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)

Recently, TRAIL has been demonstrated to selectively induce apoptosis in transformed cell lines, and subsequently four receptors (TRAIL-R1-TRAIL-R4) have been identified. The ability to transduce death signals is restricted to TRAIL-R1/TRAIL-R2. In contrast, TRAIL-R3/TRAIL-R4 are unable to activate apoptotic pathways and have therefore been suggested to act as "decoys" protecting normal tissues from cell death. However, the biological role of the TRAIL system remains incompletely understood. We analyzed the expression of TRAIL and its receptors in a panel of human brain tumors (n = 34) and in four glioma cell lines in comparison to normal brain tissue. Constant co-expression of TRAIL and of receptors TRAIL-R1, TRAIL-R2, and TRAIL-R3 in different tumor entities as well as in normal brain indicates that additional mechanisms might modulate the previously proposed "decoy" model. Furthermore, in contrast to previous reports, we demonstrate TRAIL and TRAIL-R2 to be present on a transcriptional level in normal brain tissue. Exceptional expression of TRAIL-R4 transcripts does not suggest a significant regulatory role of this receptor in the human brain and its tumors.
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PMID:Expression of TRAIL and its receptors in human brain tumors. 1019 34

Glioblastoma multiforme is a lethal neoplasm refractory to radiochemotherapy. Although glioma cells undergo apoptosis when exposed to the death ligand, CD95 (Fas/APO-1) ligand, the therapeutic use of CD95L is considered impossible because of lethal side effects. Here, we report that the locoregional application of Apo2 ligand (Apo2L) exerts strong antitumor activity on preestablished intracranially growing human U87MG glioma xenografts in athymic mice. Two repetitive intratumoral injections of 2 microg Apo2L resulted in long-term survival of mice (>100 days), whereas the median survival of mock-treated mice was 36 days. The assessment of tumor volumes at 21 and 35 days after inoculation showed complete eradication of glioma xenografts in Apo2L-treated mice. Histology and TUNEL assay confirmed the induction of apoptosis by Apo2L in glioma cells in vivo. Importantly, the intracerebral injection of Apo2L does not result in acute or delayed neurotoxicity. We propose that a phase 1 trial of intralesional Apo2L therapy for human glioblastoma multiforme is warranted.
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PMID:Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. 1055 93

APO2 ligand (APO2L)/TRAIL is a novel member of the tumor necrosis factor cytokine family and a potent inducer of apoptosis in tumor cell lines. We recently reported that APO2L is consistently expressed in low-grade astrocytomas, anaplastic astrocytomas, glioblastomas, and cell lines derived thereof, and that malignant glioma cell lines are susceptible to APO2L-induced apoptosis. In this study, we investigated whether APO2L is expressed in medulloblastoma or neuroblastoma cell lines and whether these cells are sensitive to APO2L-induced apoptosis. Immunoblot analyses revealed full-length APO2L protein expression in one (DAOY) of three medulloblastoma cell lines but not in two neuroblastoma cell lines (SKN-BE and SKN-LE). Viability assay performed after exposure to soluble APO2L for 16 h showed that DAOY medulloblastoma cells were the most sensitive and that apoptosis induced by APO2L was greatly enhanced when protein synthesis was inhibited by cycloheximide. Neuroblastoma cell lines were almost completely resistant to APO2L-induced apoptosis. We also carried out APO2L immunohistochemistry in a total of 115 tumors of the nervous system with different histogenesis and biological behavior. In all 9 pilocytic astrocytomas, the areas of dense fibrillary network showed diffuse and strong APO2L expression. In oligodendrogliomas, APO2L expression was observed in areas with a significant admixture of astrocytic cells, but was absent in neoplastic oligodendrocytes. In 13 of 14 ependymomas, APO2L was expressed in perivascular pseudorosettes. In all 12 medulloblastomas, strong APO2L expression was observed in intra-tumoral-reactive astrocytes, but neoplastic cells did not show APO2L immunoreactivity. Thus, the pattern of APO2L expression was largely similar to that of glial fibrillary acidic protein (GFAP), except for choroid plexus tumors and 3 of 8 anaplastic meningiomas, in which APO2L was focally expressed without concomitant GFAP expression. APO2L expression was absent in meningiomas, neurocytomas, and schwannomas. Thus, there is considerable heterogeneity of APO2L expression and susceptibility to APO2L-induced apoptosis among human brain tumors.
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PMID:APO2L/TRAIL expression in human brain tumors. 1065 Oct 20

Bag-1 is a heat shock 70 kDa (Hsp70)-binding protein that can collaborate with Bcl-2 in suppressing apoptosis under some conditions. Here, we report that 11 of 12 human glioma cell lines express Bag-1 protein in vitro. Moreover, 15 of 19 human glioblastomas expressed Bag-1 as assessed by immunohistochemistry in primary tumor specimens. To examine the biological effects of Bag-1 in glioma cells, we expressed Bag-1 or Bcl-2 transgenes in 2 human malignant glioma cell lines, LN-18 and LN-229. Bag-1 significantly slowed glioma cell growth and reduced clonogenicity of both cell lines in vitro. Coexpressed Bcl-2 abrogated these effects of Bag-1. Intracranial LN-229 glioma xenografts implanted into nude mice revealed a substantial growth advantage afforded by Bcl-2. Bag-1 had no such effect, either in the absence or presence of Bcl-2. Upon serum starvation in vitro, Bcl-2 prevented cell death whereas Bag-1 did not. Both Bcl-2 and Bag-1 slowed proliferation of serum-starved cells when expressed alone. Importantly, coexpression of Bcl-2 and Bag-1 provided a distinct growth advantage under conditions of serum starvation that is probably the result of (i) the death-preventing activity of Bcl-2 and (ii) the property of Bag-1 to overcome a Bcl-2-mediated enhancement of exit from the cell cycle. In contrast to these Bcl-2/Bag-1 interactions observed under serum starvation conditions, Bag-1 did not further enhance the strong protection from staurosporine-, CD95 (Fas/Apo1) ligand-, Apo2 ligand (TRAIL)- or chemotherapeutic drug-induced apoptosis afforded by Bcl-2. Taken together, these results indicate a role for Bag-1/Bcl-2 interactions in providing a survival advantage to cancer cells in a deprived microenvironment that may be characteristic of ischemic/hypoxic tumors such as human glioblastoma multiforme, and suggest that Bcl-2/Bag-1 interactions also modulate cell proliferation.
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PMID:Bag-1 and Bcl-2 gene transfer in malignant glioma: modulation of cell cycle regulation and apoptosis. 1076 42

Cellular resistance to multiple proapoptotic stimuli and invasion of surrounding brain tissue by migrating tumor cells are main obstacles to an effective therapy for human malignant glioma. Here, we report that the Wnt family of embryonic differentiation genes modulate growth of malignant glioma cells in vitro and in vivo and inhibit cellular migration in vitro. sFRPs (soluble Frizzled-related proteins) are soluble proteins that bind to Wnt and interfere with Wnt signaling. We find that sFRP-1 and sFRP-2 are produced by the majority of longterm and ex vivo malignant glioma cell lines. Glioma cells that ectopically express sFRPs exhibit increased clonogenicity and enhanced resistance to serum starvation. In contrast, sFRPs do not modulate glioma cell susceptibility to apoptosis induced by the cytotoxic cytokines, CD95 (Fas/APO-1) ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), or various cytotoxic drugs. sFRP-2 strongly promotes the growth of intracranial glioma xenografts in nude mice. In contrast, enhanced expression of sFRPs inhibits the motility of glioma cells in vitro. sFRP-mediated effects on glioma cells are accompanied by decreased expression and activity of matrix metalloproteinase-2 (MMP-2) and decreased tyrosine phosphorylation of beta-catenin. Thus, sFRPs promote survival under non-supportive conditions and inhibit the migration of glioma cells. We suggest that the regulation of these cellular processes involves expression of MMP-2 and tyrosine phosphorylation of beta-catenin. These data support a function for Wnt signaling and its modulation by sFRPs in the biology of human gliomas. Oncogene (2000) 19, 4210 - 4220
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PMID:Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells. 1098 May 94

TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in adult malignant glioma and various other human solid tumor models but not in normal tissues. To characterize the TRAIL death pathway in childhood primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. Treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising therapeutic approach for PNET that deserves further investigation.
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PMID:Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. 1103 Jan 49

Despite the considerable progress in modern tumor therapy, the prognosis for patients with glioblastoma, the most frequent malignant brain tumor, has not been substantially improved. Although cytoreductive surgery and radiotherapy are the mainstays of treatment for malignant glioma at present, novel cytotoxic drugs and immunotherapeutic approaches hold great promise as effective weapons against these malignancies. Thus, great efforts are being made to enhance antitumoral efficacy by combining various cytotoxic agents, by novel routes of drug administration, or by combining anticancer drugs and immune modulators. Immunotherapeutic approaches include cytotoxic cytokines, targeted antibodies, and vaccination strategies. However, the success of most of these experimental therapies is prevented by the marked molecular resistance of glioma cells to diverse cytotoxic agents or by glioma-associated immunosuppression. One promising experimental strategy to target glioma is the employment of death ligands such as CD95 (Fas/Apo1) ligand or Apo2 ligand (TRAIL). Specific proapoptotic approaches may overcome many of the obvious obstacles to a satisfactory management of malignant brain tumors.
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PMID:Chemotherapy and immunotherapy of malignant glioma: molecular mechanisms and clinical perspectives. 1121

Decoy receptor 3 (DcR3) is a newly identified soluble protein that binds to CD95 ligand (CD95L) and inhibits its proapoptotic activity. Here we report that DcR3 is expressed by the majority of long-term and ex vivo malignant glioma cell lines as well as in human glioblastoma in vivo. Expression of DcR3 correlates with the grade of malignancy: 15 of 18 (83%) glioblastomas (WHO grade IV) but none of 11 diffuse astrocytomas (WHO grade II) exhibited DcR3 immunoreactivity. We also demonstrate that human malignant glioma cells engineered to release high amounts of DcR3 into the cell culture supernatant are protected from CD95L-induced apoptotic cell death. In contrast, DcR3 does not confer protection from the death ligand Apo2 ligand (TRAIL). Importantly, ectopic expression of DcR3 resulted in substantial differences in immune cell infiltration in the 9L rat gliosarcoma model. Thus, the infiltration of CD4+ and CD8+ T cells as well as microglia/macrophages into glioma was substantially decreased in DcR3-producing tumors compared with control tumors. Chemotaxis assays revealed that DcR3 counteracts the chemotactic activity of CD95L against microglial cells in vitro. These findings suggest that DcR3 may be involved in the progression and immune evasion of malignant gliomas.
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PMID:Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. 1128 59

Apo2 ligand tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of the tumor necrosis factor family that interacts with cell surface "death receptors" (DR4 and DR5) to initiate programmed cell death. Apo2L/TRAIL also binds to "decoy" receptors (DcR1 and DcR2) that can antagonize its interaction with DR4 and DR5. In recent studies, Apo2L/TRAIL has been noted to produce selective toxicity toward certain neoplastic cells versus normal cells. The decoy receptors may in part contribute to this selectivity, because they are expressed in various normal tissues but are present at low or undetectable levels in certain types of neoplastic cells. In the current study, we examined the potential therapeutic applicability of recombinant soluble Apo2L/TRAIL by investigating its effects in vitro and in vivo against a series of cell lines derived from malignant gliomas, which are often resistant to conventional treatment modalities. In cell proliferation assays, Apo2L/TRAIL produced a striking decrease in cell numbers, with a median inhibitory concentration of 30-100 ng/ml, in the TP53 wild-type high-grade glioma cell lines U87 and A172, the TP53-mutated T98G, and the TP53-deleted LN-Z308. In contrast, no significant effects were observed in non-neoplastic astrocytes at concentrations up to 3000 ng/ml. Clonogenic assays showed that exposure to Apo2L produced a time-dependent decrease in the viability of glioma-derived cell lines. This correlated with the induction of apoptosis as assessed by a terminal transferase-catalyzed in situ end-labeling assay. Pretreatment of the cells with the caspase inhibitors Acetyl-Asp-Glu-Val-L-aspartic acid aldehyde or Acetyl-Tyr-Val-Ala-Asp-chlormethylketone (200 microM) largely eliminated the effects of Apo2L/TRAIL. Administration of Apo2L/TRAIL (0.3, 1, 3, 10, and 30 mg/kg/day for 7 days via i.p. infusion) to nude mice harboring established intracranial U87 xenografts produced a significant, dose-dependent prolongation of survival versus control animals. Survival in the control group was 27 +/- 1.7 days, compared with more than 50 days in each of the treatment groups (P < 0.001). At the 30 mg/kg dose level, 100% of animals survived for 120 days without evidence of tumor, a substantial improvement in comparison with lower dose levels (P < 0.01). No overt toxicity was apparent even at the highest Apo2L dose. We conclude that soluble Apo2L/TRAIL is effective in inducing apoptosis in high-grade glioma cells in vitro. Because this ligand appears to exhibit selective cytotoxicity for glioma cells versus non-neoplastic cells in vitro and demonstrates significant activity in vivo when administered systemically in an otherwise uniformly fatal central nervous system glioma model system, Apo2L may constitute a useful therapeutic agent for these challenging tumors.
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PMID:Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. 1135 Sep 7

Death ligands such as CD95 ligand (CD95L) or tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) induce apoptosis in radiochemotherapy-resistant human malignant glioma cell lines. The death-signaling TRAIL receptors 2 (TRAIL-R2/death receptor (DR) 5) and TRAIL-R1/DR4 were expressed more abundantly than the non-death-inducing (decoy) receptors TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in 12 human glioma cell lines. Four of the 12 cell lines were TRAIL/Apo2L-sensitive in the absence of a protein synthesis inhibitor, cycloheximide (CHX). Three of the 12 cell lines were still TRAIL/Apo2L-resistant in the presence of CHX. TRAIL-R2 expression predicted sensitivity to apoptosis. Coexposure to TRAIL/Apo2L and cytotoxic drugs such as topotecan, lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU) or temozolomide resulted in synergistic killing. Synergistic killing was more often observed in cell lines retaining wild-type p53 activity (U87MG, LN-229) than in p53 mutant cell lines (LN-18, T98G, U373MG). Drug exposure resulted in enhanced TRAIL-R2 expression, but decreased TRAIL-R4 expression in U87MG cells. Ectopic expression of dominant-negative p53(V135A) abrogated the drug-induced changes in TRAIL-R2 and TRAIL-R4 expression, but had no effect on synergy. Thus, neither wild-type p53 function nor changes in TRAIL receptor expression were required for synergy. In contrast, synergy resulted possibly from drug-induced cytochrome c release from mitochondria, serving as an amplifier of the TRAIL/Apo2L-mediated cascade of caspase activation. These data provide novel insights into the role of the TRAIL/Apo2L system in malignant gliomas and illustrate that TRAIL/Apo2L-based immunochemotherapy may be an effective therapeutic strategy for these lethal neoplasms.
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PMID:CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. 1146 79


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