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

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

Clinical trials of adenoviral p53 gene therapy provide the evidence that the bystander effect induced by the wild-type p53 gene transfer on adjacent tumor cells contributes to tumor progression; its mechanism, however, remains uncharacterized. We report in this work that injection of adenovirus expressing the human wild-type p53 gene (Ad5CMVp53) into established human colorectal tumors in nu/nu mice resulted in CD95 ligand (CD95L) overexpression, followed by a massive neutrophil infiltration. Culture supernatants of human colorectal cancer cells infected with Ad5CMVp53 exhibited a potent chemotactic activity against murine polymorphonuclear neutrophils, which could be abolished by the anti-CD95L mAb (NOK-1). In vivo cell depletion experiments indicated that neutrophils were in part responsible for the antitumor effect of the Ad5CMVp53 infection. Our data directly suggest that overexpression of CD95L by the wild-type p53 gene transfer induces neutrophil infiltration into human colorectal tumors, which may play a critical role in the bystander effect of p53 gene therapy.
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PMID:Contribution of CD95 ligand-induced neutrophil infiltration to the bystander effect in p53 gene therapy for human cancer. 1106 49

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

Progressive tumor growth may be associated with suppression of the immune response. Many different mechanisms may contribute to immune evasion. We investigated some of these mechanisms in melanoma cells lines generated from two patients. These cell lines show a complex pattern of altered HLA expression; however, the resulting phenotype did not satisfactorily explain the simultaneous evasion of T and NK cell cytotoxicity. Two additional alterations have now been detected in these melanoma cell lines: (1) resistance to FAS-induced apoptosis caused by defective FAS gene expression, and (2) constitutive expression of immunosuppressive cytokines. Our results show that several of the major mechanisms for immune evasion may coexist in a single tumor. This suggests that tumor progression may give rise to an extremely resistant phenotype, which may be an impediment to some immunotherapeutic strategies. We hypothesize that the simultaneous presence of several mechanisms involved in tumor immune evasion must be the result of progressive selection of characteristics that are advantageous for tumor survival in a competent host. Our findings do not support the possibility that FASL expression is a common mechanism of evasion of immune response in melanoma cells.
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PMID:Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient. 1122 93

Activation of the insulin-like growth factor-1 receptor (IGF-1R) by IGF-1 is associated with the risk and progression of many types of cancer, although despite this it remains unclear how activated IGF-1R contributes to cancer progression. In this study, gene expression changes elicited by IGF-1 were profiled in breast epithelial cells. We noted that many genes are functionally linked to cancer progression and angiogenesis. To validate some of the changes observed, the RNA and/or protein was confirmed for c-fos, cytochrome P450 1A1, cytochrome P450 1B1, interleukin-1 beta, fas ligand, vascular endothelial growth factor, and urokinase plasminogen activator. Nuclear proteins were also temporally monitored to address how gene expression changes were regulated. We found that IGF-1 stimulated the nuclear translocation of phosphorylated AKT, hypoxic-inducible factor-1 alpha, and phosphorylated cAMP-responsive element-binding protein, which correlated with temporal changes in gene expression. Next, the promoter regions of IGF-1-regulated genes were searched in silico. The promoters of genes that clustered together had similar regulatory regions. In summary, IGF-1 inscribes a gene expression profile relevant to cancer progression, and this study provides insight into the mechanism(s) whereby some of these changes occur.
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PMID:Insulin-like growth factor-1 inscribes a gene expression profile for angiogenic factors and cancer progression in breast epithelial cells. 1198 40

The CD95 (Apo-1/Fas) receptor-ligand system is a key regulator of apoptosis. Down-regulation of CD95 receptor and up-regulation of CD95 ligand has been reported in a variety of human tumors and is thought to confer a selective survival advantage. To explore the relevance of the CD95 system for tumor progression and prognosis in clear cell renal cell carcinomas (RCCs), we analyzed CD95 receptor and ligand expression in formalin-fixed tissue from 149 clear cell RCCs by immunohistochemistry. CD95 ligand expression could not be detected in nonneoplastic tubule epithelia and in clear cell RCCs. In contrast, CD95 receptor expression was found in the great majority of clear cell RCCs, and no down-regulation of CD95 receptor protein was evident when compared with nonneoplastic tubule epithelia. Although a significant increase (P = 0.004) of CD95 receptor expression was evident from well-differentiated (G1) to poorly differentiated (G3) RCCs, CD95 receptor expression was not correlated with tumor stage or survival of RCC patients. In conclusion, clear cell RCCs differ from other types of human cancer by their failure to down-regulate CD95 receptor expression or up-regulate CD95 ligand expression during tumor progression. These ex vivo observations suggest that down-regulation of CD95 receptor expression may not provide an additional selective growth advantage to RCC cells and thus further confirm our previous in vitro observations on a functional impairment of CD95-mediated apoptosis in RCC.
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PMID:Prognostic implications of CD95 receptor expression in clear cell renal carcinomas. 1261 86

FasL (CD95L) is a well-known and well-characterized death-inducing ligand. Spontaneous mutations in FasL and its cognate receptor Fas (CD95) have helped understand the role of these molecules in the disease. Once thought to be mainly involved in the homeostasis of immune system, the territory of FasL regulation has been expanded to angiogenesis and tumor progression. Here, we review what is currently known about the role of FasL in many areas of biology.
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PMID:Biology of FasL. 1278 69

Many tumors express the death ligand CD95L (CD178, APO-1L, FasL) and can kill activated T cells in vitro. This may enable the tumor cells to suppress anti-tumor immune responses, a phenomenon called "tumor counterattack". Preliminary evidence of tumor counterattack in human tumors exists. However, CD95L-expressing tumors are rapidly rejected in mice. In order to clarify this controversial situation we investigated whether the level or the time point of CD95L expression might be critical factors determining tumor counterattack versus tumor rejection. We generated CD95-resistant tumor cell lines expressing different levels of CD95L (LKC-CD95L). In nude mice the CD95L expression level had no influence on the growth of the CD95L(+) tumors. In contrast, a CD95L(-) control tumor cell line (LKC) grew much faster. In addition, we generated a CD95-resistant cell line in which CD95L was induced via the tet system (LKCR-tetCD95L). Induction of CD95Lin established tumors in nude and NOD/SCID mice led to rapid rejection of the tumors. Induction of lower CD95L expression levels delayed tumor rejection only marginally. These results demonstrate that rejection of CD95L-expressing tumors in mice is not a result of overexpression and does not depend on the presence of CD95L at the onset of tumor progression.
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PMID:The influence of CD95L expression on tumor rejection in mice. 1451 65


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