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

The diffuse, extensive infiltration of malignant gliomas into the surrounding normal brain is believed to rely on modification of the proteolysis of extracellular matrix components. Our previous results clearly demonstrate that uPA, uPAR and MMP-9 concentrations increase significantly during tumor progression and that tumor growth can be inhibited with antisense stable clones of these molecules. Because antisense-mediated gene silencing does not completely inhibit the translation of target mRNA and high concentrations of antisense molecules are required to achieve gene silencing, we used the RNAi approach to silence uPA, uPAR and MMP-9 in this study. We examined a cytomegalovirus (CMV) promoter-driven DNA-template approach to induce hairpin RNA (hpRNA)-triggered RNAi to inhibit uPA, uPAR and MMP-9 gene expression with a single construct. uPAR protein levels and enzymatic activity of uPA and MMP-9 were found to significantly decrease in cells transfected with a plasmid expressing hairpin siRNA for uPAR, uPA and MMP-9. pU(2)M-transfected SNB19 cells significantly decreased uPA, uPAR and MMP-9 expression compared to mock and EV/SV-transfected cells, determined by immunohistochemical analysis. Furthermore, the effect of the single constructs for these molecules was a specific inhibition of their respective protein levels, as demonstrated by immunohistochemical analysis. After transfection with a plasmid vector expressing dsRNA for uPA, uPAR and MMP-9, glioma-cell invasion was retarded compared with mock and EV/SV-treated groups, demonstrated by Matrigel-invasion assay and spheroid-invasion assay. Downregulation of uPA, uPAR and MMP-9 using RNAi inhibited angiogenesis in an in vitro (co-culture) model. Direct intratumoral injections of plasmid DNA expressing hpRNA for uPA, uPAR and MMP-9 significantly regressed pre-established intracranial tumors in nude mice. In addition, cells treated with RNAi for uPAR, uPA and MMP-9 showed reduced pERK levels compared with parental and EV/SV-treated SNB19 cells. Our results support the therapeutic potential of RNAi as a method for gene therapy in treating gliomas.
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PMID:Downregulation of uPA, uPAR and MMP-9 using small, interfering, hairpin RNA (siRNA) inhibits glioma cell invasion, angiogenesis and tumor growth. 1680 63

In a previous report, the recombinant kringle domain (UK1) of the urokinase type plasminogen activator (uPA) showed antiangiogenic activity. Here, we investigated in vivo antitumor effects of the UK1 of human uPA employing a brain tumor model. The systemic administration of UK1 purified from pichia expression (10 and 50 mg/kg/day intraperitoneally for 25 days) led to suppress the growth of a U87 human glioma xenograft, implanted into the brains of male BALB/cSlc nude mice, by 35% and 80%, respectively. In the immunohistochemical analysis, the tumors treated with UK1 showed decreased vascularity and expression of angiogenesis-related factors including vascular endothelial growth factor (VEGF), angiogenin, alpha-smooth muscle actin, von Willebrand's factor, and CD31 (PECAM-1 [Platelet endothelial cell adhesion molecule-1]), and increased apoptosis. UKl inhibited the in vitro proliferation and tube formation of VEGF-stimulated endothelial cells but not the proliferation of glioma cells. These results suggest that UK1 inhibits the malignant glioma growth by suppression of angiogenesis.
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PMID:The recombinant kringle domain of urokinase plasminogen activator inhibits in vivo malignant glioma growth. 1723 42

Although malignant gliomas are highly invasive tumors, a characteristic that contributes to the commonly observed therapeutic failures and local disease recurrences, the molecular events that regulate invasion in these tumors remain poorly understood. Because the transcription factor RelA/NF-kappaB has been shown to regulate invasion during several cellular processes, we have examined immunohistochemically expression of the constitutively activated RelA/NF-kappaB in tissues obtained from 49 astrocytic tumors [8 diffuse astrocytomas, 9 anaplastic astrocytomas (AAs) and 32 glioblastomas (GBMs)]. In addition, we examined the in vitro effects of antisense oligonucleotides and curcumin on the expression and activation of RelA/NF-kappaB, urokinase-type plasminogen activator (u-PA) expression, migration, and invasion in the T98G glioma cell line. Expression of the constitutively activated RelA/NF-kappaB was observed in 2 (25%) of 8 cases of diffuse astrocytomas, 5 (55.6%) of 9 cases of AAs, and 30 (93.8%) of 32 cases of GBMs. This expression was significantly correlated with the malignant potential in astrocytic tumors (P < 0.001). Moreover, antisense oligonucleotides and curcumin inhibited phorbol-12-myristate-13-acetate (PMA)-induced RelA/NF-kappaB expression or activation (or both), down-regulated u-PA expression, and reduced the migration and invasive potentials of T98G glioma cells. Thus, the expression of constitutively activated RelA/NF-kappaB is associated with malignancy potential in astrocytic tumors and may play a critical role in the regulation of u-PA expression and invasiveness in gliomas. RelA/NF-kappaB may therefore be an intriguing candidate for studies aimed at understanding and prevention of the invasiveness of gliomas.
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PMID:Expression of the constitutively activated RelA/NF-kappaB in human astrocytic tumors and the in vitro implication in the regulation of urokinase-type plasminogen activator, migration, and invasion. 1809 9

The recombinant kringle domain (UK1) of urokinase-type plasminogen activator (uPA) has been shown to possess anti-angiogenic activity in vitro and in vivo. It has also been found to inhibit in vivo malignant glioma growth. In contrast, direct interaction of the kringle domain of uPA and integrin alphavbeta3 has been reported to be involved in plasminogen and leukocyte activation by uPA. Since integrin alphavbeta3 is involved in tumor angiogenesis, we investigated whether integrin alphavbeta3 is involved in the inhibitory function of UK1 in angiogenesis, by examining its anti-migratory activity. In a modified Boyden chamber assay, the Pichia-expressed UK1 dose-dependently inhibited the VEGF-induced migration of human umbilical vein endothelial cells (HUVECs). However, in the absence of growth factor stimulation, soluble UK1 alone did not induce or inhibit HUVEC migration. In cell adhesion, immobilized UK1 promoted HUVEC adhesion and spreading which were compared to BSA. Pretreatment of the anti-alphavbeta3 integrin antibody, significantly inhibited HUVEC binding to immobilized UK1, whereas neither anti-alpha2beta1 nor anti-alpha5beta1 integrin antibody had any effect, although pre-treatment of the soluble UK1 showed no marked alteration of the binding level of anti-alphavbeta3 antibody to HUVECs in FACS analysis. In a modified Boyden chamber assay, the function blocking antibodies against integrins alphavbeta3, alpha2beta1 and alpha5beta1 did not completely prevent the inhibitory effect of UK1 in HUVEC migration. These results suggest that UK1 interacts with integrin alphavbeta3, but its anti-migratory activity on endothelial cells is not significantly mediated by integrin alphavbeta3.
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PMID:Integrin alphavbeta3 is not significantly implicated in the anti-migratory effect of anti-angiogenic urokinase kringle domain. 1869 16

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

Glioblastoma multiforme (GBM) is an aggressively invasive brain neoplasm with poor patient prognosis. We have previously shown that the bioactive lipid sphingosine-1-phosphate (S1P) stimulates in vitro invasiveness of GBM cells and that high expression levels of the enzyme that forms S1P, sphingosine kinase-1 (SphK1), correlate with shorter survival time of GBM patients. We also recently showed that S1P induces expression of CCN1 (also known as Cyr61), a matricellular protein known to correlate with poor patient prognosis, in GBM cells. In this study, we further explored the role of CCN1 as well as the urokinase plasminogen activator (uPA), a protein known to stimulate GBM cell invasiveness, in S1P-induced invasion using a spheroid invasion assay. We also investigated the roles of various S1P receptors in stimulating invasiveness through these pathways. S1P induced expression of uPA and its receptor, uPAR, in GBM cells. Whereas S1P(1), S1P(2), and S1P(3) receptors all contribute, at least partially, S1P(1) overexpression led to the most dramatic induction of the uPA system and of spheroid invasion, even in the absence of added S1P. Furthermore, neutralizing antibodies directed against uPA or CCN1 significantly decreased both basal and S1P-stimulated GBM cell invasiveness. Inhibition of SphK blocked basal expression of uPA and uPAR, as well as glioma cell invasion; however, overexpression of SphK did not augment S1P receptor-mediated enhancement of uPA activity or invasion. Thus, SphK is necessary for basal activity of the uPA system and glioma cell invasion, whereas S1P receptor signaling enhances invasion, partially through uPA and CCN1.
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PMID:Sphingosine-1-phosphate regulates glioblastoma cell invasiveness through the urokinase plasminogen activator system and CCN1/Cyr61. 1914 34

We investigated the pro-inflammatory response mediated by TNFalpha in glioblastoma and whether treatment with organoselenium Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one) can affect TNFalpha induced inflammatory response. Exposure to TNFalpha increased the expression of pro-inflammatory mediator interleukin IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and cyclooxygenase (COX-2). Treatment with Ebselen abrogated TNFalpha induced increase in pro-inflammatory mediators. Ebselen not only abrogated TNFalpha induced enhanced invasiveness of glioma cells by down-regulating matrix metallo proteinase (MMP-9) and urokinase plasminogen (uPa) activity, but also inhibited glioma cell migration. Treatment with Ebselen also down-regulated the enhanced ROS production of TNFalpha treated glioma cells. In addition, Ebselen induced DNA damage repair signaling response in glioma cells both in the presence and absence of TNFalpha. These studies indicate that together with its known ability to sensitize glioma cell to TNFalpha induced apoptosis, Ebselen can overcome TNFalpha induced pro-inflammatory mediators to prevent a build up of a deleterious pro-inflammatory tumor microenvironment.
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PMID:Ebselen abrogates TNFalpha induced pro-inflammatory response in glioblastoma. 1938 69

The kringle domain of urokinase-type plasminogen activator (UK1) has anti-angiogenic and anti-tumor effects. Celecoxib, an inhibitor of cyclooxygenase type 2, also suppresses angiogenesis and tumor growth. To look for potential additive effects in their activities, we examined the anti-angiogenic and anti-tumor effects of the combination of UK1 and celecoxib for malignant gliomas. In vitro, the combination of UK1 and celecoxib enhanced inhibition of proliferation, migration, and tube formation of endothelial cells, although showing no enhancement of inhibition of U87 cell growth. However, in vivo models, combination treatment of intracerebral U87 malignant glioma xenografts in nude mice with UK1 (10mg/kg/day) and celecoxib (10mg/kg/day) at lower doses resulted in even more potent inhibition of tumor growth than each monotherapy (by 81% compared to untreated tumors), with drastic decrease of the expression of angiogenesis-related factors and increase of apoptosis in the tumor tissues. Interestingly, UK1 inhibited VEGF or bFGF-induced phosphorylation of ERK1/2 in ECs, whereas celecoxib showed no such effects. However, celecoxib inhibited U87 cell growth and directly suppressed their VEGF production. Therefore, our data suggest that combined use at low doses of UK1 and celecoxib with different anti-angiogenic mechanisms provides a desirable strategy for anti-glioma therapy.
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PMID:Enhancement of anti-tumor activity by low-dose combination of the recombinant urokinase kringle domain and celecoxib in a glioma model. 1966 79

In contrast to pilocytic astrocytomas (WHO grade I gliomas) that are circumscribed and cured by surgical resection, invasion is a hallmark of grades II-IV gliomas. Proteases play a major role in the invasion process and correlations between glioma grading, survival and protease expression have been demonstrated. In this study, we have chosen to study using different technical approaches (Q-RT-PCR, in situ hybridization and immunohistochemistry) the expression of five molecules involved in extracellular matrix degradation (cathepsin B, MMP2, MMP9, uPA and PAI-1) in glioblastomas in order to determine their prognostic impact among grade IV gliomas. Pilocytic astrocytomas were used as controls. Q-RT-PCR showed that transcripts of uPA, PAI-1, cathepsin B and MMP9 were significantly more expressed in glioblastomas (n = 52), in comparison to pilocytic astrocytomas (n = 17) (P = 0.049, P < 0.0001, P = 0.03 and P < 0.0001, respectively). On both univariate and multivariate analyses, cathepsin B and PAI-1 were strong predictors of overall survival among the group of glioblastomas (P < 0.0001 and P = 0.01, respectively). Immunohistochemical expression of cathepsin B further confirmed its prognostic value in an independent cohort of patients with glioblastoma. In situ hybridization showed that uPA is detected at the invasive edge of glioblastomas, whereas PAI-1 is more abundant in microvascular proliferation and pseudo-palisading cells than at the infiltrative edges. These results suggest that cathepsin B and PAI-1 are important biomarkers for the stratification of glioblastoma patients with respect to survival.
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PMID:High expression of cathepsin B and plasminogen activator inhibitor type-1 are strong predictors of survival in glioblastomas. 1977 87

Glioblastoma multiforme remains one of the most devastating human malignancies because of its high infiltrative capacity. This study aimed to investigate the effects of silibinin on human glioblastoma U87MG cells. The microculture tetrazolium test, bromodeoxyuridine cell proliferation assay, cell-based nuclear factor kappa B (NF-[kappa]B) activation assessment, cathepsin B activity assay, gelatin zymography, and quantitative real-time reverse transcription-PCR were performed to appraise the effects of silibinin on the metabolic activity, DNA synthesis, NF-[kappa]B phosphorylation, cathepsin B activity, and gelatinolytic activity of U87 cells. Silibinin inhibited metabolic activity, cell proliferation, NF-[kappa]B activation, cathepsin B enzymatic levels, and gelatinase B activity in U87 cells. In addition, an expressive decrease in mRNA levels of matrix metalloproteinase-9, cathepsin B, urokinase plasminogen activator receptor, urokinase plasminogen activator, and intercellular adhesion molecule 1 coupled with a significant induction in transcriptional levels of stefin A was observed. Altogether, these issues show for the first time that silibinin treatment could trammel invasive features of a highly invasive human glioma cell line, U87, through suppression of NF-[kappa]B-mediated stimulation of matrix metalloproteinase-9. Furthermore, silibinin might cripple the activation of gelatinase B by cramping transcriptional and enzymatic activities of cathepsin B in U87 cells.
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PMID:Silibinin inhibits invasive properties of human glioblastoma U87MG cells through suppression of cathepsin B and nuclear factor kappa B-mediated induction of matrix metalloproteinase 9. 2016 42


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