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)

Destruction of the neovasculature is essential for efficient tumor eradication by photodynamic therapy (PDT). Since the over-expression of receptors for vascular endothelial growth factor (VEGF) is correlated with tumor angiogenesis and subsequent growth, we conjugated a photosensitizer (5-(4-carboxyphenyl)-10,15,20-triphenyl-chlorin, TPC), via a spacer (6-aminohexanoic acid, Ahx), to a VEGF receptor-specific heptapeptide (ATWLPPR). ATWLPPR and TPC-Ahx-ATWLPPR bound exclusively to neuropilin-1 (NRP-1) recombinant chimeric protein (IC50=19 and 171 microM, respectively) but were devoid of affinity for VEGF receptor type 2 (VEGFR-2, KDR), to which ATWLPPR was initially thought to bind. TPC-Ahx-ATWLPPR was incorporated up to 25-fold more in human umbilical vein endothelial cells (HUVEC) than TPC over a 24-h period, and the addition of 8 mM ATWLPPR induced a significant decrease of this uptake (P<0.05), corroborating a receptor-mediated incorporation. Slightly less cytotoxic in the dark, TPC-Ahx-ATWLPPR exhibited enhanced in vitro photodynamic activity (10.4-fold), compared to TPC. Pharmacokinetic analysis in nude mice xenografted with U87 human malignant glioma cells revealed relevant tumor levels as soon as 1 h after intravenous injection of TPC-Ahx-ATWLPPR, and a rapid elimination from the blood compartment. Moreover, TPC-Ahx-ATWLPPR was not degraded in vivo up to 2 h after intravenous injection. Taken together, our results demonstrate that TPC-Ahx-ATWLPPR is a much more potent photosensitizer in vitro than TPC, in NRP-1-expressing cells. Thus, it may efficiently potentiate the vascular effect of PDT in vivo.
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PMID:A peptide competing with VEGF165 binding on neuropilin-1 mediates targeting of a chlorin-type photosensitizer and potentiates its photodynamic activity in human endothelial cells. 1642 22

EGFR overexpression is the most frequent and important molecular event in the development of astrocytic gliomas, and the P13K signaling pathway is one of the most important downstream pathways of EGFR. EGFR and other members of the receptor tyrosine kinases (RTKs) family, such as VEGFR, PDGFR, and IGFR, et cetera, are often overexpressed in most of malignant gliomas and share common downstream signaling pathways. Therefore, it is considered that directly targeting the downstream PI3K pathway may be more effective in blocking multiple inputs. The PIK3CB gene encoding the class 1A PI3K catalytic subunit p110beta was selected as the target of therapeutic approach for malignant gliomas in the present study. Human U251 glioblastoma cells with high endogenous p110beta expression were transfected with plasmid-based siRNA targeting PIK3CB gene. It was found that downregulation of p110beta expression resulted in the suppression of cell proliferation, arrest of cell cycle, reduction of cell invasion, and promotion of cell apoptosis in vitro. In addition, the growth of the subcutaneous U251 glioma in the nude mice treated with siRNA targeting PIK3CB was significantly inhibited. These results demonstrate that PIK3CB overexpression may play an oncogenic role in the PI3K pathway, and the plasmid-based siRNA targeting of PIK3CB is a potential and promising approach for the treatment of malignant gliomas.
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PMID:Downregulation of PIK3CB by siRNA suppresses malignant glioma cell growth in vitro and in vivo. 1670 Jun 23

Angiogenic processes are regulated by vascular endothelial growth factors (VEGFs) and their receptors VEGFR1 (Flt-1), 2 (Flk-1) and 3 (Flt-4). While VEGFR2 is thought to play a central role in tumor angiogenesis, anti-angiogenic therapies targeting VEGFR2 in glioma models can show escape phenomena with secondary onset of angiogenesis. The purpose of this study was to find explanations for these processes by searching for alternative pathways regulating glioma angiogenesis and reveal a correlation with tumor grade. Thus, VEGFR3, which is not expressed in normal brain, and its ligands VEGF-C and -D, were assessed in high grade (WHO degrees IV, glioblastomas, GBM) and low grade gliomas [WHO degrees II astrocytomas (AII)]. In all GBM, a strong protein expression of VEGFR3 was found on tumor endothelium, VEGF-C and -D expression was found on numerous cells in areas of high vascularization. On RNA level, a significant up-regulation of VEGFR3 was detected in GBM compared to AII and non-neoplastic brain. In AII, only very moderate VEGFR3, VEGF-C and -D expression was found on protein and RNA level indicating a correlation of VEGFR3 expression with tumor grade. VEGFR3 signal in both grades was found predominantly on endothelial cells, confirmed by VEGFR3 expression on isolated CD31 positive cells and the expression of various endothelial markers on VEGFR3-positive cells isolated from GBM. The demonstration of a complete angiogenic signaling system that is dependent on tumor grade may influence the traditional paradigm of glioma angiogenesis and may provide a basis for more effective anti-angiogenic treatment strategies.
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PMID:Expression of VEGFR3 in glioma endothelium correlates with tumor grade. 1711 85

Receptor tyrosine kinase aberrations are implicated in the genesis of gliomas. We investigated expression and amplification of KIT, PDGFRA, VEGFR2, and EGFR in 87 gliomas consisting of astrocytomas, anaplastic astrocytomas, oligodendrogliomas, or oligoastrocytomas in tumor samples collected at the time of the diagnosis and in samples of the same tumors at tumor recurrence. Gene amplifications were investigated using either chromogenic in situ hybridization or fluorescence in situ hybridization, and protein expression using immunohistochemistry. In samples collected at glioma diagnosis, KIT and PDGFRA amplifications were more frequent in anaplastic astrocytomas than in astrocytomas, oligodendrogliomas, and oligoastrocytomas [28% versus 5% (P = 0.012) and 33% versus 2% (P = 0.0008), respectively]. VEGFR2 amplifications occurred in 6% to 17% of the gliomas at diagnosis, and EGFR amplifications in 0% to 12%. Amplified KIT was more frequently present in recurrent gliomas than in newly diagnosed gliomas (P = 0.0066). KIT amplification was associated with KIT protein expression and with presence of PDGFRA and EGFR amplifications both at the time of the first glioma diagnosis and at tumor recurrence, and with VEGFR2 amplification at tumor recurrence. Three (4%) primary gliomas and 10 (14%) recurrent gliomas that were evaluable for coamplification of KIT, PDGFRA, and VEGFR2 showed amplification of at least two of these genes; the amplicon contained amplified KIT in all 13 cases. In conclusion, besides glioblastoma, amplified KIT, PDGFRA, and VEGFR may also occur in lower-grade gliomas and in their recurrent tumors. It is currently not known whether specific tyrosine kinase inhibitors are effective in the treatment of such gliomas.
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PMID:Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. 1718 83

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

Vascular endothelial growth factor (VEGF) is abundantly produced by glioma cells especially glioblastoma, the most malignant form of astrocytoma. VEGF, a well known angiogenic factor, acts in a paracrine fashion on endothelial cells to develop tumor vasculature. However, recent studies have found that several tumor cells express VEGF receptors, and an autocrine action of VEGF on tumor cells has been suggested. To test this hypothesis, three human glioma cell lines (U251n, U87 and A172) were checked for VEGF and VEGFR expression. These cells express 0.1-0.6 ng/ml VEGF165 in cell culture medium within 24 hours. Western blot analysis showed that these cells express all of the VEGF receptors, VEGFR-1/Flt-1, VEGFR-2/KDR, Neuropilin-1 (NRP-1) and Neuropilin-2(NRP-2), even though tyrosine kinase receptor VEGFR-2/KDR exhibited baseline levels of expression. VEGF expression was significantly down regulated by phosphorothioate oligodeoxynucleotide (PS-ODN) and VEGF RNAi transfection. However, VEGF RNAi transfection as well as VEGF and VEGFR2 neutralization antibody treatment did not decrease cell proliferation detected by MTT and CyQuant NF proliferation assay except that PS-ODN transfection caused a non-specific decrease on cell proliferation. VEGF RNAi transfection did not alter cell invasion, as demonstrated in a matrigel invasion assay. Matrix metalloproteinase-2 (MMP-2) and MMP-9, facilitating cell invasion and over expressed in glioma cells, were not altered by VEGF RNAi transfection, as shown by zymographic assays. Our data indicate that the decrease of endogenous VEGF expression may not affect glioma cell proliferation and invasion.
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PMID:Decrease of endogenous vascular endothelial growth factor may not affect glioma cell proliferation and invasion. 1755 62

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

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

Celastrol, a compound purified from Tripterygium wilfordii whose preparations have been used for clinical treatment for rheumatoid arthritis, has been demonstrated to have antiangiogenic activity, and be inhibitory against mice tumor growth by a few recent studies. However, whether its antiangiogenic activity plays a role in the celastrol-mediated suppression of tumor growth and the molecular basis of anti-tumor activity are poorly understood. In this study, we found that celastrol inhibited the growth of human glioma xenografts in mice, which concurred with the suppression of angiogenesis. Interestingly, while celastrol had no effect on either the expression of VEGF or its mRNA levels, celastrol treatment lowered the expression levels of its receptors (VEGFR-1 and VEGFR-2) and their mRNA levels. These findings suggest that celastrol have potential to be used as an antiangiogenesis drug through its role in suppressing VEGF receptors expression that might consequently reduce the signal transduction between VEGF and VEGFR.
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PMID:Celastrol inhibits the growth of human glioma xenografts in nude mice through suppressing VEGFR expression. 1834 27

Alterations at chromosome locus 4q12 are frequently found in gliomas; this locus contains the receptor tyrosine kinase--encoding genes KIT, PDGFRA, and KDR (alias VEGFR2). Notable among the genes at this locus is LNX1, the ligand of Numb protein X. LNX1 encodes a PDZ domain containing protein, which interacts with the cell fate determinant Numbl, a Numb homolog-like gene involved in the maintenance of neural progenitor cells during embryonic neurogenesis. We performed a mutation analysis for LNX1 and Numbl genes. In addition, gene copy numbers of LNX1, Numbl, and KIT in human nervous system tumors were analyzed by chromogenic in situ hybridization. Tissue samples from 90 patients were screened for LNX1 and Numbl mutations, and tissue sections from 56 samples were analyzed for gene amplification status. Our analysis revealed missense mutations in LNX1 exons 3 and 5 and a single-nucleotide polymorphism in Numbl exon 6. In addition, polyglutamine repeat polymorphism was found in Numbl exon 10. Chromogenic in situ hybridization showed gene amplification of LNX1 in 10%, Numbl in 5%, and KIT in 6% of nervous system tumors. Both gene sequence alterations and amplifications of LNX1 and Numbl are present in a subset of human gliomas, and the role of these genes in neurogenesis suggests that they may contribute to development of glial tumors.
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PMID:Mutation and copy number analysis of LNX1 and Numbl in nervous system tumors. 1894 Apr 73


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