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)

Computed tomography (CT) findings in eleven patients with symptomatic cerebrospinal fluid (CSF) dissemination from cerebral glioblastoma were analyzed and, in seven cases subsequently autopsied, they were compared with histological observations. Each patient had multiple CT abnormalities including periventricular enhancement (5/11), subarachnoid enhancement (10/11) and progressive hydrocephalus (7/9) by cranial CT, and small filling defects with or without block (5/5) by CT myelography. The areas that showed periventricular or subarachnoid enhancement on CT were confirmed to have macroscopically detectable seeding at autopsy. On the other hand, microscopic deposits were more widely distributed than the enhancement suggested, and were hardly visualized on CT. In association with subarachnoid seeding, we found low-density lesions on CT which had resulted from ischemia or reinvasion of adjacent structures by disseminated glioblastoma and resulting parenchymal edema. By cranial CT, subarachnoid enhancement seems to be a very reliable sign of CSF seeding, whereas periventricular enhancement due to CSF metastases should be carefully distinguished from that due to periventricular tumor infiltration. CT myelography is capable of revealing minute metastatic spinal deposits and may be helpful for ruling out spinal seeding as well as its precise evaluation.
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PMID:Symptomatic cerebrospinal fluid dissemination of cerebral glioblastoma. Computed tomographic findings in 11 cases. 239 40

The creatine kinase isoenzymes play an important role in maintaining ATP levels in some cell types during times of high energy demand. We have previously shown in primary cell cultures from rat brain that glial cells express much higher levels of brain creatine kinase (CKB) mRNA than neurons. In a separate earlier study we observed that transcription of CKB mRNA in glial cells can be stimulated by a forskolin-mediated increase in cAMP via a pathway involving protein kinase A (PKA). In this report, we show that the level of CKB mRNA in human U87 glioblastoma cells can be increased by either prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), or cholera toxin (an activator of G alpha s proteins). The induction of CKB mRNA occurs rapidly (with maximal induction after 6 h), is at the level of transcription, and is mediated specifically through PKA. In addition, the results indicate that both PGE1 and PGE2 use the same or related signal transduction pathways to increase CKB transcription. These results suggest that in glial cells CKB mRNA can be regulated by extracellular signals acting through G-protein-coupled receptors. This study may contribute to an understanding of the mechanisms underlying the previously-reported, early postnatal increase in CKB enzyme activity in rat brain. The results are also discussed with regard to the potential involvement of the expression of prostaglandins and CKB during hypoxia and ischemia.
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PMID:Prostaglandin E1, E2, and cholera toxin increase transcription of the brain creatine kinase gene in human U87 glioblastoma cells. 892 40

CD95 (Fas/APO-1) and its ligand (CD95L) belong to a growing cytokine and cytokine receptor family that includes nerve growth factor (NGF) and tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low-grade to anaplastic astrocytoma and is most prominent in perinecrotic areas of glioblastoma. There is, however, no evidence that CD95 expression in malignant gliomas is triggered by hypoxia or ischemia. Agonistic antibodies to CD95, or the natural ligand, CD95L, induce apoptosis in human malignant glioma cells in vitro. Glioma cell sensitivity to CD95-mediated apoptosis is regulated by CD95 expression at the cell surface and by the levels of intracellular apoptosis-regulatory proteins, including bcl-2 family members. Several cytotoxic drugs synergize with CD95L to kill glioma cells. For as yet unknown reasons, glioma cells may co-express CD95 and CD95L in vitro without undergoing suicide or fratricide. Yet, they kill T cells via CD95/CD95L interactions and are sensitive to exogenously added CD95L. Since CD95L is expressed in gliomas in vivo, too, forced induction of CD95 expression might promote therapeutic apoptosis in these tumors. That glioma cells differ from nontransformed T cells in their sensitivity to CD95 antibodies or recombinant ligand, may allow the development of selective CD95 agonists with high antitumor activity that spare normal brain tissue. A family of death ligand/receptor pairs related to CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is beginning to emerge. Although several issues regarding glioma cell sensitivity to CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for the treatment of malignant glioma.
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PMID:CD95 ligand: lethal weapon against malignant glioma? 954 87

Glioblastomas may develop rapidly without clinical and histopathological evidence of a less malignant precursor lesion (de novo or primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas typically show overexpression of EGFR, but rarely p53 mutations, while secondary glioblastomas frequently carry a p53 mutation, but usually lack overexpression of EGFR, suggesting that these glioblastoma subtypes develop through distinct genetic pathways. In the present study, we assessed the expression of Fas/APO-1 (CD95), an apoptosis-mediating cell membrane protein, and its relation to necrosis phenotype in primary and secondary glioblastomas. Large areas of ischemic necroses were observed in all 18 primary glioblastomas, but were significantly less frequent in secondary glioblastomas (10 of 19, 53%; p = 0.0004). Fas expression was predominantly observed in glioma cells surrounding large areas of necrosis and was thus significantly more frequent in primary glioblastomas (18 of 18, 100%) than in secondary glioblastomas (4 of 19, 21%; p < 0.0001), suggesting that these clinically and genetically defined subtypes of glioblastoma differ in the extent and mechanism of necrogenesis. Necrosis and microvascular proliferation are histologic hallmarks of the glioblastoma. Following incubation of glioblastoma cell lines under hypoxic/anoxic conditions for 24-48 hours, Fas mRNA levels remained unchanged, whereas VEGF expression was markedly upregulated. This suggests that in contrast to VEGF Fas expression is not induced by ischemia/hypoxia. Analysis of Fas mRNA levels in a glioblastoma cell line containing a p53 mutation and an inducible wild-type p53 gene showed little difference under induced and noninduced conditions, suggesting that in glioblastomas, Fas expression is not directly linked to the p53 status.
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PMID:Necrogenesis and Fas/APO-1 (CD95) expression in primary (de novo) and secondary glioblastomas. 960 Feb 16

Brain angiogenesis is a tightly controlled process that is regulated by neuroectodermal derived growth factors that bind to tyrosine kinase receptors expressed on endothelial cells. In the rat brain, angiogenesis is complete around postnatal day 20, but endothelial cells can proliferate in the adult brain under pathological conditions such as hypoxia/ischemia and brain tumor growth. Current evidence suggests that physiological angiogenesis in the brain is regulated by similar mechanisms as pathological angiogenesis induced by tumors or by hypoxia/ischemia. The hypoxia-inducible endothelial cell mitogen and vascular permeability factor, vascular endothelial growth factor (VEGF) appears to play a pivotal role in most of these processes. VEGF is expressed when angiogenesis is high, as in embryonic neuroectoderm, in glioblastomas and around infarcts, but is expressed at low levels when angiogenesis is absent, as in adult neuroectoderm. Since growth factors such as VEGF and angiopoietins and their receptors appear to be necessary for angiogenesis, targeting of growth factor/receptor pathways for angiogenesis-dependent diseases such as glioblastoma might be useful for therapy. Several compounds, including anti-VEGF antibodies and VEGFR-2 inhibitors are currently in clinical trial. On the other hand, induction of angiogenesis by growth factors (pro-angiogenesis) might prove to be a rational therapy for patients with stroke.
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PMID:Mechanisms of angiogenesis in the brain. 1021 26

Adrenomedullin is a potent vasodilator peptide originally isolated from pheochromocytoma. Adrenomedullin is produced by various types of cells including neurons and astrocytes. To explore possible pathophysiological roles of adrenomedullin in hypoxic brain, we studied the effects of hypoxia on the expression of adrenomedullin in T98G human glioblastoma cells by radioimmunoassay and northern blot analysis. Expression levels of adrenomedullin mRNA and immunoreactive adrenomedullin levels in the culture medium were increased by hypoxia about six- and about threefold, respectively. Treatment with cobalt chloride increased expression levels of adrenomedullin mRNA about threefold and immunoreactive adrenomedullin levels in the culture medium about threefold in T98G cells. Using actinomycin D, we showed that hypoxia did not cause the stabilization of the adrenomedullin mRNA, suggesting that the increased adrenomedullin mRNA levels in response to hypoxia are caused mainly by increased transcription. Treatment with cycloheximide caused increases in adrenomedullin mRNA levels in both normoxic and hypoxic states, raising the possibility that some protein(s) may act as a suppressor of adrenomedullin gene expression in T98G cells. These findings indicate that adrenomedullin is highly induced during hypoxia in T98G glioblastoma cells and suggest that increased expression of adrenomedullin during hypoxia may be important in the defense against hypoxia or ischemia in the brain.
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PMID:Induction of adrenomedullin during hypoxia in cultured human glioblastoma cells. 1103 71

Immunohistochemistry for haptoglobin (Hp) in the postischemic hippocampus demonstrated an immunoreactivity visible one day after reperfusion and continuing to increase until 14 days after ischemia. The immunoreactivity was most prominent in CA1 and the dentate hilar region, especially in cells with astroglial morphology. Double immunofluorescence histochemistry confirmed colocalization of the Hp and glial fibrillary acidic protein. Furthermore, a reverse transcription-polymerase chain reaction study confirmed an elevated Hp mRNA level in the postischemic hippocampus. The Hp gene expression was also upregulated in C6 and A-172 glioblastoma cell lines after H O treatment. These findings suggest that Hp is synthesized in reactive astrocytes in response to ischemia-reperfusion injury.
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PMID:Upregulation of haptoglobin in reactive astrocytes after transient forebrain ischemia in rats. 1236 55

Nitric oxide (NO) is a chemical messenger implicated in neuronal damage associated with ischemia neurodegenerative disease and excitotoxicity. In the present study, we examined the biological effects of NO and its mechanisms in human malignant glioblastoma cells. Addition of a NO donor, S-nitroso-N-acetyl-penicillamine (SNAP), induced apoptosis in U87MG human glioblastoma cells, accompanied by opening mitochondrial permeability transition pores, release of cytochrome c and AIF, and subsequently by caspase activation. NO-induced apoptosis occurred concurrently with significantly increased levels of the Bak and Bim. Treatment with SNAP resulted in sustained activation of JNK and its downstream pathway, c-Jun/AP-1. The expression of dominant-negative (DN)-JNK1 and DN-c-Jun suppressed the activation of AP-1, the induction of Bak and Bim, and the SNAP-induced apoptosis. In addition, de novo protein synthesis was required for the initiation of apoptosis in that the protein synthesis inhibitor, cycloheximide (CHX), inhibited NO-induced apoptotic cell death as well as up-regulation of Bak and Bim. These results suggest that NO activates an apoptotic cascade, involving sustained JNK activation, AP-1 DNA binding activity, and subsequent Bak and Bim induction, followed by cytochrome c and AIF releases and caspases cascade activation, resulting in human malignant brain tumor cell death.
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PMID:Up-regulation of Bak and Bim via JNK downstream pathway in the response to nitric oxide in human glioblastoma cells. 1615 21

IL-20, an IL-10 family member, is involved in various inflammatory diseases, such as psoriasis, rheumatoid arthritis, and atherosclerosis. We investigated whether hypoxia in vitro and an in vivo model of ischemic stroke would up-regulate IL-20 expression. In vitro, IL-20 expression increased in hypoxic HaCaT, HEK293 cells, chondrocytes, monocytes, and glioblastoma cells. Inhibition of hypoxia-inducible factor 1alpha inhibited CoCl(2)-induced IL-20 expression. We identified two putative hypoxia response elements in the human il20 gene promoter. Promoter activity assays showed that CoCl(2) mimicked hypoxia-activated luciferase reporter gene expression. In vivo, experimental ischemic stroke up-regulated IL-20 in the sera and brain tissue of rats. IL-20 stained positively in glia-like cells in peri-infarcted lesions, but not in contralateral tissue. Administration of IL-20 mAb ameliorated ischemia-induced brain infarction of rats after experimental ischemic stroke. In vitro, RT-PCR analysis showed that glioblastoma cells, GBM8901, expressed IL-20 and its receptor subunits IL-20R1, IL-20R2, and IL-22R1. IL-20 induced cell proliferation in GBM8901 cells by activating the JAK2/STAT3 and ERK1/2 pathways. IL-20 also induced production of IL-1beta, IL-8, and MCP-1 in GBM8901 cells. We conclude that IL-20 was responsive to hypoxia in vitro and in the ischemic stroke model and that up-regulation of IL-20 in the ischemic brain may contribute to brain injury.
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PMID:IL-20 is regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke. 1934 80

The effect of hypoxia on glioma growth including pathological changes was investigated in an experimental model of brain ischemia in the rat C6 glioma model. C6 glioma cells were inoculated into the subcortex of adult Wistar rats. Focal cerebral ischemia near the implanted glioma area was induced by permanent middle cerebral artery occlusion (PMCAO). Ten days later, the rats were sacrificed to compare tumor volume of C6 glioma without PMCAO (control group) versus C6 glioma with PMCAO (hypoxia group). The histological features were also observed. The mean tumor volume in the hypoxia group was significantly larger than that in the control group. The most prominent histological finding in the hypoxia group was abundant formation of pseudopalisading around the necrotic areas. Immunohistological examinations showed intensive staining for vascular endothelial growth factor and hypoxia-inducible factor in these pseudopalisading cells. These findings suggest that cerebral ischemia positively modulates glioma mass growth by the formation of pseudopalisading necrosis, a characteristic histological finding of glioblastoma.
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PMID:Cerebral ischemia promotes rich pseudopalisading necrosis in the rat c6 glioblastoma model. 1963


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