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  • 1
    Keywords: APOPTOSIS ; CELLS ; HEPATOCELLULAR-CARCINOMA ; hepatocarcinogenesis ; NECROSIS-FACTOR-ALPHA ; p53 ; PROMYELOCYTIC LEUKEMIA PROTEIN ; DNA-DAMAGE RESPONSE ; VIRUS CORE PROTEIN ; SUPPRESSOR PML
    Abstract: Successful escape from immune response characterises chronic hepatitis C virus (HCV) infection, which results in persistence of infection in about 80% of the patients. The deleterious consequences are cirrhosis and hepatocellular carcinoma. HCV accounts the most frequent cause for hepatocellular carcinoma (HCC) and liver transplantation (LT) in the western world. The underlying molecular mechanisms how HCV promotes tumor development are largely unknown. There is some in vitro and in vivo evidence that HCV interferes with the tumor suppressor PML and may thereby importantly contribute to the HCV-associated pathogenesis with respect to the development of HCC. The tumor suppressor protein "promyelocytic leukemia" (PML) has been implicated in the regulation of important cellular processes like differentiation and apoptosis. In cancer biology, PML and its associated nuclear bodies (NBs) have initially attracted intense interest due to its role in the pathogenesis of acute promyelocytic leukemia (APL). More recently, loss of PML has been implicated in human cancers of various histologic origins. Moreover, number and intensity of PML-NBs increase in response to interferons (IFNs) and there is evidence that PML-NBs may represent preferential targets in viral infections. Thus, PML could not only play a role in the mechanisms of the antiviral action of IFNs but may also be involved in a direct oncogenic effect of the HCV on hepatocytes. This review aims to summarise current knowledge about HCV-related liver carcinogenesis and to discuss a potential role of the nuclear body protein PML for this this hard-to-treat cancer.
    Type of Publication: Journal article published
    PubMed ID: 25253937
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  • 2
  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; PROTEINS ; RNA ; LINES ; MICE ; TRANSDUCTION ; NF-KAPPA-B ; COMPLEX ; COMPLEXES ; MECHANISM ; CONTRAST ; hepatocytes ; CELL-LINES ; signal transduction ; SUPPRESSION ; 5-FLUOROURACIL ; ALPHA ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; EFFICACY ; SIGNAL-TRANSDUCTION ; LINE ; CANCER-CELLS ; CARCINOMA-CELLS ; KAPPA-B ; RECEPTORS ; FLOW-CYTOMETRY ; cell lines ; PROTEASOME ; TRAIL ; SIGNALING COMPLEX ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CASPASE-8 ACTIVATION ; INHIBITORS ; signaling ; RE ; INTERFERENCE ; CASPASE-8 ; MEDIATED APOPTOSIS ; TUMORICIDAL ACTIVITY ; interaction ; SIGNALING COMPLEXES ; CLINICAL-RELEVANCE ; carcinoma cell ; death receptor
    Abstract: TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-kappa B) activity, specific suppression of NF-kappa B by mut kappa B alpha failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)(L) and cFLIP(S) were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC., But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 16037944
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; CELL ; Germany ; INHIBITION ; THERAPY ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; TISSUE ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; CELL-LINES ; treatment ; hepatocellular carcinoma ; resistance ; AGE ; metastases ; NUDE-MICE ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; MODULATION ; p53 ; CANCER-PATIENTS ; CARCINOMAS ; CISPLATIN ; CANCER PATIENTS ; cell lines ; CANCER-THERAPY ; protein expression ; P53 STATUS ; GEMCITABINE ; RE ; cancer therapy ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; corticosteroids ; GLUCOCORTICOIDS ; correlation ; GAMMA-IRRADIATION ; viability ; 5-FU ; xenograft
    Abstract: The glucocorticoid dexamethasone is frequently used as co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and the supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact to cytotoxic treatment of colorectal and hepatocellular carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using 8 established cell lines, 18 surgical specimen and a xenograft on nude mice. In the presence of dexamethasone we found strong inhibition of apoptosis in response to 5-FU, cisplatin, gemcitabine or gamma-irradiation, enhanced viability and tumour growth of colorectal and hepatocellular carcinomas. No correlation with age, gender, histology, TNM, the p53 status and induction of therapy resistance by dexamethasone cotreatment could be detected. These data show that glucocorticoid-induced resistance occurs not occasionally but is common in colorectal and hepatocellular carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients. (c) 2005 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16338063
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  • 5
    Abstract: The glucocorticoid dexamethasone is frequently used as co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and the supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact to cytotoxic treatment of colorectal and hepatocellular carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using 8 established cell lines, 18 surgical specimen and a xenograft on nude mice. In the presence of dexamethasone we found strong inhibition of apoptosis in response to 5-FU, cisplatin, gemcitabine or gamma-irradiation, enhanced viability and tumour growth of colorectal and hepatocellular carcinomas. No correlation with age, gender, histology, TNM, the p53 status and induction of therapy resistance by dexamethasone co-treatment could be detected. These data show that glucocorticoid-induced resistance occurs not occasionally but is common in colorectal and hepatocellular carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients.
    Type of Publication: Journal article published
    PubMed ID: 16338063
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  • 6
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; SURVIVAL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; KINASE ; TYROSINE KINASE ; GENES ; SURGERY ; IMPACT ; ALPHA ; TARGET ; PROGRESSION ; PATTERNS ; METASTASIS ; STOMACH ; adenocarcinoma ; RECEPTORS ; CELL CARCINOMA ; PATTERN ; overall survival ; UPDATE ; LYMPH-NODE ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; gastric ; ESOPHAGEAL ; PDGFR ; gastric adenocarcinoma ; RATIONALE ; COEXPRESSION ; MOLECULAR TARGETING STRATEGY ; RECEPTOR-TYROSINE-KINASE
    Abstract: Background/Aims: This study was initiated in order to define the (co-)expression patterns of target receptor tyrosine kinases (RTKs) in human gastric adenocarcinoma and to correlate them with clinicopathological parameters. Methodology: The (co-)expression pattern of VEGFR1, VEGFR2,VEGFR3, PDGFR alpha, PDGFR beta and EGFR1 was analyzed in 56 samples of human gastric adenocarcinoma and correlated with staging and survival. Results: VEGFR1,VEGFR2, VEGFR3, PDGFRa, PDGFR beta and EGFR1 were expressed at relevant levels in 79%, 50%, 50%, 63%, 55% and 30%, respectively. VEGFR2,VEGFR3, and PDGFR beta were significantly co-expressed. Thirty-four percent of gastric adenocarcinoma samples revealed a co-expression of 6 receptors, 27% expressed 5 receptors and only 23% showed expression of 3 receptors or less. Expression of VEGFR1, VEGFR2, VEGFR3, PDGFR alpha, PDGFR beta and EGFR1 in gastric adenocarcinoma did not significantly correlate with a higher pT-category, the presence of lymph node metastasis (pN+) or overall survival. However, a trend towards a higher pT-category was seen for expression of VEGFR1 without reaching statistical significance. Conclusions: The data obtained reveal that specific RTKs are significantly co-expressed. However, co-expression of RTKs did not impact on staging or survival. It has to be further analyzed, if the expression of the respective ligands is of higher relevance than the expression of the receptor itself
    Type of Publication: Journal article published
    PubMed ID: 20583450
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  • 7
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; carcinoma ; IN-VIVO ; THERAPY ; GENE ; GENE-EXPRESSION ; HYBRIDIZATION ; TUMORS ; radiation ; PATIENT ; NF-KAPPA-B ; FAMILY ; MEMBER ; NUCLEAR-FACTOR ; NORMAL TISSUE ; CISPLATIN ; PROGRAMMED CELL-DEATH ; ALPHA-INDUCED APOPTOSIS ; DNA-DAMAGING AGENTS ; GLOMERULAR ENDOTHELIAL-CELLS ; GRANULOSA-CELLS ; LEUKEMIA- CELLS ; LUNG-CARCINOMA ; T- LYMPHOCYTES
    Abstract: Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Glucocorticoids (GCs) are frequently used as cotreatment because they may have potent proapoptotic properties and reduce nausea, hyperemesis, and acute toxicity on normal tissue. In contrast to the proapoptotic effect of GCs in lymphoid cells, resistance toward cancer therapy-mediated apoptosis was induced in solid tumors of human cervix and lung carcinomas. Filter hybridization, expression data, as well as functional assays identified multiple core apoptosis molecules, which are regulated by GCs in a pro- or antiapoptotic manner. Both antiapoptotic genes such as FLIP and members of the Bcl-2 and IAP family as well as proapoptotic elements of the death receptor and mitochondrial apoptosis pathways were down-regulated in carcinomas resulting in a decreased activity of caspase-8, caspase-9, and caspase-3. In contrast, death receptor and mitochondrial apoptosis signaling as well as caspase activity was enhanced by dexamethasone in lymphoid cells. To restore apoptosis sensitivity in dexamethasone-treated carcinomas, caspase-8 and caspase-9 were transfected. This resensitized tumor cells in vitro and xenografts in vivo to cisplatin induced cell death. These data therefore raise concern about the widespread combined use of GCs with antineoplastic drugs or agents in the clinical management of cancer patients
    Type of Publication: Journal article published
    PubMed ID: 12810637
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; IN-VITRO ; tumor ; carcinoma ; CELL ; CELL LUNG-CANCER ; Germany ; human ; IN-VIVO ; LUNG ; MODEL ; MODELS ; VITRO ; VIVO ; DEATH ; NEW-YORK ; GENE ; TUMORS ; LINES ; MICE ; FAMILY ; MEMBER ; MEMBERS ; treatment ; immunohistochemistry ; MALIGNANCIES ; ASSAY ; resistance ; CELL-DEATH ; INDUCED APOPTOSIS ; Western-blot ; NUDE-MICE ; chemotherapy ; CARCINOMAS ; STRATEGIES ; western blot ; FAILURE ; LUNG-CARCINOMA ; CASPASE 8 ; nude mice ; Bcl-2 ; CD95 ; DRUG-INDUCED APOPTOSIS ; XENOGRAFTS ; CD95/Fas/APO-1,TRAIL,gene therapy,drug reststance,cancer therapy ; IMMUNE-SYSTEM
    Abstract: Non small cell lung carcinoma (NSCLC) is a highly lethal malignancy that often becomes resistant to chemotherapy. To determine whether alterations in apoptotic signaling might contribute to such resistance, we established in vitro and in vivo models for sensitive and resistant human NSCLC. We found that resistance is due to multiple defects found in expression of CD95-L, CD95 and members of the Bcl-2 and IAP family, as well as caspase-8, -9 and -3 as examined by immunohistochemistry, Western blot analysis, gene array analysis and functional assays. Failure to activate death receptor, as well as mitochondrial apoptosis signaling, points to a central role of caspases. To restore apoptosis signaling we transfected NSCLC xenografts on nude mice with caspase-8 and -9. This treatment strongly induced apoptosis per se and sensitized the tumors to cisplatin-induced cell death. Thus, these findings indicate that re-expression of caspases might be an effective strategy to restore sensitivity for chemotherapy in NSCLC in vivo. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
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  • 9
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; COMBINATION ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; THERAPY ; GENES ; SAMPLE ; SAMPLES ; TUMORS ; ALPHA ; TARGET ; NO ; PROGRESSION ; MEMBRANE ; METASTASIS ; BETA ; CARCINOMAS ; RT-PCR ; STRATEGIES ; STOMACH ; adenocarcinoma ; ADENOCARCINOMAS ; TUMOR CELLS ; VEGF ; targeting ; molecular ; PATTERN ; THERAPIES ; EGFR ; analysis ; methods ; TUMOR-CELL ; NUCLEAR ; CANCERS ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; gastric ; PDGFR ; SUNITINIB ; VEGFR
    Abstract: AIM: To define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) in human gastric adenocarcinoma. METHODS: The (co-)expression pattern of VEGFRI-3, PDGFR alpha/beta and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. RESULTS: The majority of samples revealed a VEGFR1 (98%), VEGFR2 (80%), VEGFR3 (67%), PDGFR alpha (82%) and PDGFR beta (82%) expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRa revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additional nuclear staining for VEGFR3, EGFR1 was almost exclusively detected on the membrane of tumor cells. PDGFR,8 was restricted to stromal pericytes, which also depicted a PDGFRa expression. CONCLUSION: Our results reveal a high rate ofreceptor-tyrosine-kinases coexpression in gastric adenocarcinoma and might therefore encourage an application of multiple-target RTK-inhibitors within a combination therapy. (c) 2007 WJG. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17659711
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  • 10
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; tumor ; AGENTS ; carcinoma ; CELL ; Germany ; human ; DEATH ; HEPATOCELLULAR-CARCINOMA ; GENE ; PROTEIN ; DRUG ; TUMORS ; LINES ; gene transfer ; GENE-TRANSFER ; INFECTION ; REDUCTION ; hepatocytes ; FLOW ; CELL-LINES ; NO ; resistance ; VECTOR ; CELL-DEATH ; RATES ; CELL-LINE ; leukemia ; p53 ; TUMOR-SUPPRESSOR GENE ; DERIVATIVES ; HEPATOMA ; MINUTE VIRUS ; PARVOVIRUS H-1 ; AUTONOMOUS PARVOVIRUSES ; autonomous parvovirus ; NUCLEAR-BODIES ; CYTOTOXICITY ; WILD-TYPE P53 ; AGENT ; PANCREATIC-CANCER ; DEPENDENCE ; INCREASE ; parvovirus ; LEVEL ; methods ; P53-DEPENDENT APOPTOSIS ; DRUGS ; PEOPLE ; PROMYELOCYTIC LEUKEMIA PROTEIN ; BREAST-CANCER CELLS ; WORLD ; GEMCITABINE POTENTIATE ; human hepatocellular carcinoma
    Abstract: AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functional promyelocytic leukemia protein (PML). METHODS: The role of p53 and PML in regulating cytotoxicity and gene transfer mediated by wild-type (wt) PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Furthermore, H-1 PV infection was combined with cytostatic drug treatment. RESULTS: While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis, the cytotoxicity of H-1 PV was more pronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses, H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition, H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death. CONCLUSION: H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents, and it enhances the apoptotic process which is dependent on functional PML. Thus, H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC, particularly for p53-negative tumors. (C) 2008 The WJG Press. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18609705
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