Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in human gliomas. VEGF-induced proteins in endothelial cells, tissue factor (TF), osteopontin (OPN) and alphavbeta3 integrin have been implicated as important molecules by which VEGF promotes angiogenesis in vivo. Sixty-eight gliomas were immunohistochemically stained with TF, VEGF, OPN and alphavbeta3 integrin antibody. Twenty-three tumours, six normal brains and nine glioma cell lines were evaluated for their mRNA expression of VEGF and TF by reverse transcription polymerase chain reaction analysis. The data indicated that TF as well as VEGF was a strong regulator of human glioma angiogenesis. First, TF expression in endothelial cells which was observed in 74% of glioblastomas, 54% of anaplastic astrocytomas and none of low-grade astrocytomas, correlated with the microvascular density of the tumours. Double staining for VEGF and TF demonstrated co-localization of these two proteins in the glioblastoma tissues. Second, there was a correlation between TF and VEGF mRNA expression in the glioma tissues. Third, glioma cell conditioned medium containing a large amount of VEGF up-regulated the TF mRNA expression in human umbilical vein endothelial cells. OPN and alphavbeta3 integrin, were also predominantly observed in the microvasculature of glioblastomas associated with VEGF expression. Microvascular expression of these molecules could be an effective antiangiogenesis target for human gliomas.
 ...
PMID:Tissue factor, osteopontin, alphavbeta3 integrin expression in microvasculature of gliomas associated with vascular endothelial growth factor expression. 1086 5

Vascular endothelial growth factor (VEGF), a key regulatory protein in neoangiogenesis, is strongly expressed in a variety of primary brain tumors, particularly malignant gliomas. In previous studies, high levels of VEGF were also reported in tumor cysts of glioblastomas. Using an ELISA method we measured the concentration of VEGF in matched samples of aspiration fluid from tumor cysts and serum. Samples were collected from 14 patients with primary brain tumors of various histology (six glioblastomas, one protoplasmatic astrocytoma, two pilocytic astrocytomas, one ependymoma, one meningioma, and three craniopharyngiomas) and two patients with solitary cystic brain metastases from adenocarcinomas of the lung. Aspiration fluids of tumor cysts from all patients revealed high VEGF levels ranging between 882 and 1,263,000 pg/ml, which were 2 to more than 2,000 times higher than the corresponding serum levels. Maximum VEGF levels were detectable in cyst fluids from recurrent glioblastoma. Serum VEGF levels ranged between 125 and 716 pg/ml and did not differ from serum levels in 145 healthy volunteers. In a single patient with metastatic lung cancer the concentration of VEGF in serum and cyst fluid was determined during disease progression. During 60 days of follow-up VEGF concentrations in the cyst fluid collected by puncture of an Ommaya reservoir increased 650-fold, while serum levels remained rather constant. These findings indicate that immunoreactive VEGF is produced at the tumor site and abundantly released into the cyst fluid of primary and metastatic brain tumors. Interestingly, this abundant local release is not reflected in serum VEGF levels, even in the case of very high VEGF concentrations in tumor cysts. Thus, VEGF may be biologically relevant for the formation of tumor cysts in brain tumors and correlates with local disease progression.
 ...
PMID:Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and correlates with tumor progression. 1091 27

Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.
 ...
PMID:Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. 1093 68

Vascular endothelial growth factor (VEGF) is an important mediator of the intense angiogenesis which is characteristic of glioblastoma. While genetic manipulation of VEGF/VEGF receptor expression has previously been shown to inhibit glioblastoma growth, to date, no study has examined the efficacy of pharmacologic blockade of VEGF activity as a means to inhibit intracranial growth of human glioblastoma. Using intraperitoneal administration of a neutralizing anti-VEGF antibody, we demonstrate that inhibition of VEGF significantly prolongs survival in athymic rats inoculated in the basal ganglia with G55 human glioblastoma cells. Systemic anti-VEGF inhibition causes decreased tumor vascularity as well as a marked increase in tumor cell apoptosis in intracranial tumors. Although intracranial glioblastoma tumors grow more slowly as a consequence of anti-VEGF treatment, the histologic pattern of growth suggests that these tumors adapt to inhibition of angiogenesis by increased infiltration and cooption of the host vasculature.
 ...
PMID:Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. 1100 65

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis, where it functions as one of the major angiogenic factors sustaining growth and draining catabolites. In this study, we developed an anti-VEGF ribozyme targeted to the 5' part of human VEGF mRNA. We endowed this ribozyme with an additional feature expected to improve its activity in vivo, by cloning it into a VAI transcriptional cassette. VAI is originally part of the adenovirus genome, and is characterized by high transcription rates, good stability due to its strong secondary structure and cytoplasmic localization. Transfection of U87 human glioblastoma cells with plasmid vectors encoding for this ribozyme resulted in a strong (-56%) reduction of VEGF secreted in the extracellular medium, indicating a good biological activity of the ribozyme. Moreover, this reduction in VEGF secretion had the important functional consequence of drastically diminishing the formation of tube-like structures of human umbilical vascular endothelial cells in a Matrigel in vitro angiogenesis assay. In conclusion, our VAI-embedded anti-VEGF ribozyme is a good inhibitor of angiogenesis in vitro, in a glioblastoma cell context. Thus, it may represent a useful tool for future applications in vivo, for antiangiogenic gene therapy of glioblastoma and of highly vascularized tumors.
 ...
PMID:An anti-VEGF ribozyme embedded within the adenoviral VAI sequence inhibits glioblastoma cell angiogenic potential in vitro. 1508 86

CI-1033 (N-[4-[N-(3-chloro-4-fluorophenyl)amino-7-[3-(4-morpholynyl)propoxy]quinazolin-6-yl]acrylamide, PD 0183805-mesylate salt) was identified as a potent, selective inhibitor of erbB family tyrosine kinases, which are overexpressed in a number of solid tumors and have been shown to be involved in tumor progression. Because objective response of clinical patients to erbB-targeted therapies like CI-1033 has been observed only in a subset of cancer patients that exhibit the intended molecular targets, much emphasis has been placed on the identification of biomarkers of antitumor efficacy. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) were considered as potential biomarkers for CI-1033 due to ease of detection in patient plasma and showed roles in angiogenesis and cancer progression and positive regulation by the erbB receptor family. In the present studies, mice bearing established xenografts (A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, SF767 glioblastoma, and MDA-MB-468 mammary carcinoma) were treated with efficacious and subefficacious doses of CI-1033, and plasma levels and xenograft gene expression of VEGF and IL-8 were evaluated. Oral administration of CI-1033 to tumor-bearing mice at efficacious doses resulted in markedly decreased levels of VEGF and/or IL-8 plasma levels and tumor mRNA levels relative to vehicle-treated control mice in xenograft models that exhibited evaluable levels of these markers. In contrast, subefficacious doses of CI-1033 did not significantly affect VEGF or IL-8 levels in any of the xenograft models. These studies indicate that plasma VEGF and IL-8 may have use as biomarkers of antitumor efficacy for epidermal growth factor receptor/erbB-targeted therapies such as CI-1033 and suggest that further clinical study of these markers in cancer patients are warranted.
 ...
PMID:Plasma vascular endothelial growth factor and interleukin-8 as biomarkers of antitumor efficacy of a prototypical erbB family tyrosine kinase inhibitor. 1595 51

Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Interferons (IFNs) have been widely used in the treatment of malignant or recurrent gliomas with only marginal benefit. The association between IFNs and VEGF expression remains unclear and should be an intensively investigated subject. The present study therefore examined the effects of different types of IFNs on VEGF expression in human T98G, A172 and U251 glioblastoma cells by quantitative RT-PCR and ELISA. Both type I (alpha, beta) and type II (gamma) IFNs upregulated VEGF expression in a cell-specific but p53-independent manner. Actinomycin D experiments demonstrated that IFNs did not alter VEGF mRNA stability. In contrast, induction of VEGF mRNA by IFNs was blocked by the protein synthesis inhibitor cycloheximide. Interestingly, cycloheximide also blocked IFN-induced activation of the p44/p42 mitogen-activated protein kinase, which was partially required for induction of VEGF by IFNs. These findings suggest that VEGF might be an indirect target gene of IFNs, and might provide insights into therapeutic applications of IFNs against angiogenesis-dependent tumors.
 ...
PMID:Cell-specific but p53-independent regulation of vascular endothelial growth factor expression by interferons in human glioblastoma cells. 1628 38

Angiogenesis is required for the development and biologic progression of glioblastoma multiform (GBM), which is the most malignant infiltrative astrocytoma. Vascular endothelial growth factor (VEGF) plays a predominant role in the increased vascularity and endothelial cell proliferation in GBMs driven by the expression of pro-angiogenic cytokines. In this study, we employed a vector-encoded VEGF siRNA to impair VEGF secretion from U87 human glioblastoma cells. The direct intra-tumor injection of a siRNA-encoding plasmid complexed with linear polyethylenimine (PEI) efficiently reduced the vascularization of treated tumors in xenografts established in SCID mice by subcutaneous inoculation of U87 cells, but was not able to reduce tumor growth. We then sought to strengthen the in vivo action of our siRNA by coupling it to a well known direct antiangiogenic agent, mouse interleukin 4 (mIL4). We infected U87 cells with a retroviral vector coexpressing the VEGF siRNA and mIL4 and produced stable cell lines that we used for an in vivo experiment of subcutaneous injection in SCID mice. In this setting, the concomitant expression of mIL4 and siRNA totally abolished the growth of subcutaneous tumors. These results suggest that our retroviral vector might be employed as a potential tool in future antiangiogenic gene therapy trials for glioblastoma.
 ...
PMID:A plasmid-encoded VEGF siRNA reduces glioblastoma angiogenesis and its combination with interleukin-4 blocks tumor growth in a xenograft mouse model. 1634 Mar 8

Vascular endothelial growth factor (VEGF) and platelet-derived lipid sphingosine-1-phosphate (S1P) are two proinflammatory mediators which contribute to angiogenesis, in part through the synthesis of platelet-activating factor (PAF). The red grape skin polyphenolic extract (SGE) both prevents and inhibits angiogenesis in the Matrigel model, decreases the basal motility of endothelial and cancer cells, and reverses the chemotactic effect of S1P and VEGF on bovine aortic endothelial cells (BAECs) as well as the chemotactic effect of conditioned medium on human HT-1080 fibrosarcoma, human U-87 glioblastoma, and human DAOY medulloblastoma cells. Inhibition of VEGF- and S1P-mediated chemotaxis by SGE is associated with a down-regulation of ERK and p38/MAPK phosphorylation and a decreased in acute PAF synthesis. Notably, as do extracellular inhibitors of PAF receptor, SGE prevents S1P-induced PAF synthesis and the resulting activation of the S1P/endothelial differentiation gene-1 cascade. Given the key role of VEGF and S1P in inflammation, angiogenesis, and tumor invasion, SGE may therefore contribute to prevent (or to delay) the development of diseases associated with angiogenesis dysregulation, including cancer. The dual inhibition of S1P- and VEGF-mediated migration of endothelial cell and of serum-stimulated migration of U-87 cells suggests a usefulness of SGE against highly invasive human glioblastoma.
 ...
PMID:Inhibition of sphingosine-1-phosphate- and vascular endothelial growth factor-induced endothelial cell chemotaxis by red grape skin polyphenols correlates with a decrease in early platelet-activating factor synthesis. 1718 36

Malignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant factor in tumor recurrence following surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated vascular permeability (VP) has been associated with the progression of glioma tumor growth and infiltration into surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src+/+ or src+/-), the VP response is blocked in src-/- mice that demonstrate a 'leakage-resistant phenotype' in the brain. We used the Src-deficient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src-/- mice, the infiltrating component of glioma growth was reduced in src-/- mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect of a Src-mediated VP defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src-/- mice mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.
 ...
PMID:Reduced glioma infiltration in Src-deficient mice. 1655 22


<< Previous 1 2 3 4 5 Next >>