Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Met receptor and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly overexpressed in malignant gliomas. Signaling through c-Met as well as exposure to hypoxia can stimulate glioma cell migration and invasion. In several cancer cell types, hypoxia was shown to activate the c-met promoter, which contains hypoxia inducible factor-1 (HIF-1) binding sites. We hypothesized that hypoxia might upregulate c-Met also in glioma cells. Analyzing 18 different glioblastoma cell lines and 10 glioblastoma primary cultures, we found that in 50% of both the cell lines and the primary cultures c-Met protein levels were increased following exposure to hypoxia. Upregulation of c-met in response to hypoxia was also detected at the transcriptional level. In all primary cultures and in 16 of the 18 cell lines (89%), HIF-1 alpha levels were increased by hypoxia. Transfection of siRNA against HIF-1 alpha abgrogated the hypoxic induction of c-Met, suggesting that c-Met expression is upregulated by a HIF-1 alpha-dependent mechanism. Hypoxia sensitized glioblastoma cell lines which showed hypoxic induction of c-Met to the motogenic effects of SF/HGF. These findings suggest that approximately half of all human glioblastomas respond to hypoxia with an induction of c-Met, which can enhance the stimulating effect of SF/HGF on tumor cell migration.
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PMID:Hypoxia can induce c-Met expression in glioma cells and enhance SF/HGF-induced cell migration. 1737 7

The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T(1) relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and 'normal'brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas.
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PMID:In vivo detection of c-Met expression in a rat C6 glioma model. 1820 57

The mechanisms and biological implications of coordinated receptor tyrosine kinase coactivation remain poorly appreciated. Epidermal growth factor receptor (EGFR) and c-Met are frequently coexpressed in cancers, including those associated with hepatocyte growth factor (HGF) overexpression, such as malignant astrocytoma. In a previous analysis of the HGF-induced transcriptome, we found that two EGFR agonists, transforming growth factor-alpha and heparin-binding epidermal growth factor-like growth factor (HB-EGF), are prominently up-regulated by HGF in human glioma cells. We now report that stimulating human glioblastoma cells with recombinant HGF induces biologically relevant EGFR activation. EGFR phosphorylation at Tyr(845) and Tyr(1068) increased 6 to 24 h after cell stimulation with HGF and temporally coincided with the induction of transforming growth factor-alpha (~5-fold) and HB-EGF (~23-fold) expression. Tyr(845) and Tyr(1068) phosphorylation, in response to HGF, was inhibited by cycloheximide and actinomycin D, consistent with a requirement for DNA transcription and RNA translation. Specifically, blocking HB-EGF binding to EGFR with the antagonist CRM197 inhibited HGF-induced EGFR phosphorylation by 60% to 80% and inhibited HGF-induced S-G(2)-M transition. CRM197 also inhibited HGF-induced anchorage-dependent cell proliferation but had no effect on HGF-mediated cytoprotection. These findings establish that EGFR can be activated with functional consequences by HGF as a result of EGFR ligand expression. This transcription-dependent cross-talk between the HGF receptor c-Met and EGFR expands our understanding of receptor tyrosine kinase signaling networks and may have considerable consequences for oncogenic mechanisms and cancer therapeutics.
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PMID:Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. 1823 69

The utility of neural stem cells (NSCs) has extended beyond regenerative medicine to targeted gene delivery, as NSCs possess an inherent tropism to solid tumors, including invasive gliomas. However, for optimal clinical implementation, an understanding of the molecular events that regulate NSC tumor tropism is needed to ensure their safety and to maximize therapeutic efficacy. We show that human NSC lines responded to multiple tumor-derived growth factors and that hepatocyte growth factor (HGF) induced the strongest chemotactic response. Gliomatropism was critically dependent on c-Met signaling, as short hairpin RNA-mediated ablation of c-Met significantly attenuated the response. Furthermore, inhibition of Ras-phosphoinositide 3-kinase (PI3K) signaling impaired the migration of human neural stem cells (hNSCs) toward HGF and other growth factors. Migration toward tumor cells is a highly regulated process, in which multiple growth factor signals converge on Ras-PI3K, causing direct modification of the cytoskeleton. The signaling pathways that regulate hNSC migration are similar to those that promote unregulated glioma invasion, suggesting shared cellular mechanisms and responses. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Neural stem cell targeting of glioma is dependent on phosphoinositide 3-kinase signaling. 1833 68

Hypoxia is a critical aspect of the microenvironment in glioma and generally signifies unfavorable clinical outcome. Effective targeting of hypoxic areas in gliomas remains a significant therapeutic challenge. New therapeutic platforms using neural stem cells (NSC) for tumor-targeted drug delivery show promise in treatment of cancers that are refractory to traditional therapies. However, the molecular mechanisms of NSC targeting to hypoxic tumor areas are not well understood. Therefore, we investigated the role of hypoxia in directed migration of NSCs to glioma and identified the specific signaling molecules involved. Our data showed that hypoxia caused increased migration of human HB1.F3 NSCs to U251 human glioma-conditioned medium in vitro. In HB1.F3 NSCs, hypoxia led to up-regulation of CXCR4, urokinase-type plasminogen activator receptor (uPAR), vascular endothelial growth factor receptor 2 (VEGFR2), and c-Met receptors. Function-inhibiting antibodies to these receptors inhibited the migration of HB1.F3 cells to glioma-conditioned medium. Small interfering RNA knockdown of hypoxia-inducible factor-1alpha in glioma cells blocked the hypoxia-induced migration of NSCs, which was due to decreased expression of stromal cell-derived factor-1 (SDF-1), uPA, and VEGF in glioma cells. Our in vivo data provided direct evidence that NSCs preferentially distributed to hypoxic areas inside intracranial glioma xenografts, as detected by pimonidazole hypoxia probe, as well as to the tumor edge, and that both areas displayed high SDF-1 expression. These observations indicate that hypoxia is a key factor in determining NSC tropism to glioma and that SDF-1/CXCR4, uPA/uPAR, VEGF/VEGFR2, and hepatocyte growth factor/c-Met signaling pathways mediate increased NSC-to-glioma tropism under hypoxia. These results have significant implications for development of stem cell-mediated tumor-selective gene therapies.
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PMID:Neural stem cell tropism to glioma: critical role of tumor hypoxia. 1907 27

Angiogenesis plays an essential role in tumor growth and metastasis and is a promising target for cancer therapy. c-Met, a receptor tyrosine kinase, and its ligand, hepatocyte growth factor (HGF), are critical in cellular proliferation, motility, invasion, and angiogenesis. The present study was designed to determine the role of c-Met in growth and metastasis of glioma U251 cells using RNA interference (RNAi) technology in vitro. We constructed three kinds of shRNA expression vectors aiming at the c-Met gene, then transfected them into glioma U251 cells by lipofectamine(TM) 2000. The level of c-Met mRNA was investigated by real-time polymerse chain reaction (RT-PCR). The protein expression of c-Met was observed by immunofluoresence staining and western blotting. U251 cell growth and adherence was detected by methyl thiazole tetrazolium assay. The apoptosis of U251 cells was examined with a flow cytometer. The adherence, invasion, and in vitro angiogenesis assays of U251 cells were done. We got three kinds of c-Met specific shRNA expression vectors which could efficiently inhibit the growth and metastasis of U251 cells and the expression of c-Met in U251 cells. RT-PCR, immunofluoresence staining and western blotting showed that inhibition rate for c-Met expression was up to 90%, 79% and 85%, respectively. The expression of c-Met can be inhibited by RNA interference in U251 cells, which can inhibit the growth and metastasis of U251 cell and induce cell apoptosis. These results indicate that RNAi of c-Met can be an effective antiangiogenic strategy for glioma.
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PMID:c-Met-targeted RNA interference inhibits growth and metastasis of glioma U251 cells in vitro. 1916 19

The tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is often mutated in glioblastoma. Because PTEN can interact with c-Met-dependent signaling, we studied the effects of PTEN on c-Met-induced malignancy and associated molecular events and assessed the potential therapeutic value of combining PTEN restoration approaches with HGF/c-Met inhibition. We studied the effects of c-Met activation on cell proliferation, cell cycle progression, cell migration, cell invasion, and associated molecular events in the settings of restored or inhibited PTEN expression in glioblastoma cells. We also assessed the experimental therapeutic effects of combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition. PTEN significantly inhibited HGF-induced proliferation, cell cycle progression, migration, and invasion of glioblastoma cells. PTEN attenuated HGF-induced changes of signal transduction proteins Akt, GSK-3, JNK, and mTOR as well as cell cycle regulatory proteins p27, cyclin E, and E2F-1. Combining PTEN restoration to PTEN-null glioblastoma cells with c-Met and HGF inhibition additively inhibited tumor cell proliferation and cell cycle progression. Similarly, combining a monoclonal anti-HGF antibody (L2G7) with the mTOR inhibitor rapamycin had additive inhibitory effects on glioblastoma cell proliferation. Systemic in vivo delivery of L2G7 and PTEN restoration as well as systemic in vivo deliveries of L2G7 and rapamycin additively inhibited intracranial glioma xenograft growth. These preclinical studies show for the first time that PTEN loss amplifies c-Met-induced glioblastoma malignancy and suggest that combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition is worth testing in a clinical setting.
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PMID:Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy. 1919 Jan 20

Gliomas are the most common and deadly form of malignant primary brain tumors. Loss of the tumor-suppressor PTEN and activation of the receptor tyrosine kinases (RTKs) EGF receptor, c-Met, PDGF receptor and VEGF receptor are among the most common molecular dysfunctions associated with glioma malignancy. PTEN interacts with RTK-dependent signaling at multiple levels. These include the ability of PTEN to counteract PI3K activation by RTKs, as well as possible effects of PTEN on RTK activation of the MAPK pathway and RTK-dependent gene-expression regulation. Consequently, PTEN expression affects RTK-induced malignancy. Importantly, the PTEN status was recently found to be critical for the outcome of RTK-targeted clinical therapies that have been developed recently. Combining RTK-targeted therapies with therapies aimed at counteracting the effects of PTEN loss, such as mTOR inhibition, might also have therapeutic advantage. This article reviews the known molecular and functional interactions between PTEN and RTK pathways and their implications for glioma therapy.
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PMID:Interactions between PTEN and receptor tyrosine kinase pathways and their implications for glioma therapy. 1919 61

c-Met is a receptor tyrosine kinase involved in tumor cell growth, invasion, metastases and angiogenesis. Overexpression of c-Met is frequently observed in several tumor types. Here, we report the in vitro cell-binding properties and biodistribution and SPECT/CT imaging in glioma (U87MG) xenograft-bearing mice of (125)I-labeled c-Met-binding peptides (cMBPs) including analogs conjugated to amino acid and aliphatic carbon linkers. In vitro assays showed that the peptide without any linker and those with GGG and 8-aminooctanoic acid linkers had low cellular internalization and that IC(50) values of peptides were 1.5 microM, 65 nM and 85.3 nM, respectively. Biodistribution studies showed the GGG-containing peptide had higher tumor uptake and a higher tumor-to-blood activity concentration ratio than other receptor-binding ligands. SPECT/CT studies with a dedicated small-animal imaging system were performed in U87MG-bearing athymic mice. Although U87MG tumor xenografts could be visualized by SPECT/micro-CT using the various (125)I labeled cMBPs, image contrast and overall quality were unremarkable.
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PMID:Characterization, biodistribution and small-animal SPECT of I-125-labeled c-Met binding peptide in mice bearing c-Met receptor tyrosine kinase-positive tumor xenografts. 1942 4

Mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase that has been shown to be overexpressed and mutated in a variety of malignancies, such as glioma. We have recently found that an (125)I-radiolabeled Gly-Gly-Gly (GGG)- or 8-aminooctanoic acid (AOC)-containing c-Met binding peptide (cMBP) specifically targets c-Met receptor in vivo and in vitro. In this report, cyanine dye 5.5 (Cy5.5)-conjugated GGG- or AOC-containing cMBPs were evaluated in human cancer cell xenografts in order to investigate the possibility of c-Met receptor targeting using an optical imaging system. The receptor binding affinity of Cy5.5-conjugated peptides was tested in 96-well plates coated with a c-Met/Fc chimeric protein. Optical imaging studies were performed in U87MG and Ramos bearing athymic mice. The binding affinities of Cy5.5-conjugated GGG- or AOC-containing cMBPs were determined to be 0.318 and 0.342 microM, respectively. Confocal images show that Cy5.5-conjugated peptides bound mainly to the cell surface and that peptide binding was clearly inhibited by free cMBP. Subcutaneous U87MG tumors were clearly visualized with each of the two fluorescent probes. Of the two, cMBP-AOC-Cy5.5 displayed higher tumor uptake and tumor-to-normal tissue ratios at 10 min to 24 h postinjection in the U87MG tumor model. For the in vivo blocking study, cMBP-AOC-Cy5.5 (4 nmol) was co-injected with cold cMBP (0.13 micromol) into the U87MG xenograft mice. Image-based tumoral uptake decreased up to approximately 35%. These results suggest that Cy5.5-conjugated cMBP could potentially be used to detect c-Met-positive cancers in vivo. However, additional modifications to this optical imaging agent are needed to further improve its efficacy.
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PMID:In vivo imaging of mesenchymal-epithelial transition factor (c-Met) expression using an optical imaging system. 1953 20


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