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)

Photodynamic therapy (PDT) is an innovative strategy for the treatment of solid neoplasms of the brain. Aside from inducing cell death in tumor cells, PDT induces endothelial cell death and promotes formation of blood clots; however, exact mechanisms that trigger these phenomena remain largely unknown. We now used Western blotting to analyze secretion of regulators of angiogenesis to the supernatants of one glioma, one macrophage, and one endothelial cell line following Hypocrellin-A and -B photodynamic therapy. We observed induction of proangiogenic VEGF (vascular endothelial growth factor) and of antiangiogenic sFlt-1, angiostatin, p43, allograft inflammatory factor-1, and connective tissue growth factor. Release of thrombospondin-1 was diminished in a glioma cell line supernatant. Endostatin release was induced in glioma cells and reduced in macrophages and endothelial cells. These data show that a wide range of antiangiogenic factors are secreted by brain tumor cells following Hypocrellin photochemotherapy. However, VEGF release is also induced thus suggesting both favorable and deleterious effects on tumor outgrowth.
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PMID:Release of regulators of angiogenesis following Hypocrellin-A and -B photodynamic therapy of human brain tumor cells. 1240 83

Brain angiogenesis inhibitors (BAI) are putative transmembrane proteins containing an extracellular domain with thrombospondin type-1 repeats which can exhibit anti-angiogenic activity. BAI1 mRNA is expressed mainly in the brain, while BAI2 and BAI3 mRNAs are more widely expressed. We hypothesized that the BAI family might have anti-tumoral properties and studied the expression of BAI1 protein in normal human brain and in glioblastoma multiforme. We generated an anti-BAI1 antibody and showed that BAI1 was widely expressed in normal brain but was absent in 28 glioma cell lines and in the majority of human glioblastoma investigated. BAI1 expression did not correlate with TP53 status and we did not confirm previous findings that p53 regulates BAI1 mRNA expression in glioma cells. The finding that expression of BAI proteins may be lost during tumor formation is of special interest as restoration of their function in tumors may be of therapeutic benefit.
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PMID:Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. 1250 86

Malignant gliomas are distinguished from low-grade gliomas by their intense angiogenesis. In gliomas, p53 is the most frequently altered gene and is involved in the early phase of glioma development. In contrast, homozygous p16 gene deletion is more common in high-grade gliomas. In order to understand the mechanism by which gliomas become more angiogenic during the malignant transformation, we examined the relationship between thrombospondin-1, a negative regulator in angiogenesis, and these tumor suppressor genes in malignant gliomas. Human glioma cell line U-251 MG, which has mutated p53 and deleted p16, was transduced with recombinant replication-defective adenovirus vectors containing the cDNA of wild-type p53, p16, and p21. Only the induction of wild-type p53 enhanced expression of thrombospondin-1 mRNA and the protein in U-251 MG cells. Furthermore, thrombospondin-1 that was secreted in the culture medium was significantly increased (3.8-fold) as compared with that of the viral control 36 h after infection with Ad5CMV-p53. In the presence of wild-type p53 plasmid DNA, the promoter activity was increased 7.4-fold as compared with an empty expression vector control. These studies may suggest that mutation of p53 gene endows gliomas with an angiogenic phenotype by reducing thrombospondin-1 production as well as enhancing the angiogenesis inducers in the early phase of malignant progression.
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PMID:Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells. 1260 16

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis and an inducer of neural differentiation. We previously reported the loss of PEDF expression in glioma progression. In this study, we investigated whether PEDF overexpression could suppress glioma growth and invasion. Glioma cell line U251 was stably transfected with a full-length human PEDF expression vector. The expression and release of various cytokines and angiogenic factors into the medium were analyzed by real-time reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and gelatin zymography. Apoptosis was checked by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Growth inhibition was evaluated by using the in vitro Matrigel invasion. Tumorigenicity was examined in vivo by subcutaneous xenotransplantation into severe combined immunodeficient mice. In U251 cells overexpressing PEDF, thrombospondin-1 protein was upregulated (5.3-fold more), but the production of vascular endothelial growth factor (VEGF) (1.8-fold less) and basic fibroblast growth factor (2.5-fold less) was lower than in cells transfected with the vector only. PEDF also downregulated the production of matrix metalloproteinase-9. Conditioned medium collected from the PEDF-transfected U251 cells showed a significant reduction of VEGF expression. In vitro invasiveness was reduced by approximately 40%. PEDF expression prevented the growth of transfected cells and caused a significant increase in the percentage of cells undergoing apoptosis (50.4% in PEDF-transfected cells). Furthermore, the size of xenotransplants was significantly smaller. In conclusion, PEDF overexpression decreased malignancy, and this might be attributed to the promotion of apoptosis and the regulation of expression of angiogenic effectors. Thus, treatment with PEDF may be useful in patients with malignant gliomas. However, the mechanism of apoptosis induction needs to be investigated.
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PMID:Inhibition of glioma invasion by overexpression of pigment epithelium-derived factor. 1504 58

Malignant glioma cells secrete thrombospondin-1 (TSP-1) which participates in the motility of glioma cells, and binds to cell surface alphavbeta3 and alpha3beta1 integrins, and syndecan-1. This study evaluated the amount of TSP-1 secretion from malignant glioma cells, and the expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1. The amounts of TSP-1 in the supernatants from 10 malignant glioma cell lines and eight non-glioma malignant tumor cell lines were measured by enzyme-linked immunosorbent assay. Expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1 were examined by flow cytometry. The amounts of TSP-1 secreted by malignant glioma cells were 43 to 2431 ng/l x 10(6) cells/24 h (mean +/- SD = 626 +/- 792). Seven of 10 glioma cell lines secreted more than 100 ng of TSP-1 and three of these cell lines secreted more than 1 microg. Seven of eight non-glioma cell lines secreted less than 100 ng of TSP-1. All glioma cell lines expressed alpha3beta1 integrin and syndecan-1, and seven of 10 glioma cell lines expressed alphavbeta3 integrin. Treatment of the glioma cell lines with TGF-beta2 did not change the expression of alphavbeta3 integrin. These results suggest that malignant glioma cells secrete high levels of TSP-1, which may be important in the migration of glioma cells via interactions with alphavbeta3 and alpha3beta1 integrins, and syndecan-1.
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PMID:Quantification of thrombospondin-1 secretion and expression of alphavbeta3 and alpha3beta1 integrins and syndecan-1 as cell-surface receptors for thrombospondin-1 in malignant glioma cells. 1566 72

Angiogenesis is crucial to the growth of malignant gliomas. Therefore, antiangiogenic therapy represents a new, promising therapeutic modality for malignant gliomas. This study was designed to define the malignant glioma cases most suitable for antiangiogenic therapy in humans and to demonstrate the efficacy of antiangiogenic therapy in animals. Protein expression of the most potent angiogenic factor, vascular endothelial growth factor (VEGF), and its specific natural inhibitor, soluble Flt-1, as well as vessel architecture, including vessel density, area, and diameter, was evaluated in human malignant glioma samples (24 glioblastomas, 13 anaplastic astrocytomas). Among these, VEGF >1000ng/ml, VEGF/soluble Fltl ratio >1, vessel density >30, and vessel area >7% were prognostic factors for malignant gliomas. Based on these results, we performed three different antiangiogenic experiments targeted to inhibit VEGF expression in a human malignant glioma (U87) mouse model: anti-VEGF neutralized antibody intraperitoneal injection; interferon-beta intramusclar injection; and transfection of an endogenous nonspecific angiogenesis inhibitor, thrombospondin-1, into glioma cells caused inhibition of VEGF secretion and/or mRNA expression and resulted in glioma growth inhibition of 70%, 84%, and 50%, respectively, compared with control. We conclude that malignant gliomas with high degrees of VEGF expression and vessel areas are good candidates for antiangiogenic therapy, especially that designed to inhibit VEGF expression.
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PMID:Angiogenesis and antiangiogenic therapy for malignant gliomas. 1809 5

Human cytomegalovirus (HCMV) is a member of the beta-herpesvirus family, which has tropism for glial cells. It was recently reported that HCMV might play important roles in the pathogenesis of malignant glioma. In this study, we investigated the effects of the HCMV IE1 protein on the gene expression profile in the human glioblastoma cell line, U373MG by employing cDNA microarray technology. Using DNA chips containing approximately 1,000 human cDNAs, RNA samples from U373MG cells stably expressing IE1 were compared with those from the control cells lacking IE1 cDNA. Fluorescence intensities of 13 genes were significantly decreased in IE1-expressing cells, while one gene was found to be upregulated. Among these 14 genes, we chose to work further on glial fibrillary acidic protein (GFAP), thrombospondin-1 (TSP-1), and p53, because of their previously known involvement in tumorigenesis. The mRNA levels of all these genes were found to be decreased in IE1-expressing glioblastoma cells by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) as well as Northern blot analysis. The decreased expression of these genes was also observed at protein levels as measured by immunocytochemistry or fluorescence-activated cell sorting (FACS) analysis. Our data strongly suggested that HCMV IE1 could modulate the expression of cellular genes that might play important roles in the pathogenesis of glial tumors.
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PMID:Downregulation of GFAP, TSP-1, and p53 in human glioblastoma cell line, U373MG, by IE1 protein from human cytomegalovirus. 1577 89

Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm(3). This observation, along with the accessibility of tumor vessels to therapeutic targeting, has resulted in a research focus on inhibitors of angiogenesis. A number of endogenous inhibitors of angiogenesis are found in the body. Some of these are synthesized by specific cells in different organs, and others are created by extracellular proteolytic cleavage of plasma-derived or extracellular matrix-localized proteins. In this review, we focus on angiostatin, endostatin, PEX, pigment epithelial-derived factor, and thrombospondin (TSP)-1 and -2, either because these molecules are expressed in malignant glioma biopsies or because animal studies in malignant glioma models have suggested that their therapeutic administration could be efficacious. We review the known mechanisms of action, potential receptors, expression in glioma biopsy samples, and studies testing their potential therapeutic efficacy in animal models of malignant glioma. Two conclusions can be made regarding the mechanisms of action of these inhibitors: (1) Several of these inhibitors appear to mediate their antiangiogenic effect through multiple protein-protein interactions that inhibit the function of proangiogenic molecules rather than through a specific receptor-mediated signaling event, and (2) TSP-1 and TSP-2 appear to mediate their antiangiogenic effect, at least in part, through a specific receptor, CD36, which initiates the antiangiogenic signal. Although not proven in gliomas, evidence suggests that expression of specific endogenous inhibitors of angiogenesis in certain organs may be part of a host antitumor response. The studies reviewed here suggest that new antiangiogenic therapies for malignant gliomas offer exciting promise as nontoxic, growth-inhibitory agents.
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PMID:Endogenous inhibitors of angiogenesis in malignant gliomas: nature's antiangiogenic therapy. 1583 Dec 30

Invasion of tumor cells into the surrounding normal brain tissues is a prominent feature of malignant gliomas. Malignant glioma cells secrete thrombospondin-1 which participates in the motility of glioma cells and binds cell surface heparan sulfate proteoglycan. To clarify the invasion mechanism of tumor cells, expression of the syndecans (syndecan-1, -2, -3, and -4), a major cell surface heparan sulfate proteoglycan family, was analyzed in malignant gliomas. Involvement of nuclear factor-kappaB (NF-kappaB) on syndecan-1 expression was also investigated. Using reverse transcription-PCR, the authors analyzed the expression of syndecan-1, -2, -3, and -4 in 10 malignant glioma cell lines, 2 glioblastoma specimens, and 2 normal brain specimens. All malignant glioma cell lines and glioblastoma specimens expressed all types of syndecan mRNA, except in one glioma cell line that lacked syndecan-3 expression. On the other hand, normal brain specimens expressed syndecan-2, -3, and -4 mRNA, but did not syndecan-1 mRNA. Syndecan-1 protein was localized in the cell surface of all malignant glioma cell lines by flow cytometry. Various levels of active nuclear factor-kappa B (NF-kappaB) was detected in all malignant glioma cell lines using immunoblotting. The expression of active NF-kappaB and syndecan-1 increased in U251 glioma cells after tumor necrosis factor-alpha or interleukin-1beta treatment, which can activate NF-kappaB. The amplification of active NF-kappaB and syndecan-1 by tumor necrosis factor-alpha or interleukin-1beta was suppressed by an inhibitor of NF-kappaB activation (emodin). Emodin also downregulated the expression of syndecan-1 mRNA in U251 cells. These results indicate that malignant glioma cells express all types of syndecans and suggest that NF-kappaB participates in the upregulation of the syndecan-1 expression at the transcriptional level, and increased expression of syndecan-1 could associate with extracellular matrices including thrombospondin-1.
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PMID:Expression of syndecans, a heparan sulfate proteoglycan, in malignant gliomas: participation of nuclear factor-kappaB in upregulation of syndecan-1 expression. 1613 27

Selective cleavage of the Glu395-Ser396 bond of brevican, one of the major proteoglycans in adult brain tissues, is thought to be important for glioma cell invasion. Our previous biochemical study demonstrated that ADAMTS-4, a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, has such an activity. In the present study, we examined brevican-degrading activities of ADAMTS-1, -4 and -5 at the cellular level, and their expression and localization in human glioma tissues. In 293T transfectants expressing ADAMTS-4 or ADAMTS-5, brevican was cleaved into two major fragments in an identical pattern, but no such degradation was observed with ADAMTS-1 transfectants. When the expression levels of these ADAMTS species were examined by real-time quantitative PCR, only ADAMTS-5 was found to be overexpressed in glioblastoma tissues compared to control normal brain tissues (P <0.05). In situ hybridization and immunohistochemistry demonstrated that ADAMTS-5 is expressed predominantly in glioblastoma cells. Forced expression of ADAMTS-5 in glioma cell lines stimulated cell invasion. These results demonstrate for the first time that ADAMTS-5 is capable of degrading brevican and is overexpressed in glioblastoma cells, and suggest that ADAMTS-5 may play a role in glioma cell invasion through the cleavage of brevican.
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PMID:Human glioblastomas overexpress ADAMTS-5 that degrades brevican. 1613 47


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