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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas is a mouse monoclonal antibody-defined cell surface antigen of an unknown physiologic function. Previous studies demonstrated that the anti-Fas antibody mediated apoptosis in those cells sensitive to tumor necrosis factor (TNF) and, further, triggered the co-downregulation of tumor necrosis factor receptors (TNF-Rs). These findings led to speculation that Fas may be associated with TNF-Rs. The present studies were undertaken as an extension of our previous work on the obligate requirement for TNF in development and maintenance of cytotoxic lymphocytes and were designed to analyze the expression and consequences of Fas engagement in these cells. Herein, we demonstrate that, in contrast to TNF-R expression, both resting and IL-2-activated lymphocytes express Fas. In accordance with previous studies using tumor cell lines, lymphocytes rapidly downregulate TNF-Rs after treatment with anti-Fas. The ability of anti-Fas to mediate apoptotic cell death in lymphocytes, however, was dependent upon the status of cellular activation. For example, lymphocytes activated in IL-2 for longer than 4 days underwent rapid DNA fragmentation and cell death after anti-Fas treatment. Despite their expression of Fas, nonactivated lymphocytes and those activated for periods less than 4 days were refractory to antibody-mediated cell killing. Because anti-Fas-mediated lethality is selective for chronically activated lymphocytes, Fas may prove to be an appropriate target for immunosuppressive intervention.
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PMID:DNA fragmentation and cell death is selectively triggered in activated human lymphocytes by Fas antigen engagement. 137 Dec 42

Neoplastic transformation is one possible consequence of genomically disturbed intracellular feedback mechanisms normally governing life, differentiation, function and death of an individual cell. Neoplastic growth can be thought of as the abnormal activation of the mitotic program and/or the inactivation of programs for growth-inhibition and apoptosis. This article reviews the current knowledge on three types, or families, of proteins that act on different levels of subcellular organization and are involved in controlling the integrity of the genome, survival and death: i) the DNA-binding nuclear protein p53 inducing cell cycle arrest and apoptosis, ii) the bcl-2 family of proteins acting as regulators of prolonged survival and programmed cell death and iii) APO-1/Fas, a cell surface receptor transducing an apoptotic signal delivered either by the cell itself (cis death) or by another cell (trans death). Although much is still unknown, especially concerning the functional linkages of these three principles, the data available allow a fascinating insight into the society of cells, which we are, after all.
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PMID:Pathophysiological aspects of tumor development. 748 52

It is now well established that CD4+ T cells can express cytotoxic activity. This type of cell-mediated cytotoxicity is associated with the Th1-, but not with the Th2-phenotype. While the activation of CD4+ CTL is MHC class II-restricted, the effector phase, i.e. the target cell killing is unrestricted and antigen non-specific. In analogy to CD8+ CTL, CD4-mediated target cell death is by DNA fragmentation. However, the molecular mechanism of killing differs from CD8-mediated lysis. Thus, CD4+ CTL preferentially lyse their targets via Fas-Fas ligand interaction, whereas the major cytotoxic effect of CD8+ CTL is by granule exocytosis, i.e. perforin and granzymes. Although CD8+ CTL can also express the FasL, their lytic activity through interaction with Fas is of less importance. Likewise, some CD4+ CTL may also kill by perforin/granzymes activity, but this pathway is of minor significance. The aims of CD8- or CD4-mediated lysis are also different. Thus, the major task of CD8+ CTL which recognize and kill their targets in the context of MHC class I molecules, is the lysis of virally infected cells and battling against tumor cells. CD4+ CTL, on the other hand, have an immunomodulatory role. Thus, they preferentially eliminate activated MHC class II-positive cells, i.e. APC, be they monocytes/macrophages, B cells or T cells. They may lyse these cells in order to prevent an overreaction of the ongoing immune response or in order to remove potentially hazardous cells upon completion of the immune response. The Fas-FasL pathway is particularly suitable for this task as myeloid or lymphoid cells express Fas only if activated, while FasL is preferentially expressed on activated CD4+ Th1 cells. Moreover, activated T cells eliminate themselves by the Fas-mediated pathway. Whether this happens by fratricide only, or also by suicide or both is open. Moreover, CD4+ CTL are particularly suitable for killing tumor cells as well, as they are efficient effectors in bystander lysis in contrast to CD8+ CTL. On the other hand, the non-specific killing via Fas-FasL interaction, which is an important reason for the bystander lysis, may have unwanted effects in that cells which should not be eliminated could be killed. Such reactions affecting various organs and cells, e.g. the liver, thyroid or islet cells of the pancreas could be an explanation for certain autoimmune diseases.
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PMID:Mechanism and biological significance of CD4-mediated cytotoxicity. 749 61

The eye is a privileged site that cannot tolerate destructive inflammatory responses. Inflammatory cells entering the anterior chamber of the eye in response to viral infection underwent apoptosis that was dependent on Fas (CD95)-Fas ligand (FasL) and produced no tissue damage. In contrast, viral infection in gld mice, which lack functional FasL, resulted in an inflammation and invasion of ocular tissue without apoptosis. Fas-positive but not Fas-negative tumor cells were killed by apoptosis when placed within isolated anterior segments of the eyes of normal but not FasL-negative mice. FasL messenger RNA and protein were detectable in the eye. Thus, Fas-FasL interactions appear to be an important mechanism for the maintenance of immune privilege.
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PMID:Fas ligand-induced apoptosis as a mechanism of immune privilege. 750 38

Fas/APO-1 is a cell-surface protein capable of inducing apoptosis in a variety of cell types upon specific antibody engagement. Antibodies against Fas/APO-1 have been used successfully for the treatment of several lymphoid malignancies in mice. Before apoptosis triggered by anti-Fas can be fully exploited as a clinical therapy, Fas/APO-1 distribution, function, and regulation must be further studied. In this study, we analyzed freshly isolated B-cell and T-cell lymphomas as well as nonhematological tumor cell lines for Fas/APO-1 expression and sensitivity to the growth-inhibitory effects of anti-Fas. Constitutive Fas/APO-1 was expressed at very low levels on only one of eight B-cell lymphomas analyzed. Expression was markedly up-regulated, however, by culture with high-molecular-weight B-cell growth factor (HMW-BCGF). Fas/APO-1 was constitutively expressed on one of two T-cell lymphomas examined at levels comparable to those of activated normal lymphocytes. However, neither the B-cell nor T-cell lymphomas positive for Fas/APO-1 expression were growth inhibited by anti-Fas. Furthermore, in the case of one HMW-BCGF-activated B-cell lymphoma, a significant growth enhancement was observed upon anti-Fas treatment. Nonhematologic tumor cell lines showed a similar spectrum of biologic responses to anti-Fas, being growth inhibited, growth stimulated or unaffected by antibody treatment. In summary, these studies suggest that engagement of Fas/APO-1 may trigger a diverse spectrum of biologic effects not unlike other members of the nerve growth factor receptor/tumor necrosis factor receptor superfamily.
J Immunother Emphasis Tumor Immunol 1993 Oct
PMID:Fas/APO-1 expression and function on malignant cells of hematologic and nonhematologic origin. 750 10

The Fas Ag and the p55 TNF receptor (TNF-R1) are related molecules that can signal apoptosis. Some tumor cell lines are selectively killed by Fas activation and others by TNF-R1 activation even though both receptors are often co-expressed. TNF-R1-mediated cytotoxicity can be selectively inhibited under conditions in which Fas-mediated cell death is not affected. Activation of both receptors results in synergistic signaling of apoptosis. These results indicate that different biochemical pathways are activated by Fas and TNF-R1. Combination treatment with agonists of Fas and TNF-R1 may have therapeutic potential.
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PMID:Fas antigen and p55 TNF receptor signal apoptosis through distinct pathways. 750 28

Mice homozygous for either the lpr or gld genes develop phenotypically identical autoimmune disorders. The gene responsible for the pathology in lpr/lpr mice encodes the Fas antigen, a protein associated with the induction of programmed cell death. To determine if the defect associated with gld represents a mutation in the ligand for Fas, we have assessed the ability of lymphoid cells from homozygous gld/gld mice to lyse target cells in a Fas-dependent manner. Using an antagonistic antibody to Fas, we demonstrate that activated T cells from normal and lpr mice are capable of inducing Fas-mediated lysis of tumor target cells. In contrast, activated T cells from gld/gld mice fail to induce lysis of tumor targets, although cells from gld mice are able to lyse specific allogeneic targets following mixed lymphocyte culture. In addition, activated T cells from gld/gld homozygous animals are not capable of binding to a Fas.Fc fusion protein at high levels, whereas activated T cells from normal and lpr/lpr animals bind Fas.Fc efficiently. These data indicate that mice homozygous for gld are unable to express a functional ligand for Fas.
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PMID:gld/gld mice are unable to express a functional ligand for Fas. 751 35

Intracellular pathways leading from membrane receptor engagement to apoptotic cell death are still poorly characterized. We investigated the intracellular signaling generated after cross-linking of CD95 (Fas/Apo-1 antigen), a broadly expressed cell surface receptor whose engagement results in triggering of cellular apoptotic programs. DX2, a new functional anti-CD95 monoclonal antibody was produced by immunizing mice with human CD95-transfected L cells. Crosslinking of CD95 with DX2 resulted in the activation of a sphingomyelinase (SMase) in promyelocytic U937 cells, as well as in other human tumor cell lines and in CD95-transfected murine cells, as demonstrated by induction of in vivo sphingomyelin (SM) hydrolysis and generation of ceramide. Direct in vitro measurement of enzymatic activity within CD95-stimulated U937 cell extracts, using labeled SM vesicles as substrates, showed strong SMase activity, which required pH 5.0 for optimal substrate hydrolysis. Finally, all CD95-sensitive cell lines tested could be induced to undergo apoptosis after exposure to cell-permeant C2-ceramide. These data indicate that CD95 cross-linking induces SM breakdown and ceramide production through an acidic SMase, thus providing the first information regarding early signal generation from CD95, and may be relevant in defining the biochemical nature of intracellular messengers leading to apoptotic cell death.
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PMID:Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. 752 73

Fas/Apo-1 molecule is an apoptosis-signaling cell surface Ag belonging to the TNFR family. To investigate the possibility that soluble forms of the Fas receptor are expressed in human cells, we analyzed Fas mRNA transcripts obtained from activated peripheral mononuclear cells of healthy donors and from human tumor cell lines. We identified and characterized three human mRNA Fas variants: FasTMDel, FasDel2, and FasDel3. To determine whether the three transcripts were derived by alternative splicing, the Fas genomic intron/exon organization of the regions surrounding the deleted sequences was analyzed in Fas clones isolated from a human genomic library. Expression of the transcripts was studied in COS cells transiently transfected with the FasTMDel, FasDel2, and FasDel3 cDNAs. Immunocytochemical and in vitro apoptosis inhibition studies suggest that the transcripts are expressed as soluble Fas proteins that may play a functional role in the regulation of apoptosis.
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PMID:Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. 753 81

The Fas antigen is a transmembrane receptor that can trigger apoptosis in a variety of tumor and hematopoietic cells. Ovarian follicular atresia and luteolysis are thought to occur by apoptosis. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry, we demonstrated that human granulosa/luteal cells express the Fas antigen. An anti-human Fas antigen monoclonal antibody (Fas mAb; clone CH-11), which induces apoptosis in other cell types by binding to the Fas antigen, induced significant cell death (30%) in cultures pretreated with interferon gamma (IFN gamma). This agrees with studies on tumor cell lines showing that IFN gamma enhances cytotoxic effects of Fas mAb. Granulosa/luteal cells exhibited morphological characteristics typical of apoptosis, including membrane blebbing and condensed chromatin. DNA fragmentation into oligonucleosomal units of approximately 180 bp, typical of apoptosis, was detected at elevated levels in Fas mAb-treated cultures via 3' end-labeling and gel electrophoresis. Examination of cultured cells in situ for apoptotic DNA cleavage by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) indicated that more apoptotic death occurred in Fas mAb-treated cultures than in control cultures. Effects of hCG-induced luteinization of cultures on Fas mAb-induced cytotoxicity was examined: combined pretreatment with IFN gamma and hCG induced a synergistic increase in Fas mAb-induced cytotoxicity (40%) over that obtained with IFN gamma-pretreatment alone (15%). In summary, granulosa/luteal cells express the Fas antigen and are sensitive to Fas mAb-induced apoptosis. Human CG synergized with IFN gamma to increase Fas mAb-induced death.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fas antigen-mediated apoptosis in human granulosa/luteal cells. 753 48


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