Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epstein-Barr virus (EBV) can induce uncontrolled B lymphocyte proliferation leading to fatal lymphoma in immunocompromised patients. The sensitivity to apoptosis of B lymphoid cell lines (LCL) derived from EBV-induced lymphoproliferative disorders was investigated. In vitro and in vivo, these B LCL strongly express CD95/Apo-1/fas antigen and undergo apoptosis upon stimulation with anti-Apo-1 monoclonal antibody. When inoculated into severe-combined immunodeficient (scid) mice, human B cells lines developed into rapidly growing tumors. Administration of an agonistic anti-Apo-1 antibody significantly delayed tumor progression. Relapses were frequent, but were not caused by selection of resistant B cells, since B cells from relapsing tumors underwent apoptosis on re-exposure. Induction of apoptosis by an anti-C95/Apo-1/fas-specific antibody could be applied for therapy of EBV-induced B cell tumors and contribute to our understanding of the mechanisms of T cell-mediated elimination of EBV lymphomas in immunodeficient patients.
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PMID:Sensitivity of Epstein-Barr virus-induced B cell tumor to apoptosis mediated by anti-CD95/Apo-1/fas antibody. 904 28

Fas (CD95) and its ligand are central regulatory molecules in hematopoietic cells. Previous studies have suggested a role for Fas in the regulation of tumor progression, but Fas has not yet been conclusively identified as a tumor suppressor. Fas-deficient individuals lack malignant tumors, perhaps because of regulation by T cells. To investigate such a possibility, mice deficient in both T cells and Fas were generated, and they were found to develop severe B cell dysregulation characterized by malignant, lethal B cell lymphoma. Lymphoma arose from a monoclonal B220+CD19-CD5-CD23- B cell secreting immunoglobulin M, kappa rheumatoid factor. In contrast, animals containing alpha beta T cells, gamma delta T cells, and/or functional Fas suppressed the development of lymphoma. These data indicate that Fas functions as a tumor suppressor, and identifies roles for both alpha beta T cells and gamma delta T cells in Fas-independent tumor regulation.
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PMID:A tumor-suppressor function for Fas (CD95) revealed in T cell-deficient mice. 906 31

Apoptosis induced by Fas (CD95) ligation is frequently lost during tumor progression; however, there is no direct evidence to support an association of Fas loss-of-function with metastatic tumor behavior. To determine whether Fas loss-of-function is critical for acquisition of the metastatic phenotype, we have compared the ability of Fas-sensitive K1735 murine melanomas to form spontaneous lung metastases in wild-type and Fas ligand-deficient mice. Fas-sensitive melanoma clones are highly tumorigenic but rarely metastatic in wild-type syngeneic mice. However, in Fas ligand-deficient mice, both the incidence and number of metastases are increased. These findings provide the first evidence that Fas-Fas ligand interactions can suppress metastasis and that tumor Fas loss-of-function may be causally linked to metastatic progression.
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PMID:Fas and Fas ligand interactions suppress melanoma lung metastasis. 980 83

Chemotherapeutic drugs cause DNA damage and kill cancer cells mainly by apoptosis. p53 mediates apoptosis after DNA damage. To explore the pathway of p53-dependent cell death, we investigated if p53-dependent apoptosis after DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated hepatoma, gastric cancer, colon cancer, and breast cancer cell lines upon treatment with different anticancer agents known to act via p53 accumulation. Cisplatin, mitomycin, methotrexate, mitoxantrone, doxorubicin, and bleomycin at concentrations present in the sera of patients during therapy led to an upregulation of both CD95 receptor and CD95 ligand. Induction of the CD95 ligand occurred in p53 wild-type (wt), p53 mutant (mt), and p53 deficient (p53(-/-)) cell lines and at wt and mt conformation of temperature-sensitive p53 mutants. In contrast, upregulation of the CD95 receptor was observed only in cells with wt p53, not in cells with mt or without any p53. Restitution of inducible wt p53 function restored the ability of p53(-/-) Hep3B cells to upregulate the CD95 receptor in response to anticancer drugs. This rendered the cells sensitive to CD95-mediated apoptosis. In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, whereas mt p53 failed to induce apoptosis via activation of the CD95 gene. These observations provide a mechanistic explanation for the ability of p53 to contribute to tumor progression and to resistance of cancer cells to chemotherapy.
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PMID:p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. 984 17

Programmed cell death (apoptosis) is primarily mediated by Fas ligand (FasL; CD95L) and the Fas receptor (Fas; CD95). In this study, FasL was detected by immunohistochemical analysis in 85% of breast carcinomas and 14% of fibroadenomas randomly chosen, indicating that high expression of FasL might play a role in tumor pathology. FasL and Fas levels as well as FasL:Fas ratios were further ascertained in 215 human breast tumors, including 199 invasive ductal carcinomas, by real-time quantitative reverse transcription-PCR and compared with expression levels and ratios found in 25 normal human tissues, in 37 fibroadenomas, and in 5 normal breast tissues. Among breast carcinomas, high FasL mRNA expression seems to be positively correlated with histological grading (n = 212; P<0.0001). A ratio of FasL:Fas mRNA transcripts >1 is found to be significantly associated with decreased patient's disease-free survival (n = 211; P<0.03) and increased mortality (n = 211; P = 0.19). A FasL:Fas ratio >1 is related to tumor progression scored by histological grading (n = 212; P<0.02). The selection process leading to highly aggressive breast tumor variants might be enhanced by FasL-mediated tumor fratricide, eventually a possible target for novel therapeutic strategies.
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PMID:FasL:Fas ratio--a prognostic factor in breast carcinomas. 1070 87

CTL and NK cells use two distinct cytocidal pathways: 1) perforin and granzyme based and 2) CD95L/CD95 mediated. The former requires perforin expression by the effectors (CTL or NK), whereas the latter requires CD95 (Fas/APO-1) expression by the target. We have investigated how these two factors contribute to tumor immune surveillance by studying the immunity of perforin-deficient mice against the progressor C57BL/6 Lewis lung carcinoma 3LL, which expresses no CD95 when cultured in vitro. Unexpectedly, the results indicated that the perforin-independent CD95L/CD95 pathway of CTL/NK plays a role in acting against D122 and Kb39.5 (39.5) high and low metastatic sublines, respectively, derived from the 3LL tumor. Although no membrane-bound CD95 was detected on cultured D122 and 39. 5 cells, surface CD95 expression on both D122 and 39.5 was considerably up-regulated when the tumors were grown in vivo. A similarly enhanced expression of CD95 was observed with three additional tumors; LF-, BW, and P815, injected into syngeneic and allogeneic mice. The finding of up-regulated CD95 expression on tumor cells placed in vivo suggests that a CD95-based mechanism plays a role in tumor immunity at early stages of tumor growth. Consequently, the progressive down-regulation of CD95 expression during tumor progression may indeed be an escape mechanism as previously reported. Together, these results suggest a role for CD95-dependent, perforin-independent immunity against certain tumors.
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PMID:Tumor immunity in perforin-deficient mice: a role for CD95 (Fas/APO-1). 1070 15

Imbalanced proliferation and apoptosis is important in tumor progression. Endothelin (ET)-1, a 21-amino-acid peptide with vasoconstricting and mitogenic activities, has been shown to be involved in the regulation of apoptosis. Progressive and regressive rat colon (PROb and REGb cells) carcinoma cell lines express the components of the ET-1 system (preproET-1, ET-converting enzyme and ET-receptors) and secrete ET-1. These cells also express the Fas(APO-1, CD95)/FasL system, but are resistant to FasL-induced apoptosis. We thus addressed the role of ET-1 in FasL-dependent cell death. Bosentan, a mixed ET(A)/ET(B) receptor antagonist, potentiated FasL-induced apoptosis in these cells. At low concentrations (10(-13) to 10(-10) M), ET-1 dose-dependently reversed bosentan-induced apoptosis. Bosentan sensitization to FasL-induced apoptosis was not mediated by increased expression of Fas receptor and was blocked by the caspase inhibitor zVAD-fmk. The specific inhibition of enzymes involved in ceramide production did not restore survival of cells exposed to FasL and bosentan. Our results suggest that ET-1 is a survival factor able to protect in vitro colon carcinoma cells against FasL-induced apoptosis.
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PMID:Endothelin receptor blockade potentiates FasL-induced apoptosis in rat colon carcinoma cells. 1073 44

The CD95 (Apo-1/Fas) receptor-ligand system is one of the key regulators of apoptosis and is particularly important for the maintenance of lymphocyte homeostasis. There is now broad evidence that susceptibility of tumor cells towards CD95-mediated apoptosis is largely reduced. In the human, germline and somatic mutations of the CD95 gene are associated with a high risk of both lymphoid and solid tumors. Based on these observations a new concept defining CD95 as a tumor suppressor gene is discussed. In addition to CD95, its natural ligand (CD95L) is also implicated in malignant progression. Compared to their nonmalignant counterparts, malignant cells frequently exhibit aberrant de novo expression of CD95L and are able to induce CD95L-mediated apoptosis in bystander cells. The role for neoplastic CD95L expression in local tissue destruction, invasion, and metastatic spread has been established for many tumor types. CD95L expression by malignant cells may counteract the host's antitumor immunity and favors immune escape of the tumor. On this basis, the significance of loss of CD95 and gain of CD95L expression for tumor progression is discussed.
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PMID:Defining CD95 as a tumor suppressor gene. 1100 28

An imbalance between proliferation and apoptosis is important in tumor progression. Endothelin-1 (ET-1) has vasoconstricting and mitogenic activities and may be involved in apoptosis regulation. We found that ET-1 and FasL systems were colocalized in human colon tumors and that ET-1 was secreted by human (HT-29, SW480) and rat (PROb, REGb) colon carcinoma cell lines. Bosentan, a mixed endothelin-A- and -B- (ET(A)/ET(B)) receptor antagonist, potentiated FasL- (APO-1, CD95) induced apoptosis in these cells. The specific inhibition of enzymes involved in ceramide production did not restore survival of cells exposed to FasL and bosentan. Inhibition of PKC with bisindolylmaleimide IX enhanced FasL-induced apoptosis in HT-29, PROb and REGb cells in the absence of bosentan. These results suggest that ET-1 is an autocrine survival factor able to protect colon carcinoma cells against FasL-induced apoptosis, involving the protein kinase C (PKC) but not the sphingomyelin-ceramide signaling transduction pathways.
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PMID:Endothelin receptor blockade potentiates FasL-induced apoptosis in colon carcinoma cells via the protein kinase C-pathway. 1107 19

Interaction of CD95 ligand with its cognate receptor CD95 induces apoptotic cell death. Alterations in this pathway within tumor cells can result in escape from apoptosis and from immune surveillance. Melanoma cells recently were found to escape an immune attack via high expression of CD95 ligand, thereby inducing apoptosis of activated T lymphocytes. When screening four human melanoma cell lines for expression of CD95 and CD95 ligand, respectively, an inverse correlation was found, i.e., cells expressing high levels for CD95 ligand (CD95L(high)) were almost negative for CD95 and vice versa. Since coexpression of CD95 and CD95 ligand may lead to apoptosis by autocrine suicide or fratricide, it was tested whether overexpression of CD95 in CD95L(high) melanoma cells results in apoptotic cell death. Upon transfection with a cytomegalovirus-promoter-driven expression vector encoding the CD95 gene, CD95L(high) melanoma cells underwent apoptosis at a much higher level than CD95L(low) melanoma cells. Apoptosis appeared to be due to the activation of CD95 as cell death was inhibited by cotransfection with a dominant negative mutant for the CD95 signaling protein, Fas-associated protein with death domain. Tumor progression of CD95L(high) melanoma cells transplanted into nude mice was significantly reduced when recipient animals were injected with liposomes containing the CD95 expression vector. As demonstrated by immunohistochemistry and TUNEL staining, in vivo transfected tumor cells expressed CD95 and underwent apoptotic cell death. Hence, this study indicates that delivery of the CD95 gene inhibits tumor growth in vivo and thus might be a therapeutic strategy to treat tumor cells that express high levels of CD95 ligand. J Invest Dermatol 115:1008-1014 2000
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PMID:Inhibition of growth of melanoma cells by CD95 (Fas/APO-1) gene transfer in vivo. 1112 Nov 34


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