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

Connective tissue growth factor (CTGF) was recently described as a cysteine-rich mitogenic peptide that is the prototypic member of the CCN family of protein including CTGF/fisp12, cef/10/cyr61 and nov. Recently CTGF was reported to have a function of mediating endothelial cell adhesion and migration through integrin alpha(v)beta3, promoting endothelial cell survival, and inducing angiogenesis in vivo. To clarify involvement of CTGF in tumor angiogenesis, using brain tissues with glioblastoma, we examined CTGF expression and localization by immunohistochemical staining and reverse transcription-polymerase chain reaction. The result showed that both glioblastoma tumor cells and proliferating endothelial cells are positive for CTGF by immunohistochemical staining, and CTGF mRNA expression was evaluated by RT-PCR in the brain tissues of glioblastoma. These findings suggest that CTGF may have the potential to stimulate angiogenesis in glioblastoma and function as an angiogenic factor in the process of tumor growth.
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PMID:Neoplastic cells and proliferating endothelial cells express connective tissue growth factor (CTGF) in glioblastoma. 1239 5

Angiogenesis is essential for the growth of solid tumors. We have observed previously that the vascular endothelial cells of astrocytic brain tumors express human telomerase reverse transcriptase (hTERT) mRNA, suggesting a role for telomerase in the angiogenesis of these neoplasms. Here, we used an in vitro model to demonstrate that the telomerase machinery might be trans-activated in primary endothelial cells by glioblastoma tumor cells. We found that glioblastoma cells in vitro do induce hTERT mRNA and hTERT protein expression, as well as telomerase enzyme activity in the endothelial cells, and that this phenomenon is mediated by diffusible factor(s). These results provide strong evidence of the involvement of telomerase in tumor angiogenesis and will stimulate research on antitelomerase drugs for treatment of malignant brain gliomas.
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PMID:Glioblastoma induces vascular endothelial cells to express telomerase in vitro. 1283 70

The inhibition of tumor angiogenesis could be an efficient therapeutic strategy for the treatment of malignant gliomas. Prominent neovascularization is induced by these tumors, and microvascular proliferation is a malignancy grading criterion. However, glioma cells can also invade the brain diffusely over long distances without necessarily requiring angiogenesis. Experimentally, it was shown that especially during early stages of growth in rodent brain, glioma cells can coopt the preexistent host vasculature to recruit their blood supply in the absence of neovascularization. This phenomenon was only observed in orthotopic models in which the tumor cells were implanted into the brain which is a densely vascularized environment, but not in subcutaneous models in which tumor cells are implanted into a virtual space. Using an orthotopic mouse model, we analyzed whether systemic anti-angiogenic therapy with an antibody against the vascular endothelial growth factor receptor-2 (VEGFR-2) could inhibit intracerebral growth of xenografted human glioblastoma cells and what effect this treatment had on tumor morphology and invasiveness. We found that anti-angiogenic therapy inhibited tumor growth by 80% compared to buffer-treated controls. The intratumoral microvessel density was reduced by at least 40% in treated animals compared to controls. However, in mice treated with the anti-VEGFR-2 antibody, we noticed a striking increase in the number and total area of small satellite tumors clustered around the primary mass. These satellites usually contained central vessel cores, and tumor cells often had migrated along blood vessels over long distances to eventually reach the surface and spread in the subarachnoid space. Systemic anti-angiogenic therapy can thus apparently increase the invasiveness of gliomas in the orthotopic model. Tumor cell invasion was tightly associated with preexistent blood vessels, suggesting that increased cooption of the host vasculature could represent a compensatory mechanism that is selected for by inhibiting adequate tumor vascularization.
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PMID:Invasion as limitation to anti-angiogenic glioma therapy. 1453 75

Angiogenic factors are necessary for tumor proliferation and thus are attractive therapeutic targets. In this study, we have used engineered zinc finger protein (ZFP) transcription factors (TFs) to repress expression of vascular endothelial growth factor (VEGF)-A in human cancer cell lines. We create potent transcriptional repressors by fusing a designed ZFP targeted to the VEGF-A promoter with either the ligand-binding domain of thyroid hormone receptor alpha or its viral relative, vErbA. Moreover, this ZFP-vErbA repressor binds its intended target site in vivo and mediates the specific deacetylation of histones H3 and H4 at the targeted promoter, a result that emulates the natural repression mechanism of these domains. The potential therapeutic relevance of ZFP-mediated VEGF-A repression was addressed using the highly tumorigenic glioblastoma cell line U87MG. Despite the aberrant overexpression of VEGF-A in this cell line, engineered ZFP TFs were able to repress the expression of VEGF-A by >20-fold. The VEGF-A levels observed after ZFP TF-mediated repression were comparable to those of a nonangiogenic cancer line (U251MG), suggesting that the degree of repression obtained with the ZFP TF would be sufficient to suppress tumor angiogenesis. Thus, engineered ZFP TFs are shown to be potent regulators of gene expression with therapeutic promise in the treatment of disease.
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PMID:Repression of vascular endothelial growth factor A in glioblastoma cells using engineered zinc finger transcription factors. 1469 15

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.
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PMID:An anti-VEGF ribozyme embedded within the adenoviral VAI sequence inhibits glioblastoma cell angiogenic potential in vitro. 1508 86

Gabexate mesilate (GM), a synthetic protease inhibitor, has an antiproteinase activity on various types of plasma serine proteases. However, its role on matrix metalloproteinases (MMPs) has not been identified. In this study, we investigated the effect of GM on MMPs and on the invasion and metastasis of human colon cancer cell lines and neoangiogenesis. The activities of MMPs secreted from these cells were significantly reduced by GM but unaffected by the serine protease inhibitor aprotinin. GM directly inhibited purified progelatinase A derived from T98G human glioblastoma cells. In vitro, GM significantly reduced the invasive ability of colon cancer cells but not cellular motility, whereas aprotinin affected neither. Liver metastatic ability and tumorigenic potential in nude mice were remarkably reduced on treatment with GM. Immunohistochemical analysis of GM-treated tumors in mice showed a marked increase in apoptosis and a significant reduction in tumor angiogenesis. Human umbilical vein endothelial cell proliferation, tube formation, and neoangiogenesis in the rabbit cornea and Matrigel implanted in mice were significantly inhibited by GM. These results suggest that GM is a novel inhibitor of MMPs and that it may inhibit the invasion and metastasis of human colon cancer cells by blocking MMPs and neoangiogenesis.
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PMID:Gabexate mesilate inhibits colon cancer growth, invasion, and metastasis by reducing matrix metalloproteinases and angiogenesis. 1524 May 44

Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. The use of other methods (ELISA, Western blotting, and confocal microscopy) provided additional evidence that cannabinoids depressed the VEGF pathway by decreasing the production of VEGF and the activation of VEGF receptor (VEGFR)-2, the most prominent VEGF receptor, in cultured glioma cells and in mouse gliomas. Cannabinoid-induced inhibition of VEGF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis. These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid Delta9-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.
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PMID:Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. 1531 99

Interleukin-6 (IL-6) expression is strongly correlated with the degree of human glioma malignancy and necessary for tumor formation in a mouse model of spontaneous astrocytomas. Yet, exactly how IL-6 contributes to malignant progression of these brain tumors is still unclear. We have scrutinized the mechanism of transcriptional activation of vascular endothelial growth factor (VEGF) expression by IL-6 in the mouse brain and in glioblastoma cells. We demonstrate here that IL-6 drives transcriptional upregulation of VEGF in astrocytes in vivo using glial fibrillary acidic protein (GFAP)-IL-6/VEGF-green fluorescent protein (GFP) double transgenic mice. We further show that IL-6-induced VEGF transcription and VEGF secretion by human glioblastoma cells is dependent on signal transducer and activator of transcription 3 (STAT3). By progressive 5'-deletion analysis we defined the minimal VEGF promoter region for IL-6-responsiveness to nucleotides -88/-50. Surprisingly, this promoter region is rich in GC-boxes and does not contain STAT3 binding elements. Electrophoretic mobility shift and supershift assays revealed binding of Sp1 and Sp3 to the -88/-50 element upon IL-6 stimulation. Interestingly, preincubation with STAT3 antibody prevented the binding of Sp1 and Sp3 to the -88/-50 element, indicating that STAT3 is involved in IL-6-driven Sp1/Sp3 protein-DNA complex formation. Physical interaction of STAT3 and Sp1 was demonstrated by coimmunoprecipitation. The functional relevance of the STAT3/Sp1 association was corroborated by transient transfection experiments, which showed that overexpression of constitutively active STAT3 increased the minimal VEGF promoter activity. Taken together, our study suggests that IL-6 promotes tumor angiogenesis in gliomas and describes a novel transcriptional activation mechanism for STAT3 in the context of a STAT3 binding element (SBE)-free promoter.
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PMID:Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. 1568 1

We have previously proposed that intravascular thrombosis and subsequent vasoocclusion contribute to the development of pseudopalisading necrosis, a pathologic hallmark that distinguishes glioblastoma (WHO grade 4) from lower grade astrocytomas. To better understand the potential prothrombotic mechanisms underlying the formation of these structures that drive tumor angiogenesis, we investigated tissue factor (TF), a potent procoagulant protein known to be overexpressed in astrocytomas. We hypothesized that PTEN loss and tumor hypoxia, which characterize glioblastoma but not lower grade astrocytomas, could up-regulate TF expression and cause intravascular thrombotic occlusion. We examined the effect of PTEN restoration and hypoxia on TF expression and plasma coagulation using a human glioma cell line containing an inducible wt-PTEN cDNA. Cell exposure to hypoxia (1% O(2)) markedly increased TF expression, whereas restoration of wt-PTEN caused decreased cellular TF. The latter effect was at least partially dependent on PTEN's protein phosphatase activity. Hypoxic cells accelerated plasma clotting in tilt tube assays and this effect was prevented by both inhibitory antibodies to TF and plasma lacking factor VII, implicating TF-dependent mechanisms. To further examine the genetic events leading to TF up-regulation during progression of astrocytomas, we investigated its expression in a series of human astrocytes sequentially infected with E6/E7/human telomerase, Ras, and Akt. Cells transformed with Akt showed the greatest incremental increase in hypoxia-induced TF expression and secretion. Together, our results show that PTEN loss and hypoxia up-regulate TF expression and promote plasma clotting by glioma cells, suggesting that these mechanisms may underlie intravascular thrombosis and pseudopalisading necrosis in glioblastoma.
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PMID:PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. 1573 28

Hypoxia inducible factors (HIF) are transcription factors regulating expression of several genes related to oxygen homeostasis in response to hypoxic stress. Although HIF1-alpha and platelet derived growth factor-B (PDGF-B) are expressed in glioma tissue and closely related to tumor angiogenesis mediating vascular endothelial growth factor (VEGF) activity, their direct relationship has not yet been clarified. The aim of this study is to investigate whether HIF1-alpha regulates PDGF-B expression. The human glioblastoma cell lines, U87MG, U251MG, and A172, were exposed to 1-21% oxygen for 24 h. PDGF-B mRNA expression were quantitatively analyzed by real time RT-PCR, their intracellular protein levels were determined by computerized image analysis supported by flow cytometry to detect intracellular PDGF-B, and the concentration of secreted PDGF-B protein was assayed by ELIA. We also assayed following transfection of the cells with short interference RNA (siRNA) targeting HIF1-alpha mRNA. Relative PDGF-B mRNA and secretion of PDGF-B protein were significantly elevated at 1% oxygen. Following transfection of HIF1-alpha siRNA at 1% oxygen, PDGF-B expression was significantly suppressed at mRNA level. Our findings indicated that HIF1-alpha up-regulated expression of PDGF-B in human glioblastoma cells and showed the feasibility of siRNA technology in glioblastoma cell lines.
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PMID:Hypoxia inducible factor 1-alpha regulates of platelet derived growth factor-B in human glioblastoma cells. 1613 72


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