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)

Malignant gliomas are typically angiogenic and secrete high levels of VEGF. Hypoxia has been identified as an important regulator of VEGF. However, malignant gliomas express high levels of VEGF in both hypoxic perinecrotic and vital tumor areas. In this study, we examined intracellular signaling pathways involved in the secretion of VEGF in glioma cells under normoxic conditions. Human malignant glioma cell lines, T98G, U373MG, U87MG, and A172, and human fetal lung fibroblasts (HFL) were cultured both with and without IL-1beta under normoxic conditions. VEGF, IL-1, IL-6, and TNF-alpha were measured with ELISA. VEGF mRNA levels were estimated by RT-PCR. Inhibitors of COX-2, MAPK, and phosphatidyl inositol 3-kinase (PI3-K), and blocking antibodies to TGF-beta II and TNF-alpha, or IL-1 receptor antagonist, were used to examine their effects on VEGF secretion. Phosphorylation of MAPK was examined by immunoblotting. The basal levels of VEGF secretion were significantly higher in U87MG, U373MG, and T98G, than HFL. IL-1beta significantly stimulated VEGF secretion in these glioma cells. Inhibitors of p38 MAPK and/or JNK significantly suppressed VEGF secretion both in the presence and absence of IL-1beta, while inhibitors of COX-2, ERK1/2, and PI3-K did not. Constitutive phosphorylation of p38 MAPK and JNK was observed in these glioma cells. The levels of IL-1beta in U87MG were significantly higher than in other glioma cell lines, and IL-1 receptor antagonist suppressed basal secretion of VEGF from U87MG. In conclusion, p38 MAPK and JNK pathways play an important role in VEGF secretion from malignant glioma cells under normoxic conditions, possibly contributing to VEGF-induced angiogenesis in malignant gliomas at vital tumor areas where there is no hypoxia.
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PMID:Activation of p38 MAPK and/or JNK contributes to increased levels of VEGF secretion in human malignant glioma cells. 1696 94

The hypoxic microenvironment of solid tumors is associated with malignant progression and it renders tumors more resistant to cancer therapies. Endothelial cell damage may occur following hypoxic conditions and lead to dysfunction; however, endothelial cells in tumors survive hypoxic conditions providing nutrients and oxygen to facilitate tumor growth. In this study, we investigated the effects of tumor-conditioned medium on hypoxia-induced changes in endothelial cell growth, migration and survival. Tumor conditioned medium collected from U87 human glioblastoma cells were applied to endothelial cultures in normoxia or hypoxia conditions. Hypoxia caused a reduction in clonogenic cell survival response and an increase of the sub-G1 phase of the cell cycle in endothelial cells. Cell migration was measured by spheroid and wound-induced migration assays and hypoxia compared with normoxia significantly increased the number of migrating endothelial cells. Nuclear staining with Hoechst 33258 and caspase-9 and -3 activation in endothelial cells show that hypoxia-induced apoptosis involves caspase-dependent mechanism. Exposure to hypoxia caused an increase in gene expression of VEGF and VEGFR2 and activities of MMP-2 and MMP-9. Furthermore, hypoxia induced an increase in capillary-like structure formation in endothelial cells seeded into Matrigel. Tumor conditioned medium enhanced survival and rescued endothelial cells from apoptosis induced by hypoxia. These molecular changes in endothelial cells could, in part, contribute to the angiogenic response that occurs during hypoxia-induced angiogenesis in glial tumors.
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PMID:Glioma cells suppress hypoxia-induced endothelial cell apoptosis and promote the angiogenic process. 1727 72

Overcoming the metabolic restrictions of hypoxia may allow the progression of lower-grade tumors to glioblastoma multiforme. Our findings of up-regulation of HIF-1alpha and its downstream targets VEGF, GLUT-1, and CAIX in higher-grade gliomas support this hypothesis. We compared the gene expression profiles of the U-251 malignant glioma cell line under normoxic and hypoxic conditions to discover future research targets. U-251 cells were grown to 75% confluence and exposed to either normoxic or hypoxic conditions for 24 h. RNA was extracted, amplified, and hybridized to a cDNA microarray chip containing ~8,800 universal cellular genes. A threefold increase in mRNA expression was used as a threshold value for differential expression. Identified genes were divided into cell cycle control, stress response, and "newly connected" genes. Hybridization identified 11 hypoxia-induced genes: 1 involved with cell cycle control (CCNG2), 6 in stress response (IGFBP3, SLC2A3, GSTT2, FOS, DDIT3, AKR1C3), and 2 newly connected genes (Depp, AKAP4). One stress-related gene (AKR1C3) encodes for an enzyme that synthesizes progesterone. Of newly connected genes, the gene decidual protein induced by progesterone (Depp) showed the highest expression (4.2-fold increase). Possible future targeting for "hypoxic" glioma cells includes the targets for the AP-1 transcription factor complex (FOS), as well as blockade of the enzyme AKR1C3 with nonsteroidal anti-inflammatory drugs. Possible functions of the highly expressed gene Depp include tumor vascularization. Future studies will focus on the hypothesis that Depp is up-regulated in an autocrine fashion by the AKR1C3 enzyme in U-251 glioma cells under hypoxic conditions.
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PMID:Identification of hypoxia-induced genes in a malignant glioma cell line (U-251) by cDNA microarray analysis. 1748 80

Leucine-rich repeat C4 (LRRC4) has been shown to inhibit glioma cell proliferation, however, little is known about the mechanism(s) underlying the action of LRRC4. Here, we show that two glioblstoma U251 cell clones stably expressing LRRC4 were established. LRRC4 expression significantly inhibited the expression of some cytokines and their receptors determined by microarray and Western blot assays, and dramatically reduced cytokine-induced AP-1, NF-kB, and CyclinD1 activation in glioma cells. Furthermore, LRRC4 expression in glioma cells significantly downregulated spontaneous and cytokine-induced expression of K-RAS and phosphorylation of c-Raf, ERK, AKT, NF-kBp65, p70S6K, and PKC, suggesting that LRRC4 inhibited receptor tyrosine kinase (RTK) signaling pathways. Moreover, treatment with bFGF, IGF1, or IGF2 stimulated LRRC4(-/-), but not the LRRC4(+), glioma cell proliferation, indicating that LRRC4 mitigated cytokine-stimulated proliferation in glioma cells. In addition, treatment of LRRC4(-/-) glioma cells with EGF, IGF2, or PDGF promoted long distance mobilization, but induced little migration in LRRC4(+) glioma cells, suggesting that LRRC4 retarded cytokine-promoted glioma cell migration in vitro. Finally, human vessel endothelial cells (ECV304) treated with VEGF grew, aligned and formed hollow tube-like structures in vitro. In contrast, LRRC4(+) ECV304 treated with VEGF failed to form vessel-tube structures. Collectively, LRRC4 expression inhibited the expression of some growth factors, cytokines and their receptors, and the capacity of glioma cells responding to cytokine stimulation, leading to inhibition of glioma cell proliferation. Conceivably, induction of LRRC4 expression may provide new intervention for human glioma in the clinic.
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PMID:LRRC4 inhibits glioblastoma cell proliferation, migration, and angiogenesis by downregulating pleiotropic cytokine expression and responses. 1754 39

The objective of the current study was to investigate the behavioral changes of glioma-bearing nude mice and functional outcome from treatment with a novel antiangiogenesis regimen, which is a combination of monoclonal antibodies against both vascular endothelial growth factor receptor (VEGFR)-1 (MF1) and VEGFR-2 (DC101). The reliability and responsiveness of behavioral measurement with the rearing test were first examined in nude mice bearing two kinds of gliomas--9L gliosarcoma and U87 human glioma, which have different growth rates. Using immunohistochemical staining and fluorescent imaging techniques, upregulation of the angiogenesis marker VEGF, coincident with the abnormal neovascular architecture, was confirmed in the human U87 glioma model. The behavioral measurement was then applied to assess functional outcome with the combination antibody treatment in the orthotopic mouse model of human U87 glioma. The combination antibody therapy retarded tumor progression and delayed the onset of significant behavioral deficits. Histologically, tumor necrosis and apoptosis were increased and tumor cell proliferation was decreased after treatment. In clinical trials for novel interventions, functional end points typically are included in the assessment of potential efficacy. Because certain interventions that successfully treat tumor progression in animal models might interfere with compensatory neuroplasticity, functional measurement may be valuable for improving the clinical relevance of translational brain tumor research.
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PMID:Using behavioral measurement to assess tumor progression and functional outcome after antiangiogenic treatment in mouse glioma models. 1757 15

Angiogenesis is a key event in the natural progression of gliomas. Nestin, a marker for multipotential neuroepithelial stem cells, is detected in neuroepithelial tumors and in proliferating endothelial cells (ECs) and is involved in the early stages of lineage commitment, proliferation and differentiation. Nestin expression is correlated with proangiogenic chemokines (CXCL12 and its receptor CXCR4) and growth factors (VEGF, PDGF-B and its receptor PDGFRbeta). VEGF expression upregulates CXCR4 on endothelial cells, binding the chemokine SDF1/CXCL12 (Stromal Derived Factor) that has a role on angiogenesis and chemotaxis of endothelial cells; PDGF (platelet-derived growth factor) and PDGFRbeta are also crucial by increasing the expression of VEGF. We performed a retrospective study on the presence and role of nestin-expressing cells in 102 patients with glioma, relating the findings to VEGF, CXCL12, PDGFRbeta expression and to clinical outcome (time to tumor progression-TTP and survival time-ST). Our results suggest that in gliomas the detection of proliferating ECs expressing nestin correlates to histological malignancy grade and clinical outcome. Also, the expression of CXCL12 in low-grade gliomas was the only factor associated with a significantly shorter TTP, suggesting a role of this chemokine in angiogenic shift and/or disease progression.
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PMID:Nestin, PDGFRbeta, CXCL12 and VEGF in glioma patients: different profiles of (pro-angiogenic) molecule expression are related with tumor grade and may provide prognostic information. 1761 2

Activation of the formylpeptide receptor (FPR), a G-protein-coupled receptor, by its chemotactic peptide ligand N-formylmethionyl-leucyl-phenylalanine (fMLF) promotes the directional migration and survival of human glioblastoma cells. fMLF also stimulates glioblastoma cells to produce biologically active VEGF, an important angiogenic factor involved in tumor progression. In this study, we examined the capacity of FPR to regulate the production of another angiogenic factor, the chemokine IL-8 (CXCL8), in addition to its demonstrated ability to induce VEGF secretion by malignant glioma cells. We showed that the human glioblastoma cell line U87 secreted considerable levels of IL-8 (CXCL8) upon stimulation by the FPR agonist peptide fMLF. Tumor cells transfected with small interference (si)RNA targeting FPR failed to produce IL-8 as well as VEGF in response to fMLF. Glioblastoma cells bearing FPR siRNA exhibited reduced rate of tumorigenicity in nude mice and tumors formed by such tumor cells showed less active angiogenesis and lower level expression of both IL-8 and VEGF. These results suggest that FPR plays an important role in the angiogenesis of human malignant gliomas through increasing the production of angiogenic factors by FPR positive tumor cells.
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PMID:Production of angiogenic factors by human glioblastoma cells following activation of the G-protein coupled formylpeptide receptor FPR. 1761 13

Our results demonstrate the first findings of expression and function of the purinergic P2X7 receptor (P2X7R) in rat C6 glioma cells. P2X7R mRNA and protein were present in unstimulated C6 cells and were up-regulated by cell exposure to the P2X7R agonist, 2',3'-(benzoyl-4-benzoyl)-ATP (BzATP). Activation of P2X7R in C6 in response to BzATP led to increased mobilization of intracellular calcium [Ca2+]i and formation of large pores. Chronic exposure of C6 cells to BzATP enhanced the expression of pro-inflammatory factors including MCP-1, IL-8 and VEGF. In a scratch-wound migration assay, the P2X7R was shown to regulate cell mobility. The overall results suggest that P2X7R activation in C6 is linked with increased pro-inflammatory factors and tumor cell migration.
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PMID:Expression and function of the P2X(7) receptor in rat C6 glioma cells. 1803 56

The objective of this study was to evaluate the effects of combination therapy with photodynamic therapy (PDT) and a novel antiangiogenic regimen using monoclonal antibodies against both vascular endothelial growth factor receptors (VEGFR)-1 (MF1) and VEGFR-2 (DC101) on intracranial glioblastoma xenografts in nude mice. Nude mice bearing intracerebral U87 glioblastoma were treated with PDT and the antiangiogenic regimen (MF1 and DC101) either alone or in combination, while those left untreated served as tumor controls. Tumor volume and animal survival time were analyzed to evaluate the outcome of different treatment modalities. In addition, the immunohistochemical expression of VEGF in the brain adjacent to the tumor, von Willebrand factor (vWF), apoptotic, and proliferative markers in the tumor area were examined. PDT or MF1 + DC101 alone significantly reduced the tumor volume and prolonged the survival time of glioma-implanted animals. Combined therapy markedly reduced tumor volume and increased survival time with significantly better outcomes than both monotherapies. Both vWF and VEGF levels significantly increased after PDT while they both significantly decreased after antiangiogenic treatment, compared with no treatment. PDT plus antiangiogenic treatment led to significant decreases in both vWF and VEGF expression, compared with PDT alone. Either PDT or antiangiogenic treatment alone significantly increased tumor cell apoptosis compared with no treatment, while combination therapy resulted in further augmentation of apoptosis. Antiangiogenic treatment with or without PDT significantly decreased tumor cell proliferation, compared with either no treatment or PDT alone. In summary, we demonstrate both significant inhibition of tumor growth and extended survival of mice treated by the combination therapy with PDT and antiangiogenic agents, compared with each single treatment, suggesting that the combination therapy may be a promising strategy to improve clinical outcomes in glioblastoma.
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PMID:Combination therapy with antiangiogenic treatment and photodynamic therapy for the nude mouse bearing U87 glioblastoma. 1817 12

Terameprocol, a novel, semisynthetic derivative of a naturally occurring plant lignan, is under development by Erimos Pharmaceuticals LLC for the potential treatment of cancer. The antitumor activity of terameprocol is based on the selective inhibition of specificity protein 1 (Sp1)-regulated proteins, including cyclin-dependent kinase 1, survivin and VEGF. With this mechanism of action, terameprocol potentially inhibits the cell cycle, triggers apoptosis and decreases angiogenesis. Several preclinical studies have demonstrated the potent anticancer activity of terameprocol in tumor cell lines and animal models. In addition, terameprocol prevented the proliferation of HIV, HSV and HPV by a deactivation of viral Sp1-dependent promoters in preclinical studies. In a phase I clinical trial in patients (25 evaluable) with solid tumors administered intravenous terameprocol, 8 patients exhibited stable disease and 17 had progressive disease; the drug was generally well tolerated. A good safety and efficacy profile has also been observed with the intratumoral and intravaginal administration of terameprocol in patients with head and neck or squamous cell carcinoma and in patients with cervical dysplasia, respectively. At the time of publication, terameprocol was in phase I or I/II clinical development for the treatment of glioma, treatment-refractory solid tumors and cervical dysplasia; a phase I clinical trial was also planned in patients with hematological cancers. Thus, the favorable tolerability and efficacy profile demonstrated for terameprocol to date suggests that the further investigation of this drug is warranted.
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PMID:Terameprocol, a novel site-specific transcription inhibitor with anticancer activity. 1831 58


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