification frequency than previously suggested. Amplifications in low-grade glioma were smaller in size and displayed clearly different distribution patterns than amplifications in glioblastoma. One glioblastoma and its recurrencies revealed an amplified subregion of 5 Mb that was stable for 6 years. Expression analysis of the amplified region revealed 10 overexpressed genes (i.e., KUB3, CTDSP2, CDK4, OS-9, DCTN2, RAB3IP, FRS2, GAS41, MDM2, and RAP1B) that were consistently overexpressed in all cases that carried this amplification. Our data indicate that amplifications on 12q13-21 (a) are more frequent than previously thought and present in low-grade tumors and (b) are maintained as extended regions over long periods of time.
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PMID:A different view on DNA amplifications indicates frequent, highly complex, and stable amplicons on 12q13-21 in glioma. 1840 36

We report on three adult patients with primary glioblastomas showing prominent adipocytic (lipomatous) differentiation, hence referred to as "glioblastomas with adipocyte-like tumor cell differentiation." Histologically, the tumors demonstrated typical features of glioblastoma but additionally contained areas consisting of glial fibrillary acidic protein (GFAP)-positive astrocytic tumor cells resembling adipocytes, that is, containing large intracellular lipid vacuoles. Comparative genomic hybridization (CGH) and focused molecular genetic analyses demonstrated gains of chromosomes 7, losses of chromosomes 9 and 10, as well as homozygous deletion of p14(ARF) in one of the tumors. The second tumor showed gains of chromosomes 3, 4, 8q and 12 as well as losses of chromosomes 10, 13, 15q, 19 and 22. In addition, this tumor carried homozygous deletions of CDKN2A and p14(ARF) as well as point mutations in the TP53 and PTEN genes. The third tumor also had a mutation in the PTEN gene. None of the tumors demonstrated EGFR, CDK4 or MDM2 amplification. Taken together, our results define a rare glioblastoma differentiation pattern and indicate that glioblastomas with adipocyte-like tumor cell differentiation share common molecular genetic features with other primary glioblastomas.
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PMID:Glioblastoma with adipocyte-like tumor cell differentiation--histological and molecular features of a rare differentiation pattern. 1869 Dec 68

Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.
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PMID:Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array. 1930 58

The Fibroblast Growth Factor (FGF) signaling pathway is reported to stimulate glioblastoma (GBM) growth. In this work we evaluated the effect of FGF2, FGF receptor (FGFR), and small molecule inhibition on GBM cells grown in traditional media, or cultured directly in stem-cell media. These lines each expressed the FGFR1, FGFR3 and FGFR4 receptors. Addition of FGF2 ligand showed significant growth stimulation in 8 of 10 cell lines. Disruption of FGF signaling by a neutralizing FGF2 monoclonal antibody and FGFR1 suppression by RNA interference both partially inhibited cell proliferation. Growth inhibition was temporally correlated with a reduction in MAPK signaling. A receptor tyrosine kinase inhibitor with known FGFR/VEGFR activity, PD173074, showed reproducible growth inhibition. Possible mechanisms of growth suppression by PD173074 were implicated by reduced phosphorylation of AKT and MAPK, known oncogenic signal transducers. Subsequent reduction in the cyclin D1, cyclin D2 and CDK4 cell cycle regulators was also observed. Our results indicate that FGF signaling pathway inhibition as a monotherapy will slow, but not arrest growth of glioblastoma cells.
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PMID:Glioblastoma cell growth is suppressed by disruption of Fibroblast Growth Factor pathway signaling. 1934 Mar 97


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