UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis induced by rat glioma cells was examined in vitro using a double chamber co-culture system. Cultured microvascular endothelial cells from Fisher 344 rat brain, rat C6 glioma cells and rat T9 gliosarcoma cells were used for this study. Endothelial cells, cultured on type I collagen, formed capillary-like structures. In the co-culture system, C6 glioma cells promoted this formation. On the other hand T9 gliosarcoma cells had no effect on it. The supernatants of C6 glioma cells and T9 gliosarcoma cells suppressed the proliferation of the endothelial cells. C6 glioma cells probably produce and release soluble factors promoting angiogenesis. The proliferation of endothelial cells is thus suppressed while angiogenesis is made more intense. This in-vitro model is useful to elucidate the mechanism of tumor angiogenesis and to evaluate the promoting and inhibiting factors of angiogenesis.
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PMID:[Angiogenesis induced by rat glioma cells in vitro]. 128 Mar 47

Malignant gliomas are difficult to treat systemically because of exclusion of many chemotherapeutic agents by the blood brain barrier. Furthermore, as opposed to other neoplasms, malignant gliomas recur locally, at the site of original presentation. These tumors are remarkably vascular and hence may be more dependent on angiogenesis for continued growth than other tumors. The inhibition of tumor angiogenesis can control tumor growth by preventing the exponential vascular growth phase. We report the inhibition of the growth of the 9L glioma by the localized, controlled release of known angiogenesis inhibitors administered in a biodegradable polyanhydride polymer matrix. In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction, respectively, in the growth of the 9L glioma. We compared these results to the inhibition of tumor neovascularization in the rabbit cornea by the localized delivery of the same agents. In the rabbit cornea model, the local release of heparin and cortisone and of cortisone alone resulted in a 2.5- and 2.0-fold reduction, respectively, in the angiogenesis response evoked by the VX2 carcinoma. This study introduces two new potential therapeutic modalities for the treatment of malignant gliomas: the use of the combination of heparin and cortisone as antineoplastic agents and the use of polymeric carriers for the local delivery of such agents in the central nervous system.
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PMID:Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate. 170 49

We have previously suggested that tumor angiogenesis in human gliomas is regulated by a paracrine mechanism involving vascular endothelial growth factor (VEGF) and flt-1 (VEGF-receptor 1). VEGF, an endothelial-cell-specific mitogen, is abundantly expressed in glioma cells which reside along necrotic areas, whereas flt-1, a tyrosine-kinase receptor for VEGF, is expressed in tumor endothelial cells, but not in endothelial cells in normal adult brain. Recently, a second tyrosine-kinase receptor which binds VEGF with high affinity, designated KDR or flk-1, has been described. We performed in situ hybridization for VEGF mRNA, flt-1 mRNA and KDR mRNA on serial sections of normal brain, low-grade and high-grade glioma specimens. We show that KDR mRNA is co-expressed with flt-1 in vascular cells in glioblastoma but not in low-grade glioma. Since flt-1 and KDR are not expressed in endothelial cells in the normal adult brain, the coordinate up-regulation of 2 receptors for VEGF appears to be a critical event which controls tumor angiogenesis. Immunocytochemistry with a monoclonal anti-VEGF antibody revealed significant amounts of VEGF protein in the same glioma cells that expressed VEGF mRNA. The largest amount of VEGF immunoreactivity, however, was detected on the vasculature of glioblastomas, the site where VEGF exerts its biological functions. These findings suggest that VEGF is produced and secreted by glioma cells and acts on tumor endothelial cells which express VEGF receptors. To further characterize VEGF-producer cells in vivo, we investigated cellular proliferation, immunoreactivity to the p53 tumor-suppressor gene product and epidermal-growth-factor-receptor (EGFR) expression on serial sections by immunocytochemistry. VEGF-producer cells did not show increased cellular proliferation, p53 immunoreactivity or EGFR immunoreactivity as compared with glioma cells which did not express VEGF. Our studies therefore do not demonstrate evidence for a growth advantage of VEGF-producer cells in vivo or VEGF induction by p53 mutation or EGFR over-expression.
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PMID:Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. 752 92

Perfusion insufficiency, and the resultant hypoxia, often induces a compensatory neovascularization to satisfy the needs of the tissue. We have used multicellular tumor spheroids, simulating avascular microenvironments within a clonal population of glioma tumor cells, in conjunction with in situ analysis of gene expression, to study stress inducibility of candidate angiogenic factors. We show that expression of vascular endothelial growth factor (VEGF) is upregulated in chronically hypoxic niches (inner layers) of the spheroid and that expression is reversed when hypoxia is relieved by hyperoxygenation. Acute glucose deprivation--another consequence of vascular insufficiency--also activates VEGF expression. Notably, glioma cells in two distinct regions of the spheroid upregulated VEGF expression in response to hypoxia and to glucose starvation. Experiments carried out in cell monolayers established that VEGF is independently induced by these two deficiencies. Upon implantation in nude mice, spheroids were efficiently neovascularized. Concomitant with invasion of blood vessels and restoration of normoxia to the spheroid core, VEGF expression was gradually downregulated to a constitutive low level of expression, representing the output of nonstressed glioma cells. These findings show that stress-induced VEGF activity may compound angiogenic activities generated through the tumor "angiogenic switch" and suggest that stress-induced VEGF should be taken into account in any attempt to target tumor angiogenesis.
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PMID:Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. 753 42

Vascular endothelial growth factor (VEGF) is an endothelial specific angiogenic mitogen secreted from various cell types including tumor cells. Increasing evidence suggests that VEGF is a major regulator of physiological and pathological angiogenesis, and the VEGF/VEGF receptor system has been shown to be necessary for glioma angiogenesis. Hypoxia seems to play a critical role in the induction of VEGF expression during glioma progression. C6 glioma cells provide an in vivo glioma model for the study of tumor angiogenesis, and the expression of VEGF in C6 cells has been shown to be up-regulated by hypoxia in vitro. However, little is known about the molecular mechanism of hypoxic induction of VEGF. Here, we demonstrate that hypoxic induction of VEGF in C6 cells is due to both transcriptional activation and increased stability of mRNA. Nuclear run-on assays revealed a fast and lasting transcriptional activation, whereas the determination of mRNA half-life showed a slower increase of mRNA stability during hypoxia. Reporter gene studies revealed that hypoxia responsive transcription-activating elements were present in the 5'-flanking region of the VEGF gene. These results suggested that several distinct molecular mechanisms were involved in hypoxia-induced gene expression and were activated in a biphasic manner.
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PMID:Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. 754 46

Intracranial tumor classification is paralleled by a grading system that empirically compares tumor entities with "progression stages" of supratentorial gliomas of the adult. This grading system is an integral part of the WHO classification. Glioma progression has originally been defined by descriptive morphology. In this respect, morphological key features of high-grade gliomas (WHO grades III and IV) are microvascular proliferation and the formation of tumor necroses. Glioma progression is now more accurately defined on the molecular genetic level by a stepwise accumulation of oncogene activation and/or tumor suppressor gene inactivation. Angiogenesis occurs during development and progression of glial tumors. Pathological vessels are a hallmark of malignant glioma and it has therefore been suggested that malignant glioma cells are able to induce neovascularization. Despite the exuberant neovascularisation, however, vascular supply may not be sufficient for tumor areas with high cell proliferation, and necroses may develop. Malignant transformation of blood vessel itself is a rare event but may be the underlying mechanism of gliosarcoma development. The recently purified vascular endothelial growth factor (VEGF) is at present the only mitogen known to selectively act on endothelial cells. Growing evidence suggests that VEGF is the key regulator of developmental and pathological angiogenesis. In vivo, VEGF mRNA is upregulated in a subpopulation of malignant glioma cells adjacent to necroses. Since VEGF is hypoxia-inducible, hypoxia may be an important regulator of VEGF mRNA expression and tumor angiogenesis in vivo. Two tyrosine kinase receptors for VEGF are expressed in vessels which invade the tumor, suggesting that tumor angiogenesis is regulated by a paracrine mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular morphology and angiogenesis in glial tumors. 758 Jan 12

Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca2+ ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca2+]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGF-mediated [Ca2+]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.
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PMID:Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. 768 Feb 47

We have developed two different models of tumor angiogenesis by human brain tumors: one being tube formation by bovine aortic endothelial (BAE) cells cocultured with tumor cells in vitro, and other being in vivo angiogenesis in mice when tumor cells are transplanted into the dorsal sac. We investigated whether tube formation could be induced in BAE cells in type I collagen gel when these cells were cocultured with seven human glioma cell lines. Four of the seven glioma cell lines, which had high levels of basic fibroblast growth factor (bFGF) mRNA, induced tube formation by BAE cells. The tube formation was blocked by coadministration of anti-bFGF antibody. In in vivo model system of tumor angiogenesis in mice, these four cell lines were highly angiogenic. In contrast, with the other three glioma cell lines, which had poor expression of bFGF, BAE cells showed no apparent tube formation. These three cell lines did not efficiently develop capillary networks in mice. The results demonstrated a correlative relationship in the tubulogenesis of BAE cells, bFGF mRNA levels and angiogenesis in mice. The present study with two model systems of tumor angiogenesis suggests that the angiogenesis of some human glioma cell lines is mediated by bFGF, possibly via paracrine control.
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PMID:Induction of vascular endothelial tubular morphogenesis by human glioma cells. A model system for tumor angiogenesis. 768 24

We have recently shown that vascular endothelial growth factor (VEGF) is produced by human malignant glioma cells and acts on tumor endothelial cells, which express VEGF receptors, suggesting that VEGF is a regulator of tumor angiogenesis. To investigate the feasibility of antiangiogenic brain tumor therapy, we developed an intracerebral (i.c.) rat glioma model. We used two transplantable rat glioma cells lines, C6 and GS-9L, to analyze VEGF regulation in vitro and expression of VEGF and its high affinity tyrosine kinase receptors, flt-1 and flk-1, in vivo. Glioma cells were transplanted i.c. or s.c. into syngeneic rats. C6 gliomas exhibit morphological characteristics of human glioblastoma multiforme such as necroses with palisading cells. Immunocytochemistry with von Willebrand factor showed that C6 gliomas are highly vascularized and therefore show another prominent feature of human glioblastoma. GS-9L gliosarcomas were less vascularized. In situ hybridization showed that VEGF is expressed in vivo in rat glioma cells which reside along necrotic areas and therefore closely mimicks the expression pattern of VEGF observed in human glioblastoma. flt-1 and flk-1 are specifically expressed in endothelial cells in the tumor and at the border between tumor and normal brain but are absent from endothelial cells in the normal brain proper. The action of VEGF may therefore be restricted to tumor endothelium. Upregulation of VEGF, but not acid fibroblast growth factor, basic fibroblast growth factor, and platelet-derived growth factor B messenger RNA was observed in hypoxic C6 and GS-9L cells in vitro. These observations are consistent with a role for VEGF in tumor- and hypoxia-induced angiogenesis. Since the expression pattern of VEGF and its receptors in rat glioma appears to be indistinguishable from human glioblastoma multiforme, this model provides an excellent tool to study anti-angiogenic therapy.
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PMID:Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. 769 95

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell-specific mitogen that is structurally related to platelet-derived growth factor (PDGF). Vascular endothelial growth factor/vascular permeability factor induces angiogenesis in vivo and may play a critical role in tumor angiogenesis. Using immunohistochemical analysis, the authors demonstrated the presence of VEGF/VPF protein in surgical specimens of glioblastoma multiforme and cultured glioma cells. By means of an enzyme-linked immunosorbent assay (ELISA) of cell supernatants, the authors showed that VEGF/VPF is variably secreted by all nine cultured human malignant glioma cell lines (CH-235MG, D-37MG, D-54MG, D-65MG, U-87MG, U-105MG, U-138MG, U-251MG, U-373MG) and by a single meningioma cell line (CH-157MN). An immunocytochemical survey of these cell lines revealed a cytoplasmic and cell-surface distribution of VEGF/VPF. In the U-105MG glioma cell line, VEGF/VPF secretion was induced with physiological concentrations of epidermal growth factor, PDGF-BB, or basic fibroblast growth factor, but not with PDGF-AA. Moreover, it was observed that activation of convergent growth factor signaling pathways led to increased glioma VEGF secretion. Similar results were obtained using these growth factor combinations in the D-54MG glioma cell line. The data obtained suggest a potential role for VEGF/VPF in tumor hypervascularity and peritumoral edema. These observations may lead to development of new therapeutic strategies.
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PMID:Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. 771 13

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