Fas Ligand Expression in Glioblastoma Cell Lines and Primary Astrocytic Brain Tumors

Gratas, Catherine; Tohma, Yasuo; Meir, Erwin G. Van; Klein, Michael L.; Tenan, Mirna; Ishii, Nobuaki; Tachibana, Osamu; Kleihues, Paul; Ohgaki, Hideaki

doi:10.1111/j.1750-3639.1997.tb00889.x

Cited by 135 publications

(68 citation statements)

References 31 publications

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“…In LN18 cells, FasL induced death in the absence of bosentan, whereas in LN215 and LN319 cells, FasL had no effect. It was previously shown that the cell lines used in this study express Fas and FasL, and that Fas engagement induced apoptosis only in LN18 cells (Gratas et al, 1997). Our results confirm those findings.…”

Section: Discussionsupporting

confidence: 82%

“…Interaction between the Fas receptor (CD95/APO-1), a member of the TNF-receptor superfamily, and the Fas ligand (FasL), triggers a pathway to cell death involving caspase activity. Although the expression of Fas and FasL has been demonstrated in glioblastoma (Saas et al, 1997), not all glioblastoma cell lines were able to respond to Fas engagement (Gratas et al, 1997). Tumor cell resistance to FasL-induced apoptosis has been described in different cancers by various mechanisms, including upregulation of caspase inhibitory molecules such as the pro-caspase-8 (FLICE)/ caspase-8 inhibitory proteins (FLIP) (Irmler et al, 1997).…”

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confidence: 99%

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The Endothelin System in Human Glioblastoma

Egidy

Eberl

Valdenaire

et al. 2000

Laboratory Investigation

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SUMMARY:Endothelin-1 (ET-1) is a powerful mitogenic and/or anti-apoptotic peptide produced by many cancer cells. To evaluate the potential role of the endothelin system in glioblastoma we first determined the cellular distribution of the mRNA and proteins of the components of the endothelin system, preproendothelin-1 (PPET-1), endothelin-converting enzyme-1 (ECE-1), and ET A and ET B receptors in human glioblastoma tissue and glioblastoma cell lines. PPET-1, ECE-1, and ET A receptor were highly expressed in glioblastoma vessels and in some scattered glioblastoma areas whereas ET B receptor was mainly found in cancer cells. This suggests that glioblastoma vessels constitute an important source of ET-1 that acts on cancer cells via the ET B receptor. Four human glioblastoma cell lines expressed mRNA for all of the components of the ET-1 pathway. Bosentan, a mixed ET A and ET B receptor antagonist, induced apoptosis in these cell lines in a dose-dependent manner. Apoptosis was potentiated by Fas Ligand (APO-1L, CD95L), a pro-apoptotic peptide, only in LNZ308 cells, corresponding to the known functional Fas expression in these cell lines. LNZ308 cells also expressed the long and short forms of the cellular FLICE/caspase-8 inhibitory protein (FLIP). Bosentan and a protein kinase C inhibitor down-regulated short FLIP in these cells. ET-1 induced transient phosphorylation of extracellular signal-regulated kinase but did not induce long-term thymidine incorporation in LNZ308 glioblastoma cells. These results suggest that, in glioblastoma cells, ET-1, mainly acting via the ET B receptor, is a survival/antiapoptotic factor produced by tumor vasculature, but not a proliferation factor, involving protein kinase C and extracellular signal-regulated kinase pathways, and stabilization of the short form of FLIP. (Lab Invest 2000, 80:1681-1689.

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Section: Discussionsupporting

confidence: 82%

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confidence: 99%

The Endothelin System in Human Glioblastoma

Egidy

Eberl

Valdenaire

et al. 2000

Laboratory Investigation

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“…Recently, uncharacterized glioma-generated soluble factors have been reported to suppress T cell responses to and enhance IL-10 expression by PBMC (22). Gliomas are common tumors in the CNS and express high levels of Fas-L (23,24). These findings raise the questions of whether cross-talk between tumor and immune cells through the Fas system is connected to IL-10, and whether this is the way in which tumor cells evade immune surveillance.…”

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confidence: 94%

Mediation of Enhanced Transcription of the IL-10 Gene in T Cells, Upon Contact with Human Glioma Cells, by Fas Signaling Through a Protein Kinase A-Independent Pathway

Yang

Lin

Hor

et al. 2003

The Journal of Immunology

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Elevated expression of IL-10 has been frequently observed in tumor tissues and tumor-infiltrating cells. We show herein that transcription of the IL-10 gene in primary peripheral T cells and T cell lines is up-regulated upon contact with glioma cells without an induction of apoptosis in those T cells. Glioma-associated IL-10 induction was suppressed by interrupting the engagement of Fas and its ligand (Fas-L) with the antagonistic Ab, ZB4, by reducing Fas-L expression of glioma cells using the Fas-L-specific ribozyme, or by preventing cell-to-cell contact in a Transwell culture setting. Cross-linking of Fas with the agonistic Ab, CH-11, triggered apoptosis and enhanced the expression of IL-10 in Jurkat cells at the transcriptional and translational levels. Inhibiting caspase activities by caspase inhibitors, Z-VAD (Z-Val-Ala-Asp(Ome)-fluoromethylketone) and Z-IETD (Z-Ile-Glu(Ome)-Thr(Ome)-Asp(Ome)-fluoromethylketone), abolished this IL-10 induction in Jurkat cells. Intracellular staining detected IL-10 proteins in Fas-cross-linked Jurkat cells and in PHA-activated T cells. However, few IL-10 proteins were detectable in Jurkat cells cocultured with glioma cells, indicating a requirement of other factors for IL-10 production. Direct activation of protein kinase A (PKA) by forskolin elevated the transcription of IL-10 in Jurkat cells. However, KT5720, a selective PKA inhibitor, reduced neither anti-Fas-triggered nor glioma-associated IL-10 expression. Phosphorylation of cAMP response element binding protein and activating transcription factor-1 in Jurkat cells was not affected by coculturing with glioma cells or by anti-Fas treatment, further suggesting a PKA-independent pathway. In summary, our results demonstrate nonlethal cross-talk between tumor and immune cells leading to IL-10 dysregulation in T cells, which might contribute to Fas-L+ tumor-associated immunosuppression.

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“…18,19 Both Fas and FasL messenger RNA (mRNA) levels are higher in astrocytomas than normal brain and correlate with tumor grade. 20,21 Most Fas expression in GBM is within pseudopalisades corresponding to their higher levels of apoptosis. 22,23 Contact between tumor cells expressing FasL and those expressing Fas may facilitate apoptosis.…”

Section: Necrogenesis In Gbmmentioning

confidence: 99%

Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma

Brat

Meir

2004

Laboratory Investigation

286

276

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Glioblastoma (GBM) has explosive biologic properties with rapid clinical progression leading to death. Its distinguishing pathologic features, necrosis with surrounding pseudopalisades and microvascular hyperplasia, are believed to be instrumental to its accelerated growth. Microvascular hyperplasia arises in response to the secretion of proangiogenic factors by hypoxic pseudopalisades and allows for peripheral neoplastic expansion. Mechanisms underlying necrosis and hypoxia remain obscure, but vaso-occlusive and prothrombotic contributions could be substantial. Recent investigations on the origin of pseudopalisades suggest that this morphologic phenomenon is created by a tumor cell population actively migrating away from a central hypoxic region and that, in at least a significant subset, hypoxia-induced migration appears due to vasoocclusion caused by intravascular thrombosis. Both vascular endothelial growth factor induced vascular permeability to plasma coagulation factors and the increased neoplastic expression of tissue factor likely contribute to a prothrombotic state favoring intravascular thrombosis. In addition to prothrombotic mechanisms, vaso-occlusion could also result from angiopoietin-2-mediated endothelial cell apoptosis and vascular regression, which follows neoplastic co-option of native vessels in animal models of gliomas. Vasoocclusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisades and coagulative necrosis in tissue sections, the emergence of central contrast enhancement and its rapid peripheral expansion on neuroimaging, and the dramatic shift to an accelerated rate of clinical progression. Since the hypoxic induction of angiogenesis appears to support further neoplastic growth, therapeutic targeting of the underlying vascular pathology and thrombosis could provide a new means to prolong time to progression.

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Fas Ligand Expression in Glioblastoma Cell Lines and Primary Astrocytic Brain Tumors

Cited by 135 publications

References 31 publications

The Endothelin System in Human Glioblastoma

The Endothelin System in Human Glioblastoma

Mediation of Enhanced Transcription of the IL-10 Gene in T Cells, Upon Contact with Human Glioma Cells, by Fas Signaling Through a Protein Kinase A-Independent Pathway

Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma

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