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 multiforme (GBMs) are highly vascular brain tumors characterized by abnormal vessel structures in vivo. This finding supports the theory that glioma-associated endothelial cells (ECs) have intrinsically different properties from ECs in normal human brain. Therefore, identification of the functional and phenotypic characteristics of tumor-associated ECs is essential for designing a rational antiangiogenic therapy. The GBM-associated ECs have a large, flat, and veil-like appearance, in contrast to normal ones, which are small and plump. Although the tumor ECs have the typical markers, they proliferate more slowly than these cell types in normal brain. The GBM-associated ECs are resistant to cytotoxic drugs, and they undergo less apoptosis than control cells. Also, GBM-associated ECs migrate faster than controls and constitutively produce high levels of growth factors such as endothelin-1, interleukin-8, and vascular endothelial growth factor. An understanding of these unique characteristics of glioma-associated ECs is important for the development of novel antiangiogenic agents that specifically target tumor-associated ECs in gliomas.
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PMID:Characteristics of tumor-associated endothelial cells derived from glioblastoma multiforme. 1670 28

In this study, we investigated the mRNA and protein expression of nine tumour antigens in human glioblastoma multiforme with a view to their possible use in dendritic cell-based immunotherapy. Expression of ALK, EGFRvIII, GALT3, gp100, IL-13Ralpha2, MAGE-A3, NA17-A, TRP-2 and tyrosinase were studied by real-time RT-PCR on frozen tissues using a series of 47 tumour samples from patients with glioblastoma. Results were compared with non-neoplastic brain expression or glioblastoma samples with very low levels of expression near the limits of detection for EGFRvIII and MAGE-A3, as these latter two antigens were not detected in non-neoplastic brain. Tumour antigens showing a 5-fold increase in mRNA expression were considered as positive, and only antigens displaying an mRNA over-expression in a significant number of cases were analysed by immunohistochemistry on paraffin-embedded sections. Using real time RT-PCR, we found EGFRvIII, gp100, IL-13Ralpha2 and TRP-2 to be positive in 64, 38, 32 and 21% of cases, respectively. While we observed no over-expression for ALK, GALT3 and tyrosinase, 3 samples out of 47 were positive for MAGE-3 and 1 sample for NA17-A. More than 25% of tumour cells showed strong protein expression in 13, 34, 85 and 96% of GBM samples for gp100, TRP-2, EGFRvIII and IL-13Ralpha2, respectively. Interestingly, protein expression of at least 3 antigens was observed in 38% of cases. These results point out the importance of EGFRvIII, IL-13Ralpha2 and, to a less extent gp100 and TRP-2, for developing an immunotherapy strategy against glioblastoma.
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PMID:Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy. 1700 3

Astrocytomas represent the most common form of glial tumors. The most malignant grade of these tumors, glioblastoma multiforme, may arise as a malignant progression from low-grade astrocytoma through anaplastic astrocytoma to secondary GBM, or else it may arise "de novo" as primary GBM. Both types of glioblastoma are usually histologically indistinguishable. However, distinct molecular alterations have been described between them that potentially allow differentiation between the two mechanisms of origin. Since malignant transformation is a multistep process, we summarize in this review the earliest genetic changes that seem to be involved in the appearance and development of low-grade astrocytic tumors, where early detection and treatment could be possible.
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PMID:Early genetic changes involved in low-grade astrocytic tumor development. 1702 34

Glioblastomas are a highly aggressive brain tumor, with one of the highest rates of new blood vessel formation. In this study we used a combined experimental and bioinformatics strategy to determine which genes were highly expressed and specific for glioblastoma endothelial cells (GBM-ECs), compared to gene expression in normal tissue and endothelium. Starting from fresh glioblastomas, several rounds of negative and positive selection were used to isolate GBM-ECs and extract total RNA. Using Serial Analysis of Gene Expression (SAGE), 116,259 transcript tags (35,833 unique tags) were sequenced. From this expression analysis, we found 87 tags that were not expressed in normal brain. Further subtraction of normal endothelium, bone marrow, white blood cell and other normal tissue transcripts resulted in just three gene transcripts, ANAPC10, PLXDC1(TEM7), and CYP27B1, that are highly specific to GBM-ECs. Immunohistochemistry with an antibody for PLXDC1 showed protein expression in GBM microvasculature, but not in the normal brain endothelium tested. Our results suggest that this study succeeded in identifying GBM-EC specific genes. The entire gene expression profile for the GBM-ECs and other tissues used in this study are available at SAGE Genie (http://cgap.nci.nih.gov/SAGE). Functionally, the protein products of the three tags most specific to GBM-ECs have been implicated in processes critical to endothelial cell proliferation and differentiation, and are potential targets for anti-angiogenesis based therapy.
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PMID:PLXDC1 (TEM7) is identified in a genome-wide expression screen of glioblastoma endothelium. 1703 59

Mutations involving the TP53 gene are frequently identified in up to 50% of all human tumors, including glioblastomas. Analysis of expression patterns of TP53 in glioblastomas shows that it is mainly mutated in secondary glioblastomas and is less common in primary GBMs. However, the prognostic significance of TP53 loss of function in astrocytomas has always been controversial. In contrast, EGFR/erbB2 complexes have been implicated in the poor prognosis of several cancers, including glioblastomas. Our previous work showed that transforming phenotypes could be inhibited by interfering with active EGFR/erbB2 complex using mutant erbB2 proteins in wild-type p53 GBM cells. To assess the dependence of EGFR inhibited phenotype on p53, we used three mutant p53 glioblastoma cell lines in the present study and showed that mutant erbB2 can be exploited to inhibit EGFR-mediated oncogenic transformation irrespective of p53 status. Ectopic expression of a mutant erbB2 receptor (T691S) in mutant p53 GBM cells resulted in slower growth rate than empty vector controls. T691S-expressing clones exhibited a more flattened and nontransformed morphology. Consistently, T691S inhibited transformation in soft agar assays and tumor formation in nude mice independent of p53 status. Biochemical analysis showed reduced Akt and GSK-3 alpha/beta, but not p42/44MAPK phosphorylation, in T691S-expressing cells, when compared to parental controls, suggesting the P13-K pathway may be more relevant than MAPK for glial cell transformation. Cell cycle analysis showed reduced cyclin D1 and CDK6 and increased phospho-Cdc-2 (Tyr15) and p15INK4B in erbB2-inhibited cells, suggesting that nonfunctional EGFR/erbB2 complexes exert their inhibitory effects at various stages of the cell cycle to block the progression of cells through G2/M via Akt/GSK-3/Cdc2 pathway. Collectively, these observations provide a basis for receptor-based therapies that disable erbB receptors and inhibit proliferative signals in erbB-expressing human cancers including glioblastomas, regardless of their TP53 status.
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PMID:EGFR inhibition in glioblastoma cells induces G2/M arrest and is independent of p53. 1745 42

The purpose of this study was to assess the relationship between progression-free survival (PFS) in patients treated with DFMO + PCV (procarbazine, CCNU, vincristine) chemotherapy for malignant gliomas with tumor cell ornithine decarboxylase (ODC) activity. Formalin-fixed slides were obtained for study patients with anaplastic gliomas (AGs) and glioblastoma treated on protocol DM92-035. ODC levels were measured using an antibody to ODC coupled to Alexa 647 dye (Ab-ODC-Alexa 647). Ab-ODC-Alexa 647 intensity in transgenic murine hearts of differing ODC activity was used to calculate ODC activity in tumor cell nucleoplasm. In total, tumor specimens for 31 of 114 (27%) patients treated on the AG strata and 10 patients from the GBM strata were obtained. We found that tumor ODC level heterogeneity increased with increasing tumor malignancy. In a Cox proportional hazards model, PFS was found to be inversely related to median tumor ODC activity, with an unadjusted hazard ratio for median ODC group (>3.3 vs. </=3.3 nmol/30 min/mug protein) of 5.8 (p < 0.0001); a median PFS of 522 weeks for patients with AGs with median ODC activity </= 3.3 and 31 weeks for the 8 AG and 10 glioblastoma patients with ODC activity > 3.3 nmol/30 min/mug protein. Of AG tumors in which ODC activity was evaluated, 26% had ODC levels > 3.3 nmol/30 min/mug protein. This study shows that Ab-ODC-Alexa 647 fluorescence intensity can be used as a surrogate marker of ODC biochemical activity in AGs and can predict PFS to DFMO-based chemotherapy.
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PMID:Relationship between ornithine decarboxylase levels in anaplastic gliomas and progression-free survival in patients treated with DFMO-PCV chemotherapy. 1758

O6-methylguanine-DNA methyltransferase (MGMT) expression has been recently proposed as a useful prognostic and/or predictive marker in glioblastoma patients receiving adjuvant therapy after the surgery. We studied samples from 50 patients with histologically confirmed GBM to evaluate MGMT expression by immunohistochemistry and its relation to promoter methylation status. Genomic DNA was extracted from scrapings of formalin-fixed, paraffin-embedded tissue corresponding to hematoxylin and eosin sections. Using the mouse monoclonal antibody MT3.1, MGMT expression was assessed and scored in tumor cells: (1=negative or limited to <10% positive tumor cells, 2=10% to 50%, 3=>50%). Methylation-specific polymerase chain reaction was performed after bisulfite treatment. Assessment of MGMT expression in neoplastic tissue required careful scrutiny because of its expression in a variety of non-neoplastic cells. MGMT expression was present in tumor cells with a score of 1, 2, and 3, respectively in 36 (72%), 13 (26%), and 1 (2%) cases. Methylation-specific polymerase chain reaction yielded interpretable results in 39 cases (78%). MGMT promoter methylation was detected in 15 cases (38.5%), whereas 24 (61.5%) were unmethylated. Among the methylated samples, 14 (of 15) had a score of 1, and 1 had a score of 3 by immunohistochemistry. Of the 24 unmethylated samples, 18 had a score of 1, and 6 of 2. There was no significant correlation between MGMT expression and methylation, and no significant survival difference was observed between patients whose tumors were negative versus positive for MGMT protein by immunohistochemistry. This study underscores some of the difficulties in applying immunohistochemistry to assess MGMT expression.
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PMID:MGMT immunohistochemical expression and promoter methylation in human glioblastoma. 1809 18

The presence of necrosis within a diffuse glioma is a powerful predictor of poor prognosis, yet little is known of its origins. Intravascular thrombosis is a frequent finding in glioblastoma [GBM; World Health Organization (WHO) grade IV] specimens and could potentially be involved in astrocytoma progression to GBM or represent a surrogate marker of GBM histology. We investigated whether intravascular thrombosis was more frequent or prominent in GBM than other central nervous system (CNS) malignancies and considered its prognostic significance in anaplastic astrocytoma (AA; WHO grade III), which lacks necrosis. Histologic sections were examined for thrombosis, necrosis and microvascular hyperplasia from each of 297 CNS tumors, including 103 GBMs, 46 AAs, 20 diffuse astrocytoma (DAs; WHO grade II), eight anaplastic oligodendrogliomas (AOs; WHO grade III), 20 oligodendrogliomas (ODs; WHO grade II), 49 metastatic carcinomas (METs), 31 primary central nervous system lymphomas (PCNSLs) and 20 medulloblastomas (MBs). Among newly diagnosed tumors, thrombosis was present in 92% of GBM resections, significantly greater than other types of CNS malignancies. Of tumors with thrombosis, GBMs had a higher frequency of affected vessels than AAs, DAs, AOs, ODs and MBs, but had a frequency similar to METs and PCNSLs. The sensitivity of thrombosis for the diagnosis of GBM in this set of tumors was 92% and the specificity was 91%. Intravascular thrombosis was uncommon in AAs and was only noted in stereotactic biopsies. This subset of patients had shorter survivals than those AAs without thrombosis. Thus, intravascular thrombosis is more frequent in GBM than other CNS malignancies. When present in AAs, it appears to indicate aggressive clinical behavior.
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PMID:Intravascular thrombosis in central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma. 1809 51

Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo.
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PMID:Yes and PI3K bind CD95 to signal invasion of glioblastoma. 1832 27

The anti-neoplastic effects of histone deacetylase inhibitors (HDACi), Trichostatin A (TSA) and 4-phenylbutyrate (4-PB) on the human glioblastoma cell lines GBM-29, U-343 MG and U-343 MGa Cl. 2:6 were investigated. TSA and 4-PB induced apoptosis in the three cell lines in a dose- and time-dependent manner. Whereas caspase-3 activation was detected in all three cell lines, U-343 MG cells were more sensitive to the apoptotic effect of HDACi compared with U-343 MGa Cl. 2:6. TSA and 4-PB induced differentiation in the three cell lines, each cell line developing unique phenotypic characteristics. During long-term treatment with a low dose of HDACi U-343 MGa Cl. 2:6 cells developed an astrocytic morphology with expression of glial fibrillary acidic protein (GFAP). GFAP-negative U-343 MG cells changed their morphology in response to HDACi and down-regulated their expression of vimentin. The nestin and vimentin positive GBM-29 cells also showed a morphological differentiation, while the expression of the two malignancy markers decreased. In summary, our results showed that these three glioblastoma cell lines display unique phenotypes and differentiation patterns in response to HDACi.
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PMID:HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin. 1836 Jul 9


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