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)

Bioluminescence imaging has previously been used to monitor the formation of grafted tumors in vivo and measure cell number during tumor progression and response to therapy. The development and optimization of successful cancer therapy strategies may well require detailed and specific assessment of biological processes in response to mechanistic intervention. Here, we use bioluminescence imaging to monitor the cell cycle in a genetically engineered, histologically accurate model of glioma in vivo. In these platelet-derived growth factor (PDGF)-driven oligodendrogliomas, G1 cell-cycle arrest is generated by blockade of either the PDGF receptor or mTOR using small-molecule inhibitors.
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PMID:Dissecting tumor maintenance requirements using bioluminescence imaging of cell proliferation in a mouse glioma model. 1550 45

The highly invasive and angiogenic characteristics of malignant gliomas depend on the production of growth factors and angiogenic factors. Heparin-binding growth-associated molecule (HB-GAM) is a secreted growth factor that is mitogenic for endothelial cells. To examine the expression profile of HB-GAM in malignant glioma cells, messenger ribonucleic acid (mRNA) expression was analyzed in 10 malignant glioma cell lines, two glioblastoma tissue specimens, and two normal brain tissue specimens by the reverse transcription-polymerase chain reaction. HB-GAM mRNA was expressed in all specimens including normal brain tissue specimens. Western blot analysis revealed that HB-GAM protein contents in glioma cell lines and glioblastoma tissues were 1.8 to 6.3 times higher than those in normal brain tissues. The effect of neutralizing anti-platelet-derived growth factor (PDGF) antibody was also examined on the production of HB-GAM in malignant glioma cells, since malignant glioma cells secrete PDGF that upregulates HB-GAM expression. Treatment of U251 and T98G glioblastoma cells with the anti-PDGF antibody did not affect the HB-GAM production. These results suggest that HB-GAM is overexpressed in malignant glioma cells and is involved in tumor growth.
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PMID:Overexpression of heparin-binding growth-associated molecule in malignant glioma cells. 1568 95

Retroviral tagging previously identified putative cancer-causing genes in a mouse brain tumor model where a recombinant Moloney murine leukemia virus encoding the platelet-derived growth factor B-chain (MMLV/PDGFB) was intracerebrally injected in newborn mice. In the present study, expression analysis using cDNA arrays revealed several similarities of virus-induced mouse gliomas with human brain tumors. Brain tumors with short latency contained on average 8.0 retroviral insertions and resembled human glioblastoma multiforme (GBM) whereas long-latency gliomas were of lower grade, similar to human oligodendroglioma (OD) and had 2.3 insertions per tumor. Several known and novel genes of tumor progression or cell markers were differentially expressed between OD- and GBM-like tumors. Array and quantitative real-time PCR analysis demonstrated elevated expression similar to Pdgfralpha of retrovirally tagged genes Abhd2, Ddr1, Fos, Ng2, Ppfibp1, Rad51b and Sulf2 in both glioma types compared to neonatal and adult normal brain. The retrovirally tagged genes Plekhb1, Prex1, Prkg2, Sox10 and 1200004M23Rik were upregulated in the tumors but had a different expression profile than Pdgfralpha whereas Rap1gap, Gli1, Neurl and Camk2b were downregulated in the tumors. The present study accentuates the proposed role of the retrovirally tagged genes in PDGF-driven gliomagenesis and indicates that insertional mutagenesis can promote glioma progression.
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PMID:Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice. 1575 Jun 23

Angiotensin II (Ang II) is a main effector peptide in the renin-angiotensin system and participates in the regulation of vascular tone. It also has a role in the expression of growth factors that induce neovascularisation which is closely associated to the growth of malignant gliomas. We have shown that the selective blockage of the AT1 receptor of angiotensin inhibits tumour growth, cell proliferation and angiogenesis of C6 rat glioma. The aim of this study was to study the effects of the blockage of AT1 receptor on the synthesis of growth factors, and in the genesis of apoptosis in cultured C6 glioma cells and in rats with C6 glioma. Administration of losartan at doses of 40 or 80 mg kg(-1) to rats with C6 glioma significantly decreased tumoral volume and production of platelet-derived growth factor, vascular endothelial growth factor and basic fibroblast growth factor. It also induced apoptosis in a dose-dependent manner. Administration of Ang II increased cell proliferation of cultured C6 cells which decreased by the administration of losartan. Our results suggest that the selective blockage of AT1 diminishes tumoral growth through inhibition of growth factors and promotion of apoptosis.
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PMID:Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. 1578 46

The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.
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PMID:Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. 1583 64

Chronic platelet-derived growth factor (PDGF) signaling in glial progenitors leads to the formation of oligodendrogliomas in mice, whereas chronic combined Ras and Akt signaling leads to astrocytomas. Different histologies of these tumors imply that the pathways activated by these two oncogenic stimulations are different, and that the apparent lineage of the tumor cells may result from specific signaling activity. Therefore, we have investigated the signaling effects of PDGF in culture and in gliomas in vivo. In culture, PDGF transiently activates ERK1/2 and Akt, and subsequently elevates p21 and PCNA expression similar to chronic PDGF autocrine signaling in cultured astrocytes and PDGF-induced oligodendrogliomas in vivo. Culture experiments show that autocrine PDGF stimulation, and combined active Ras and Akt generate signaling patterns that are in some ways mutually exclusive. Furthermore, forced Akt activity in the context of chronic PDGF stimulation results in cells with an astrocytic differentiation pattern both in culture and in vivo. These data imply that these two interconvertible signaling motifs are distinct in mice and lead to gliomas resembling the two major glioma histologies found in humans. The ability of signaling activity to convert tumor cells from one lineage to another presents a mechanism for the development of tumors apparently comprised of cells from multiple lineages.
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PMID:The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats. 1596 17

A complex profile of gene expression elicited by autocrine platelet-derived growth factor (PDGF) signaling was identified in U87 MG glioblastoma cells by microarray analysis. The most striking pattern observed was a PDGF-dependent activation of at least 25 genes involved with biosynthesis and/or uptake of cholesterol and isoprenoids, including mevalonate pyrophosphate decarboxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, and low-density lipoprotein receptor. Activity of the HMG-CoA synthase promoter was induced by autocrine PDGF activity as indicated by significant reductions following forced expression of dominant-negative PDGF-A (88%) or treatment with the PDGF receptor antagonist CT52923 (50%). Induction of the HMG-CoA synthase promoter required a binding site for sterol regulatory element binding proteins (SRE-BP), consistent with a key role for these transcription factors in the induction of this gene network. Neither proteolytic activation nor nuclear localization of SRE-BP was affected by disruption of the PDGF autocrine loop, indicating that PDGF signaling is required for other signaling events involved in activation of SRE-BP target genes. Analysis of an expression databank derived from human glial tumors (n = 77) identified a subgroup exhibiting a profile consistent with PDGF dependence, including increased expression of SRE-BP target genes. This subgroup displayed an absence of epidermal growth factor receptor gene amplification, decreased incidence of allelic loss of 10q, increased frequency of TP53 mutations and allelic losses of 1p and 19q, and longer patient survival. This study identifies genes associated with oncogenic activity of PDGF and provides important insights into biomarkers and therapeutic targets in malignant gliomas.
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PMID:Autocrine platelet-derived growth factor-dependent gene expression in glioblastoma cells is mediated largely by activation of the transcription factor sterol regulatory element binding protein and is associated with altered genotype and patient survival in human brain tumors. 1599 24

Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in approximately 70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo. Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G1 and G2, and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the effect of perifosine in combination with temozolomide. We observed an enhanced effect when both were used in culture. With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice. Animal studies showed that perifosine and temozolomide combination therapy was more effective than temozolomide treatment alone (P < 0.01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic.
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PMID:Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. 1610 96

Previously we have shown that platelet-derived growth factor (PDGF) rapidly increases the activity of the neuronal glutamate transporter, EAAC1. This increase in activity is associated with a rapid (within minutes) redistribution of transporter from a subcellular compartment to the plasma membrane and is blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K). Similar effects of PI3K inhibitors have been observed for insulin-dependent up-regulation of the GLUT4 subtype of glucose transporter. Although GLUT4 regulation also depends on the serine-threonine kinase (Akt/protein kinase B), a downstream target of PI3K, the downstream effectors responsible of PDGF-dependent regulation of EAAC1 have not been identified. In the present study, PDGF increased the level of Akt phosphorylation (Ser 473) in C6 glioma cells, a cell line that has been used to study regulated trafficking of endogenous EAAC1. Two inhibitors of PI3K blocked this effect. In transient transfection studies, a dominant negative mutant of Akt-1 blocked PDGF-induced redistribution of epitope-tagged EAAC1 (myc-EAAC1). Conversely, constitutively active Akt-1 (CA Akt-1) increased the cell surface expression of myc-EAAC1. A lentiviral vector engineered to express CA Akt-1 increased Akt activation, cell surface expression of endogenous EAAC1, and Na(+)-dependent glutamate transport activity. Together, these studies suggest that Akt is required for PDGF-induced regulation of EAAC1.
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PMID:Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1. 1618 22

The neuronal glutamate transporter, EAAC1 (excitatory amino acid carrier 1), undergoes rapid regulation after treatment with platelet-derived growth factor (PDGF) or phorbol ester in C6 glioma cells and neurons. A large intracellular pool of EAAC1 exists, from which transporters are redistributed to the cell surface in response to these signals. Here we show that PDGF had no effect on subcellular localization of the glial glutamate transporter, GLT-1, after transfection into C6 glioma cells. Chimeras consisting of domains from EAAC1 or GLT-1 were used to investigate structural motifs involved in PDGF-dependent redistribution of EAAC1. PDGF did not induce trafficking of an EAAC1 chimera containing the carboxyl-terminal domain of GLT-1; however, it did induce trafficking of a GLT-1 chimera containing the carboxyl-terminal domain of EAAC1. A truncated mutant of EAAC1 lacking 10 carboxyl-terminal amino acids was responsive to PDGF, whereas a mutant lacking 20 residues was not. Alanine substitution mutagenesis in this region revealed a short motif, (502)YVN(504), necessary for regulated trafficking. This motif was also involved in protein kinase C-dependent trafficking, as mutant transporters exhibited an attenuated response to phorbol ester. Interestingly, the presence of YVN in the homologous region of a nonresponsive chimera was not sufficient to confer regulated trafficking; however, the presence of a 12-amino acid motif starting at this Tyr residue was sufficient to confer responsiveness to PDGF. These studies identify a novel motif within the carboxyl terminus of EAAC1 which is required for regulated trafficking. The possibility that this motif targets EAAC1 to an intracellular, "regulated pool" is discussed.
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PMID:A carboxyl-terminal determinant of the neuronal glutamate transporter, EAAC1, is required for platelet-derived growth factor-dependent trafficking. 1636 96


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