UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has previously been implicated that nerve growth factor (NGF) with its high-affinity receptor tyrosine kinase A (TrkA) could play an important role in the growth modulation of human tumor cells, such as glioblastoma multiform cell lines and human breast cancer cell lines. However, the direct mitogenic effects of NGF and TrkA in these tumor cells still remain to be elucidated. Herein we show, by immunofluorescence staining, that NGF was colocalized with gamma-tubulin at the centrosomes or the spindle poles throughout the cell cycle and phosphorylated TrkA was colocalized with alpha-tubulin at mitotic spindle in the glioma cell line U251. The results suggest that NGF concentrated to centrosome can recruit its receptor TrkA there and cause phosphorylation of the latter. The phosphorylated TrkA with the tyrosine kinase activity may phosphorylate the tubulin and promote the mitotic spindle assembly. By these mechanisms, NGF can modulate the mitosis of human glioma cells.
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PMID:Localization of NGF and TrkA at mitotic apparatus in human glioma cell line U251. 1618 9

The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conversely, inhibition of SF/HGF and c-Met in experimental tumor xenografts leads to inhibition of tumor growth and tumor angiogenesis. SF/HGF is expressed and secreted mainly by tumor cells and acts on c-Met receptors that are expressed in tumor cells and vascular endothelial cells. Activation of c-Met leads to induction of proliferation, migration, and invasion and to inhibition of apoptosis in tumor cells as well as in tumor vascular endothelial cells. Activation of tumor endothelial c-Met also induces extracellular matrix degradation, tubule formation, and angiogenesis in vivo. SF/HGF induces brain tumor angiogenesis directly through only partly known mechanisms and indirectly by regulating other angiogenic pathways such as VEGF. Different approaches to inhibiting SF/HGF and c-Met have been recently developed. These include receptor antagonism with SF/HGF fragments such as NK4, SF/HGF, and c-Met expression inhibition with U1snRNA/ribozymes; competitive ligand binding with soluble Met receptors; neutralizing antibodies to SF/HGF; and small molecular tyrosine kinase inhibitors. Use of these inhibitors in experimental tumor models leads to inhibition of tumor growth and angiogenesis. In this review, we summarize current knowledge of how the SF/HGF:c-Met pathway contributes to brain tumor malignancy with a focus on glioma angiogenesis.
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PMID:Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. 1621 9

Previously it was shown that stimulation of the P2Y12 receptor activates PKB signalling in C6 glioma cells [K. Van Kolen and H. Slegers, J. Neurochem. 89, 442.]. In the present study, the mechanisms involved in this response were further elucidated. In cells transfected with the Gbetagamma-scavenger beta-ARK1/GRK2 or Rap1GAPII, stimulation with 2MeSADP failed to enhance PKB phosphorylation demonstrating that the signalling proceeds through Gbetagamma-subunits and Rap1. Moreover, Rap1-GTP pull-down assays revealed that P2Y12 receptor stimulation induced a rapid activation of Rap1. Treatment of cells with the Ca2+ chelator BAPTA-AM and inhibition of Src and PLD2 with PP2 or 1-butanol, respectively, abrogated P2Y12 receptor-mediated activation of Rap1 and PKB. In addition inhibition of PKCzeta decreased basal and 2MeSADP-stimulated phosphorylation of PKB indicating a role for this PKC isoform in PKB signalling. Although the increased PKB phosphorylation was abolished in the presence of the IGF-I receptor tyrosine kinase inhibitor AG 1024, 2MeSADP did not significantly increase receptor phosphorylation. Nevertheless, phosphorylation of a 120 kDa IGF-I receptor-associated protein was observed. The latter protein was identified by MALDI-TOF/TOF-MS as the proline-rich tyrosine kinase 2 (Pyk2) that co-operates with Src in a PLD2-dependent manner. Consistent with the signalling towards Rap1 and PKB, activation of Pyk2 was abrogated by Ca2+ chelation, inhibition of PLD2 and IGF-I receptor tyrosine kinase activity. In conclusion, the data reveal a novel type of cross-talk between P2Y12 and IGF-I receptors that proceeds through Gbetagamma-, Ca2+-and PLD2-dependent activation of the Pyk2/Src pathway resulting in GTP-loading of Rap1 required for an increased PKB phosphorylation.
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PMID:P2Y12 receptor signalling towards PKB proceeds through IGF-I receptor cross-talk and requires activation of Src, Pyk2 and Rap1. 1623 84

Gliosarcomas are rare and poorly characterized malignant brain tumors that exhibit a biphasic tissue pattern with areas of gliomatous and sarcomatous differentiation. These tumors are histological variants of glioblastoma, displaying a similar genetic profile and dismal prognosis. Up-regulation of PDGFR subfamily of tyrosine kinase members, PDGFR-alpha and c-Kit, and their intracellular effectors RAS/RAF/MAPK has a crucial role in the cancer development. In addition, signal transduction mediated by activating mutations of c-Kit and PDGFR can be effectively blocked by specific tyrosine kinase inhibitors, such as Imatinib mesylate. The aim of this study was to characterize the molecular alterations of PDGFR signaling in gliosarcomas. Six cases were analyzed by immunohistochemistry for the expression of PDGFR-alpha, c-Kit and their ligands PDGF-A and SCF, respectively. The cases were further evaluated for the presence of activating mutations of PDGFR-alpha (exons 12 and 18) and c-kit (exons 9, 11, 13, and 17), as well as B-RAF (exons 11 and 15). Expression of PDGF-A was found in all cases and co-expression of PDGFR-alpha was observed in three cases. Four cases showed expression of SCF, and c-Kit was observed only in one case that also expressed SCF. Generally, immunoreaction predominates in the glial component. The mutational analysis of PDGFR-alpha showed the presence of an IVS17-50insT intronic insertion in two cases, one of them also with a 2472C > T silent mutation; this silent mutation was also found in another case. Glioma cell line analysis of IVS17-50insT insertion showed no influence on PDGFR-alpha gene splicing. No mutations were detected in c-kit and B-RAF oncogenes. Our results indicate that activating mutations of PDGFR-alpha, c-kit and B-RAF are absent in gliosarcomas. Nevertheless, the presence of a PDGFR-a/PDGFA and c-Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in the treatment of gliosarcomas.
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PMID:Molecular characterization of PDGFR-alpha/PDGF-A and c-KIT/SCF in gliosarcomas. 1637 64

Gliomas are the most common primary central nervous system tumours and about 55% are glioblastoma multiforme (GBM). Between 40% and 50% of GBM have dysregulated epidermal growth factor receptor (HER1/EGFR), and almost half of these co-express the mutant receptor subtype EGFRvIII, which may contribute to the aggressive and refractory course of GBM. Limited therapeutic options exist for GBM, and recurrence is common. Standard therapy is surgical resection, where possible, and radiotherapy. Adjuvant chemotherapy provides a modest survival benefit. New therapies are essential, and HER1/EGFR-targeted agents may provide a viable strategy. The HER1/EGFR tyrosine kinase inhibitors erlotinib and gefitinib are in advanced clinical development for glioma, and a number of trials are in progress, or have recently been completed. Preliminary results with gefitinib show no objective responses, but do provide evidence of disease control. In contrast, preliminary data with erlotinib appear more encouraging. Erlotinib inhibits wild-type HER1/EGFR and EGFRvIII, which may underlie its promising clinical activity. Other HER1/EGFR-targeted agents are also being investigated for glioma, including monoclonal antibodies, radio-immuno conjugates, ligand-toxin conjugates, antisense oligonucleotides and ribozymes. Further studies will define their clinical potential and hopefully provide new, effective treatments for GBM and other malignant brain tumours.
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PMID:Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. 1648 82

ZD1839 ("Iressa") is an orally active, selective epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor. We evaluated the antitumor activity of ZD1839 in combination with HSP90 antagonist, 17-AAG in malignant human glioma cell lines. ZD1839 independently produced a dose-dependent inhibition of cellular proliferation in glioma cells grown in culture with time- and dose-dependent accumulation of cells in G(1) phase of the cell cycle on flow cytometric analysis, although the concentrations required for optimal efficacy were at or above the limits of clinically achievable levels. Because the heat shock protein (HSP) is involved in the conformational maturation of a number of signaling proteins critical to the proliferation of malignant glioma cells, we hypothesized that the HSP90 inhibitor 17-AAG would potentiate ZD 1839-mediated glioma cytotoxicity by decreasing the activation status of EGF receptor, as well as down regulating the levels of other relevant signaling effectors. We, therefore, examined the effects of ZD1839 and 17-AAG, alone and in combination, on signal transduction and apoptosis in a series of malignant glioma cell lines. Simultaneous exposure to these inhibitors significantly induced cell death and quantitative analysis revealed that interaction between ZD1839 and 17-AAG-induced cytotoxicity was synergistic, leading to a pronounced increase in active caspase-3 and PARP cleavage. No significant growth inhibition or caspase activation was seen in control cells. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and a significant downregulation of EGFR receptor, Raf-1 and mitogen activated protein kinase (MAPK). Cells exposed to 17-AAG and ZD1839 displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that ZD1839, an EGF receptor tyrosine kinase inhibitor, plays a critical role in regulating the apoptotic response to 17-AAG and that multi-site targeting of growth signaling and cell survival pathways could provide a potent strategy to treat patients with malignant gliomas.
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PMID:Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth. 1655 Jun 10

The poor prognosis of patients with high-grade glioma has led to the search for new therapeutic strategies. More than half of these tumors overexpress Epidermal Growth factor Receptor (EGFR). h-R3 is a humanized monoclonal antibody that recognize the EGFR external domain with high affinity, inhibiting tyrosine kinase activation. In order to evaluate safety, immunogenicity and preliminary efficacy of h-R3 in newly diagnosed high-grade glioma patients, we conducted a Phase I/II trial. Patients received six weekly infusions of h-R3 at the dose of 200 mg in combination with external beam radiotherapy. Twenty-nine patients (mean age, 45 years and median KPS 80) were entered into the study. Tumor types were: glioblastoma (GB) (16 patients), anaplastic astrocytoma (AA) (12 patients) and anaplastic oligodendroglioma (AO) (1 patient). All patients underwent debulking surgery or biopsy before entering the trial. The antibody was very well tolerated. No evidences of grade 3/4 adverse events were detected. None of the patients developed acneiform rash or allergic reactions. One patient developed a positive anti-idiotypic response. Objective response-rate was 37.9% (17.2% complete response, 20.7% partial response) while stable disease occurred in 41.4% of the patients. With a median follow up time of 29 months, the median survival is 22.17 months for all subjects. Median survival time (MST) is 17.47 months for GB, whereas MST is not reached for AA patients.
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PMID:Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3: report from a phase I/II trial. 1657 3

The platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase, implicated in the development and progression of different tumors, including gliomas. Chemoresistance is a common feature of malignant gliomas. Since receptor tyrosine kinases contribute to chemoresistance in tumors, we addressed whether PDGFR signaling might confer selective growth advantage to chemoresistant cells. The effects of the PDGFR inhibitor STI571 on proliferation and PDGFR signaling were compared in chemosensitive and cisplatin-selected, chemoresistant sublines derived from glioma and from two other PDGFR-expressing tumors (ovarian carcinoma and neuroblastoma). The chemoresistant glioma U87/Pt cells were twofold more sensitive to STI571 growth-inhibitory effects than the chemosensitive U87 cells, and two- to threefold more sensitive than five unrelated glioma cell lines. The other two paired cell lines were equally responsive. Sensitization of U87/Pt cells correlated with upregulation of the PDGF-B isoform and with PDGF-BB-induced Akt overactivation, which was prevented by STI571. STI571 specifically inhibited PDGF-BB-, but not PDGF-AA- or stem cell factor-mediated signaling. In serum-containing medium, STI571 decreased phospho-Akt in U87/Pt cells, but not in U87, while activating extracellular signal-regulated kinase (Erk) in both. STI571 antiproliferative effects were partially reverted by constitutively active Akt. Cotreatment with inhibitors of phosphatidylinositol 3'-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK) resulted in enhanced growth inhibition in glioma cells. Our results suggest that increased PDGF-BB signaling may sensitize chemoresistant glioma cells to STI571, suggesting a therapeutic potential for STI571 in patients with malignant gliomas refractory to chemotherapy. Simultaneous blockade of PDGFR and PI3K or Erk pathway may enhance therapeutic targeting in gliomas.
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PMID:Increased sensitivity to the platelet-derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF-BB-mediated signaling and STI571-induced Akt inactivation. 1657 5

Gefitinib (ZD1839, Iressa), a member of the 4-anilinoquinazoline class of compounds, has the chemical name 4-quinazolinamine, N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. Gefitinib often is referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor (EGFR). EGFR expression has been noted in neuroblastoma and rhabdomyosarcoma cell lines and in tumor specimens from children with Wilms tumor, osteosarcoma, and glioma. Thus, gefitinib, the first marketed EGFR tyrosine kinase inhibitor, was chosen for study in children with refractory solid tumors and central nervous system (CNS) malignancies. This review discusses findings from 3 clinical trials of gefitinib in children with refractory solid tumors and CNS malignancies, focusing on the clinical pharmacology of the compound. To date, gefitinib has been studied in children as a single agent and in combination with irinotecan. Overall, the compound has been well tolerated in children and has a safety profile similar to that observed in adults. The clinical pharmacokinetics of gefitinib in children are similar to those observed in adults. Finally, the future for the use of gefitinib in pediatrics is similar to that of other molecularly targeted agents and awaits definition of tumors and patient populations in which it will be most advantageous.
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PMID:Evaluation of gefitinib for treatment of refractory solid tumors and central nervous system malignancies in pediatric patients. 1680 60

Pilocytic astrocytoma (PA) is the most common glioma of childhood. Despite their relatively high incidence, the molecular mechanisms responsible for tumorigenesis and growth of PA are poorly understood. Previous in vitro studies in our laboratory showed that despite the absence of ErbB1, PA was sensitive to ErbB1 tyrosine kinase inhibitor gefitinib. To identify alternative targets of gefitinib in PA, we studied other members of the ErbB receptor tyrosine kinase family that have been identified in brain tumors. Using gene expression microarray and Western blot analyses, we found that ErbB3 is highly overexpressed in PA compared with other pediatric brain tumors (glioblastoma, ependymoma, medulloblastoma, atypical teratoid/rhabdoid tumor, and choroid plexus papilloma). Developmental biology studies have identified Sox10 as a regulator of ErbB3 expression during development of the neural crest. Investigation of Sox10 in PA revealed that it is highly overexpressed relative to other pediatric brain tumors, lending support to the theory that Sox10-regulated overexpression of ErbB3 may be driving growth in PA. Sox10-regulated ErbB3 overexpression is a novel insight into the biology of PA, suggests possible recapitulation of developmental pathways in tumorigenesis, and presents possible targets for therapeutic intervention that might be used for hypothalamic variants not amenable to surgical cure.
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PMID:Paired overexpression of ErbB3 and Sox10 in pilocytic astrocytoma. 1689 10

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