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)

We previously showed that enhanced expression of MMP-9, an endopeptidase that digests basement-membrane type IV collagen, is related to tumor progression in vitro and in vivo; antisense-MMP-9 stably transfected clones were less invasive than untransfected parental cells and did not form tumors in nude mice. In this study, we examined the role of ERK-1 in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which ERK1 is constitutively activated. SNB19 cells were stably transfected with mt-ERK, a vector encoding ERK-1 cDNA in which the conserved lysine at codon 71 was changed to arginine, thus impairing the catalytic efficiency of this enzyme. Gelatin zymography showed reduced levels of MMP-9 in the mt-ERK-transfected cell lines relative to those in vector-transfected and parental control cells. Reductions in MMP-9 protein mRNA levels were also detected in the mt-ERK-transfected cells by Western and Northern blotting. The mt-ERK-transfected cells were much less invasive than parental or vector control cells in a Matrigel invasion assay and in a spheroid coculture assay. Thus an ERK-dependent signaling pathway seems to regulate MMP-9 mediated glioma invasion in SNB19 cells; interfering with this pathway could be developed into a therapeutic approach, which aims at a reduction of cancer cell invasion.
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PMID:Downregulation of MMP-9 in ERK-mutated stable transfectants inhibits glioma invasion in vitro. 1216 59

Glioblastoma is the commonest neuroectodermal tumor and the most malignant in the range of cerebral astrocytic gliomas. The prognostic utility of various biological markers for glioblastomas has been broadly tested but the results obtained are regarded as controversial. In the present study, 302 glioblastoma specimens were studied to evaluate a possible association between clinical outcome and expression of some immunohistochemical variables. Furthermore, tumors examined were subdivided on the three cytological subsets--small-cell (SGB), pleomorphic-cell (PGB) and gemistocytic (GGB). Immunohistochemical variables differed between various subsets: the number of p53-positive tumors was found to be prevailed among the PGB, whereas the number of tumors with EGFR and mdm2 positivity was significantly greater in SGB. GGB contained significantly lowest mean proliferating cell nuclear antigen (PCNA) labeling index (LI), greater number of p21ras positive cases, and higher mean apoptotic index (AI). Survival time in patients with SGB, EGFR and mdm2-positivity and PCNA LI >40% was found to be significantly shorter, whereas presence of p21ras and AI >0.5% were associated with prolonged survival. Multivariate analysis revealed that survival time is associated with SGB, EGFR-positivity, and AI (p = 0.0023, p = 0.0035 and p = 0.0029 respectively). We conclude that although some immunohistochemical variables were found to be significant for glioblastoma outcome, they appear to be closely related to biology of single cytological subsets. Furthermore, these variables exhibited no prognostic value when they were analyzed within each cytological subset separately. Therefore, the glioblastoma subdivision on three cytological subsets proposed by us is carrying some element of rationality but, undoubtedly, requires further prospective studies.
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PMID:Immunohistochemical markers for prognosis of cerebral glioblastomas. 1218 57

Amplification of the EGFR, mdm2, CDK4 and PDGFR A genes has been widely demonstrated in adult malignant gliomas, almost exclusively glioblastomas. To determine the role of these mutational events in pediatric astrocytic gliomas we investigated the presence of EGFR, mdm2, CDK4 and PDGFR A gene amplification in 38 childhood brain tumor biopsies, including 24 low-grade astrocytomas and 14 malignant tumors. We used differential PCR assay on DNA extracted either from paraffin embedded or frozen tissues. EGFR gene amplification was detected in 4 out of 14 malignant tumors; no low-grade astrocytoma showed amplification. Tumors with EGFR gene amplification were negative for the presence of p53 mutations, as observed in a previous study. One glioblastoma showed PDGFR A amplification, while no amplifications were observed for mdm2 and CDK4 genes. These data are in line with those obtained from studies on gliomas of adults and suggest the existence of two different subsets of malignant gliomas also in pediatric brain tumors: one carrying EGFR gene amplification, the other showing p53 mutations.
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PMID:Molecular genetic changes in a series of neuroepithelial tumors of childhood. 1224 Nov 4

In this study, we have identified novel regulatory steps involved in the cross-talk between protein kinase B (PKB) and MAPK signaling pathways. We found that PKB down-regulates the Ras-Raf-MEK-ERK pathway by reducing the activity of ERK, which leads to inactivation of the transcription factor Elk1. In addition, PKB is able to reduce protein levels of Elk1. Both events lead to suppression of serum response element (SRE)-dependent transcription and a consequent decrease in the transcription of SRE-containing genes, such as c-fos. Because activation of the Ras/MAPK cascade is reported to increase c-fos transcription before apoptosis, our results are consistent with a specific role for PKB in promoting cell survival. Decrease in c-Fos protein levels in glioblastoma cells with constitutively active PKB provides further support for our observations. Therefore, our findings delineate a novel mechanism regulating immediate-early transcription, which may be involved in the initial steps in PKB-induced oncogenic transformation.
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PMID:Negative regulation of ERK and Elk by protein kinase B modulates c-Fos transcription. 1246 35

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

Our previous work showed that, compared with parental U87MG human glioblastoma cells, vascular endothelial growth factor (VEGF) mRNA levels are decreased in U87/T691, a derivative line in which epidermal growth factor receptor (EGFR) signaling is inhibited by introduction of a truncated p185(Neu) protein (A. Maity et al., Cancer Res., 60: 5879-5886, 2000). The effect of EGFR activation on VEGF was mediated at the level of transcription via a phosphatidylinositol 3'-kinase (PI3K)-dependent pathway. In the current study we investigated the effect of PTEN, a negative regulator of PI3K signaling commonly mutated in glioblastoma cells, on VEGF expression. Several glioblastoma cell lines containing mutant PTEN, including U87MG, U87/T691, and U251MG, were infected with adenovirus expressing wild-type PTEN. This led to a decrease in the levels of both VEGF mRNA and phosphorylated Akt, a marker for PI3K activation. Treatment of U87MG cells with LY294002, a PI3K inhibitor, or cotransfection with a vector expressing wild-type PTEN decreased VEGF promoter activity using reporters containing either 1.5 kb of the promoter or a fragment extending from -88 to +54 bp. Activity of the -88/+54 VEGF promoter was down-regulated by dominant negative Akt and up-regulated by constitutively active myristoylated Akt. Introduction of wild-type PTEN and pharmacological inhibition of EGFR decreased VEGF mRNA expression and VEGF promoter activity in U87MG cells to a greater extent that did either manipulation by itself. Therefore, in human glioblastoma cells, PTEN mutation can cooperate with EGFR activation to increase VEGF mRNA levels by transcriptionally up-regulating the proximal VEGF promoter via the PI3K/Akt pathway.
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PMID:PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. 1251 3

Overexpressed epidermal growth receptor factor receptors (EGFRs) are thought to contribute to the malignant phenotype of human glioblastomas (GBMs), but the mechanism is not well understood. We found that SKMG-3 cells, a rare GBM cell line that maintains EGFR gene amplification in vitro, produced high levels of EGFR protein. The cells also expressed the related receptors HER2/neu and HER4, but not HER3. Immunoblots and tryptic phosphopeptide maps showed that the SKMG-3 EGFRs were intact and functional and that a subset of these receptors were spontaneously autophosphorylated. EGF treatment stimulated phosphorylation of the EGFRs as well as the downstream effectors Erk, AKT1, stat3 and c-Cbl. Under minimal growth conditions, the unstimulated SKMG-3 cells contained constitutively phosphorylated Erk and AKTI but no detectable stat3 DNA-binding complexes. The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1. In contrast, inhibition of phosphatidylinositol-3-kinase (PI3K) blocked the constitutive phosphorylation of Erk and AKT-1 but not the EGFR. We conclude that the SKMG-3 cells represent the subset of GBMs with amplified EGFR genes that overexpress intact receptors. The results also suggest that in some GBMs, signals from overexpressed EGFRs contribute to the constitutive phosphorylation of Erk, but these signals may not required for the constitutive activation of PI3K or AKT1.
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PMID:Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells. 1253 15

Aberrant receptor tyrosine kinase signaling plays an important role in the molecular pathogenesis of brain tumors. We have been studying a previously identified human glioblastoma-derived PDGFR-alpha mutant that has an in-frame deletion in the extracellular domain, causing loss of exons 8 and 9 (PDGFR-alpha(delta8,9)). In the primary tumor, this deletion mutant receptor was shown to be amplified and overexpressed. The purpose of this study was to determine the expression, activity, localization, and transformation properties of this deletion mutant. In the absence of serum, or PDGF-AA, PDGFR-alpha(delta8,9) was phosphorylated on tyrosine residues, indicating ligand-independent autoactivation. Localization by staining and cell surface biotinylation studies revealed expression of the deletion mutant predominantly in the cytoplasm, with very little present on the cell surface. To determine if PDGFR-alpha(delta8,9) was oncogenic, we transfected wild-type and mutant receptors into Rat1 cells and performed analyses of cell growth, in vitro transformation, and subcutaneous growth in the nude mouse. PDGFR-alpha(delta8,9)-expressing cells displayed enhanced cell growth and survival in low serum, and formed foci in monolayer cultures. PDGFR-alpha(delta8,9)-expressing Rat1 cells were also tumorigenic when injected subcutaneously into nude mice. Expression of PDGFR-alpha(delta8,9) was also associated with increased c-Jun phosphorylation in the absence of PDGF ligand, demonstrating also that the mutant receptor is associated with altered intracellular signaling. These data demonstrate that PDGFR-alpha(delta8,9) is transforming, and it is the first demonstration of a naturally occurring tumor-derived mutant PDGFR-alpha with oncogenic properties.
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PMID:A human brain tumor-derived PDGFR-alpha deletion mutant is transforming. 1256 64

Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.
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PMID:Targeted molecular therapy of GBM. 1258 May 45

Glioblastoma multiform is one of the most devastating primary tumors in neurooncology. We analyzed prognosis factors in patients with grade IV glioblastoma treated between 1993 and 1997. The 22 long-term survival patients (survival over 26 months) were extracted from our 30 years archives and the 2 populations are compared. The incidence was 2.6/100,000h/year, 62% male and 38% female, mean age 59 years, mean survival 12 months, median survival time 9 months. Multivariate analysis showed that younger age, surgical treatment and radiotherapy were all dependent prognosis factors for better survival. Statistically, survival was best for total surgical removal of tumors, followed by tumor gross resection then biopsy. Clinical status and inextirpable tumor location were also prognosis factors. The free interval time between total surgery and tumor reappearance was strongly correlated with survival (r=0.94). This suggests that some grade IV gliomas follow a quicker course, others exhibiting slow growth. Each of the prognosis factors was confirmed in the long-survival patients. Prevalence of all glioblastomes was 4.3%. Their mean age was 42 and mean survival 62 months. A larger proportion of these patients had total surgery and radiotherapy. The time lapse before tumor reappearance was longer. Deep tumor locations were less frequent. The proportion of secondary versus primary glioblastomas was the greatest difference between the long-term and regular survivors. Secondary glioblastomas were found in only 4% of the standard population and in 23 to 41% in the long-term survivors (p<0.01). Primary glioblastomas typically show EGFR over expression and mutation (variant III). The pathway to secondary glioblastoma involves early P53 mutation. Despite the fact that the anatomopathologist regards similar tissues under the microscope, these subtypes of glioblastomas are distinct disease entities which evolve through different genetic pathways and exhibit different outcomes.
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PMID:[Glioblastomas: clinical study and search for prognostic factors]. 1259 6


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