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 have detected a tyrosine phosphorylated 200 kDa glycoprotein (gp200) on the surface of two tumour cells of neural origin, namely A1235 glioma and A172 glioblastoma. gp200 (polypeptide mass of 165-170 kDa) has all the structural features of a growth factor receptor and it appears to display high basal tyrosine kinase activity, a characteristic associated with transforming proteins. Another interesting feature of gp200 is that it is immunologically highly related to the EGF receptor (polypeptide mass of 135 kDa), a member of the erb-B family of proteins; however, it lacks EGF binding activity. gp200 also differs from all other EGF-receptor-related oncogenic proteins, namely erb-B-2, erb-B-3 and erb-B-4 gene products, and hence appears to be yet another member of the erb-B family of proteins. This is further strengthened by the fact that both gp200 and the EGF receptor are also recognized by a conformation-specific anti-peptide antibody to the cytoplasmic domain of the beta-type PDGF receptor. In the EGF- and the PDGF receptors, this peptide epitope is cryptic and receptor phosphorylation unmasks this site [Panneerselvam K, Reitz H, Khan S A, and Bishayee S (1995) J Biol Chem 270, 7975-7979] indicating that this epitope might be important in biological message transmission. In this context, the expression of a novel EGF-receptor-related 200 kDa protein with high basal kinase activity in certain tumour cells of neural origin and the fact that it contains an important peptide epitope suggest its possible role in normal and abnormal cell growth.
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PMID:A novel 200 kDa plasma membrane glycoprotein with high basal tyrosine kinase activity in tumour cells. 934 24

Recent studies show that tyrosine phosphorylation by a number of neuropeptides may be an important intracellular pathway in mediating changes in cell function, particularly related to growth. Neuromedin B (NMB), a mammalian bombesin related peptide, functions through a distinct receptor, the neuromedin B receptor (NMB-R), of which little is known about its cellular basis of action. In the present study we explored the ability of NMB-R activation to cause tyrosine phosphorylation of focal adhesion kinase (p125(FAK)), an important substrate for tyrosine phosphorylation by other neuropeptides. NMB caused rapid increases in p125(FAK) phosphorylation which reached maximum at 2 min in both rat C6 glioblastoma cells which possess native NMB-Rs and rat neuromedin B receptor (rNMR-R) transfected BALB 3T3 cells. NMB had a half-maximal effect was at 0.4 nM and was 30-fold more potent than gastrin-releasing peptide (GRP). The stoichiometric relationships between increased p125(FAK) tyrosine phosphorylation and other cellular processes was similar in both C6 cells and rNMB-R transfected cells. TPA (1 microM) caused 45% and the calcium ionophore, A23187, 11% of maximal tyrosine phosphorylation of p125(FAK) seen with NMB. A23187 potentiated the effect of TPA. Pretreatment with the selective PKC inhibitor, GF109203X, inhibited TPA-induced p125(FAK) tyrosine phosphorylation, but it had no effect on the NMB stimulation. Pretreatment with thapsigargin completely inhibited NMB-stimulated increases in [Ca2+]i, but had no effect on NMB-stimulation of p125(FAK) phosphorylation either alone or with GF109203X. The tyrosine kinase inhibitor, tyrphostin A25, inhibited NMB-induced phosphorylation of p125(FAK) by 52%. However, tyrphostin A25 did not inhibit NMB-stimulated increases in [3H]inositol phosphates. Cytochalasin D, an agent which disrupts actin microfilaments, inhibited BN- and TPA-induced tyrosine phosphorylation of p125(FAK) completely. In contrast, colchicine, an agent which disrupts microtubules, had no effect. Pretreatment with Clostridium botulinum C3 exoenzyme which inactivates the small GTP-binding protein rho p21, also inhibited tyrosine phosphorylation of p125(FAK) by 55%. These results demonstrate that activation of NMB-R can cause rapid tyrosine phosphorylation of p125(FAK). NMB-induced tyrosine phosphorylation of p125(FAK) is independent of NMB-induced changes in [Ca2+]i or PKC. The integrity of the actin cytoskeleton but not of microtubules is necessary for NMB-stimulated phosphorylation of p125(FAK). The ras-related small GTP-binding protein rho p21 is at least partially involved in mediating NMB-induced tyrosine phosphorylation of p125(FAK). These results suggest that similar to some other neuropeptides, activation of this pathway may be an important mechanism in mediating cellular changes by this receptor such as growth.
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PMID:Neuromedin B receptor activation causes tyrosine phosphorylation of p125FAK by a phospholipase C independent mechanism which requires p21rho and integrity of the actin cytoskeleton. 940 68

Recent data have suggested that mitochondria play a supportive role in maintaining the tumorigenic phenotype. Indeed, antimitochondrial agents have been hypothesized to be potential chemosensitizers to human malignancy. We assessed the utility of this approach by characterizing the antimitochondrial activity of 3,5-di-tert-butyl-4-hydroxybenzylidene-malononitrile (AG17), in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in two human glioblastoma cell lines. AG17 (NSC 242557) is a tyrphostin that has been thought to have some antimitochondrial activity, with limited tyrosine kinase antagonism, and was used at noncytotoxic and nongrowth-inhibitory concentrations (0.25 microM). Glioblastoma cells were incubated in AG17, and changes in mitochondrial activity were determined. Tumor cells became auxotrophically dependent on uridine and pyruvate, indicating the lack of a functioning respiratory chain. Despite this, cells continued to exhibit no growth-inhibitory effects. Exposure to AG17 was associated with significant depolarization of the mitochondrial membrane potential and decreases in mitochondrial mass in both glioblastoma cell lines, correlating with the finding of auxotrophic dependence. In contrast, normal human astrocytes treated with the same dose of AG17 did not show changes in growth, mitochondrial membrane potential, or mass. Indeed, auxotrophic dependence on uridine and pyruvate could not be established in these cells. Glioblastoma cells became significantly more responsive to BCNU chemotherapy with AG17 pretreatment; a linear relationship was noted that correlated the number as well as percentage of polarized mitochondria with glioblastoma cell survival at the highest dose of BCNU used (144 microg/ml). Normal human astrocytes did not change with regard to the dose response to BCNU with previous incubation with AG17. No difference was found in the type of cellular death (apoptosis) in either of the glioblastoma cell lines, with BCNU treatment alone, or with the combination AG17 and BCNU, despite the decrease in polarized mitochondria and mitochondrial mass. AG17 has antimitochondrial properties when used at low dose in human glioblastoma, which are relatively specific to tumor cells when compared with normal astrocytes. The use of AG17 as a chemosensitizer, with drugs such as BCNU, offers a new and possibly effective approach to be developed in patients with glial tumors.
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PMID:Chemosensitization of glioblastoma cells to bis-dichloroethyl-nitrosourea with tyrphostin AG17. 953 47

Epidermal growth factor receptor (EGFR) gene overexpression and mutations play an important role in the pathogenesis of a variety of malignant human cancers. In this study, we tested the effects of a novel EGFR tyrosine kinase inhibitor, ethyl-2,5-dihydroxycinnamate (EtDHC), against related human glioblastoma cell lines expressing specific forms of EGFR gene mutations. EtDHC more potently inhibited cell growth and DNA synthesis in glioblastoma cells with endogenous or overexpressed wild-type EGFR compared with those with truncated EGFR, by preferentially inhibiting the tyrosine kinase activity and autophosphorylation of the wild-type EGFR. Higher concentrations of EtDHC were required to inhibit cells expressing the truncated EGFR. These findings are the reverse of another highly specific tyrosine kinase inhibitor, tyrphostin AG 1478, which preferentially inhibited glioblastoma cells with truncated EGFR compared with those with wild-type EGFR. The differential susceptibility of various glioblastoma cells to highly specific tyrosine kinase inhibitors is significant because human gliomas are composed of heterogeneous cells with subsets of cells expressing specific gene mutations. This cellular heterogeneity could be one of the reasons why tumor cells are resistant to chemotherapy. Thus, EtDHC, especially when in combination with drugs targeting other specific gene mutations (such as tyrphostin AG 1478), holds a significant potential for chemotherapy for human glioblastomas.
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PMID:Preferential inhibition of glioblastoma cells with wild-type epidermal growth factor receptors by a novel tyrosine kinase inhibitor ethyl-2,5-dihydroxycinnamate. 956 5

Glioblastoma multiforme is a malignant primary brain tumor associated with short patient survival in part because of the ability of individual cells to migrate significant distances into brain tissue. Invasion is a difficult process to model, because many such human tumors do not invade immunologically competent animal tissue, tumors grown in animals do not invade human tissue, and relevant human tissue substrates are not easily reproduced. We discuss models for examining invasion in vitro, and in particular review work using the tumor spheroid--fetal rat brain aggregate co-culture model, assessed with confocal microscopy and four-dimensional imaging. Quantitation of invasion in this model is discussed, as well as the invasion-inhibitory properties of tyrosine kinase (TK) inhibitors. The effects of receptor-specific tyrphostins strongly support a dominant role for Epidermal Growth Factor Receptor activation in this process and show that invasion can be effectively inhibited at much lower concentrations of TK inhibitors than is necessary for growth suppression. Inhibition of activation of the purported growth factor receptor second messenger phospholipase C- gamma 1, by pharmacological means and gene transfection, also profoundly inhibits the invasive properties of human glioblastoma and rat C6 glioma cells. We have assessed invasiveness in several human tumor specimens, which may provide information relative to prognosis and recurrence risk. Our data supports the concept of differential control of invasion and proliferation, and points to possible strategies for anti-invasive therapy for glioblastoma multiforme.
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PMID:Inhibition of glioma invasion of fetal brain aggregates. 957 29

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic factor, which is known to be upregulated in most cases of glioblastoma multiforme (GBM). The expression of VEGF and its receptors in ependymomas, oligodendrogliomas, and particularly the expression during anaplastic progression of these three types of gliomas has not been studied extensively. Fifty-six gliomas, consisting of 10 ependymomas, 12 oligodendrogliomas, 3 anaplastic oligodendrogliomas, 6 astrocytomas grade II, 5 anaplastic astrocytomas, and 20 glioblastoma multiformes, were investigated for VEGF and receptor expression using in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Results showed that VEGF was moderately to strongly expressed in 8 of 10 ependymomas and in all anaplastic oligodendrogliomas and glioblastoma multiforme cases. These tumors displayed similar degrees of extensive necrosis and vascular proliferation, with VEGF expression consistently seen in tumor cells around necrotic areas. The VEGF expression, although present at a lower level, also was shown in 4 of 12 oligodendrogliomas, in 3 of 6 astrocytomas grade II, and in 2 of 5 anaplastic astrocytomas, with a regional rather than diffuse pattern of positive result. The findings from the in situ hybridization study correlated with the expression index, as determined by reverse transcription polymerase chain reaction. Expression of VEGF was correlated significantly with vascular proliferation (p < 10(-5)) and necrosis (p < 10(-5)), as well as with microvessel density (p = 0.002, rs = 0.41). The VEGF receptors, kinase domain region (KDR) and Fms-like-tyrosine kinase (Flt-1), also were upregulated in the tumor vasculature of glioblastoma multiforme, anaplastic oligodendrogliomas, and ependymomas with necrosis, whereas the astrocytomas grade II, anaplastic astrocytomas, and oligodendroglioma tumors tended to express a weak to nondetectable signal. Anaplastic progression in all three types of gliomas is heralded by the occurrence of small zones of VEGF-expressing cells and early vascular proliferation, followed by an accelerated phase of angiogenesis closely associated with VEGF induction around areas of necrosis and with the expression of VEGF receptors in the tumor vasculature.
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PMID:Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. 966 44

The tyrosine kinase family includes growth factor receptor and cytoplasmic enzymes. It plays a key role in normal cell division and abnormal cell proliferation and differentiation. The most common tyrosine kinases are the epidermal-growth factor (EGFR) and platelet-derived growth factor (PDGF) receptors, and a chromosome Philadelphia product, the Bcr-abl oncogene. Many studies have attempted to correlate clinical evolution of tumors with tyrosine kinase expression. However, clinical application of these new prognostic factors has not yet been demonstrated. More recently, tyrosine-phosphorylation inhibitors (tryphostin) have been developed in phase I studies. Results that were obtained show some objective responses in patients with glioblastoma and polymetastatic cancer. Another approach to block tyrosine kinase expression is the use of monoclonal antibodies. Trials using such antibodies have shown interesting preliminary results.
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PMID:[Tyrosine kinase: implications in tumor pathology and therapeutic perspectives]. 977 78

Various growth factors and basement membrane proteins have been implicated in the pathobiology of astrocytomas. The goal of this study was to determine the relative contribution of these two factors in modulating the phenotype of U-373 MG glioblastoma cells as determined by the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, and nestin. For these determinations, cells plated in serum-free medium were treated either with growth factors binding to tyrosine kinase receptors including transforming growth factor-alpha, epidermal growth factor, platelet-derived growth factor-AA, basic fibroblast growth factor, and insulin-like growth factor-1 or with basement membrane proteins including collagen IV, laminin, and fibronectin. The changes in the expression levels of intermediate filament proteins in response to these treatments were analyzed by quantitation of immunoblots. The results demonstrate that collagen IV and growth factors binding to tyrosine kinase receptors decrease the glial fibrillary acidic protein content of U-373 MG cells. Growth factors binding to tyrosine kinase receptors also decrease the vimentin content of these cells but do not affect their nestin content. On the other hand, basement membrane proteins decrease the nestin content of U-373 MG cells but do not affect their vimentin content. The significance of these results with respect to the role played by different factors in modulating the phenotype of neoplastic astrocytes during tumor progression is discussed.
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PMID:Effects of growth factors and basement membrane proteins on the phenotype of U-373 MG glioblastoma cells as determined by the expression of intermediate filament proteins. 977 47

Brain angiogenesis is a tightly controlled process that is regulated by neuroectodermal derived growth factors that bind to tyrosine kinase receptors expressed on endothelial cells. In the rat brain, angiogenesis is complete around postnatal day 20, but endothelial cells can proliferate in the adult brain under pathological conditions such as hypoxia/ischemia and brain tumor growth. Current evidence suggests that physiological angiogenesis in the brain is regulated by similar mechanisms as pathological angiogenesis induced by tumors or by hypoxia/ischemia. The hypoxia-inducible endothelial cell mitogen and vascular permeability factor, vascular endothelial growth factor (VEGF) appears to play a pivotal role in most of these processes. VEGF is expressed when angiogenesis is high, as in embryonic neuroectoderm, in glioblastomas and around infarcts, but is expressed at low levels when angiogenesis is absent, as in adult neuroectoderm. Since growth factors such as VEGF and angiopoietins and their receptors appear to be necessary for angiogenesis, targeting of growth factor/receptor pathways for angiogenesis-dependent diseases such as glioblastoma might be useful for therapy. Several compounds, including anti-VEGF antibodies and VEGFR-2 inhibitors are currently in clinical trial. On the other hand, induction of angiogenesis by growth factors (pro-angiogenesis) might prove to be a rational therapy for patients with stroke.
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PMID:Mechanisms of angiogenesis in the brain. 1021 26

Interleukin-17 (IL-17) has been characterized as a proinflammatory cytokine produced by CD4+ activated memory T cells. In an effort to elucidate the biological effects of IL-17 in glial cells, we investigated the ability of this cytokine in order to activate nuclear factor (NF)-kappaB, which is being discussed as one of the most important transcription factors in the regulation of neuronal and glial cell function. Activation of NF-kappaB involves the degradation of its cytoplasmatic inhibitor IkappaB-alpha, which allows the nuclear translocation of NF-kappaB, and ensures transcriptional activation of genes including IkappaB-alpha itself. Using a competitive RT-PCR, we examined the IL-17-induced IkappaB-alpha mRNA expression in glioblastoma cells, and we examined IL-17 up-regulated IkappaB-alpha mRNA expression in a dose- and time-dependent fashion with a maximum time between 1 and 3 h. This induction could be inhibited by Calphostin C (protein kinase C inhibitor) and genistein (tyrosine kinase inhibitor). After 60 min of IL-17 stimulation, a degradation of the IkappaB-alpha protein was detectable. Furthermore, IL-17 stimulated the secretion of IL-6 and IL-8 in glial cells, and IL-17 and IL-1beta in combination showed a superadditive effect. We suggest IL-17 to play a role as an immune factor, possibly involved in complex pathophysiological interactions of neurodegenerative diseases.
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PMID:Interleukin-17 stimulates the expression of IkappaB alpha mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines. 1058 Aug 7


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