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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; AGENTS ; human ; KINASE ; DISEASE ; LONG-TERM ; GENE ; GENES ; PROTEIN ; DRUG ; PATIENT ; ACTIVATION ; primary ; TRANSPLANTATION ; INDUCTION ; T-CELLS ; BINDING ; protein kinase ; TARGET ; CELL-DEATH ; INDUCED APOPTOSIS ; MODULATION ; LYMPHOCYTES ; CROHNS-DISEASE ; INFLAMMATORY-BOWEL-DISEASE ; 6- MERCAPTOPURINE ; CD28 ; COLITIS IN-VIVO ; GTPASE
    Abstract: Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine- generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L), was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation
    Type of Publication: Journal article published
    PubMed ID: 12697733
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  • 2
    Keywords: CANCER ; CANCER CELLS ; CELLS ; IN-VITRO ; tumor ; AGENTS ; Germany ; human ; PHASE-I ; VITRO ; DEATH ; TUMORS ; MICE ; TIME ; GENE-TRANSFER ; MARKER ; ANTIGEN ; DENDRITIC CELLS ; H-1 ; cytokines ; MATURATION ; virus ; VECTORS ; VECTOR ; CELL-DEATH ; MARKERS ; MELANOMA ; LYMPHOCYTES ; CANCER-CELLS ; MINUTE VIRUS ; IMMUNE-RESPONSE ; T-LYMPHOCYTES ; CTL ; AUTONOMOUS PARVOVIRUSES ; T lymphocytes ; CROSS-PRESENTATION ; HEAT-SHOCK PROTEINS ; CYTOLYTIC T-LYMPHOCYTES ; STANDARD ; AGENT ; VARIANT ; oncolytic virus ; ONCOLYTIC PARVOVIRUS ; HLA-A2 MELANOMAS ; cell death ; dendritic cell ; APOPTOTIC CELLS ; APC ; FUTURE-DIRECTIONS ; HUMAN-MELANOMA CELLS ; SERUM-FREE CONDITIONS
    Abstract: Oncotropic and oncolytic viruses have attracted high attention as antitumor agents because they preferentially kill cancer cells in vitro and reduce the incidence of spontaneous, induced, or implanted animal tumors. Some autonomous parvoviruses (H-1, minute virus of mice) and derived recombinant vectors are currently under preclinical evaluation. Still not fully understood, their antitumor properties involve more than just tumor cell killing. Because wild-type parvovirus-mediated tumor cell lysates (TCLs) may trigger antigen-presenting cells (APCs) to augment the host immune repertoire, we analyzed phagocytosis, maturation, and cross-presentation of H-1-induced TCLs by human dendritic cells (DCs). We first established H-1-mediated oncolysis in two HLA-A2(+) and A2(-) variant melanoma cell clones. Monocyte-derived immature DCs phagocytosed H-1-infected TCLs as well as ultraviolet-induced apoptotic TCLs and better than freeze-thaw-induced necrotic TCLs. Immature DCs incubated with H-1-induced TCLs acquired specific maturation markers comparable to a standard cytokine cocktail. Furthermore, A2(+) DCs pulsed with H-1-infected A2(-) TCLs cross-presented melanoma antigens to specific cytotoxic T lymphocytes (CTLs) and released proinflammatory cytokines. This shows for the first time that tumor cell killing by a wild-type oncolytic virus directly stimulates human APCs and CTLs. Because H-1-infected tumors enhance the immune repertoire, the clinical perspectives of parvoviral vectors are even more promising
    Type of Publication: Journal article published
    PubMed ID: 16076257
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  • 3
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; SURVIVAL ; tumor ; TUMOR-CELLS ; carcinoma ; CELL LUNG-CANCER ; Germany ; VITRO ; DISEASE ; LINES ; PATIENT ; ACTIVATION ; RECEPTOR EXPRESSION ; prognosis ; CELL-LINES ; PROGRESSION ; ASSAY ; DESIGN ; NUMBER ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; LINE ; CANCER-CELLS ; MIGRATION ; RECEPTORS ; BEHAVIOR ; POOR-PROGNOSIS ; cell lines ; CELL-MIGRATION ; chemokine ; LOCATION ; ANTAGONIST ; intensity ; LYMPH-NODE METASTASIS ; CHEMOKINE RECEPTORS ; cell migration ; ASSAYS ; DISSEMINATION ; CELL-DERIVED FACTOR ; DISEASE PROGRESSION ; MATURE DENDRITIC CELLS
    Abstract: Purpose: The expression of chemokine receptors CXCR4 and CCR.7 has been associated with tumor dissemination and poor prognosis in a limited number of tumor entities. However, no data are currently available on the impact of chemokine receptor expression on disease progression and prognosis in human colorectal cancer. Experimental Design: The expression of CXCR4 and CCR7 was evaluated in 96 patients with histologically confirmed colorectal cancers and in four colorectal cancer cell lines by immunohistochemical staining. Furthermore, cell migration assays were done with SW480, SW620, and LS174T cancer cells to confirm the effect of the CXCR4 ligand stromal cell-derived factor 1alpha on migration. Results: Human colorectal cancer specimens and cell lines displayed a CXCR4 and CCR7 expression with variable intensities. Interestingly, strong expression of CXCR4, but not of CCR7, was significantly associated with higher Union International Contre Cancer stages 3/4 (P = 0.0017), lymph node metastasis (P = 0.00375), and distant metastasis (P = 0.00003) and further correlated with a reduced 3-year survival rate (P = 0.1). Strong CXCR4 and CCR7 expression positively correlated with the location of the primary tumor in the rectum (P 〈 0.01). Furthermore, activation of CXCR4-expressing cancer cells by stromal cell-derived factor 1alpha resulted in a significant increase of cell migration (P 〈 0.014). Conclusion: Strong expression of CXCR4 by colorectal cancer cells is significantly associated with lymphatic and distant dissemination in patients with colorectal cancer as well as with cancer cell migration in vitro
    Type of Publication: Journal article published
    PubMed ID: 15755995
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  • 4
    Keywords: CANCER ; EXPRESSION ; Germany ; GENE ; PROTEIN ; PROTEINS ; transcription ; TISSUE ; SURGERY ; LINES ; PATIENT ; COMPLEX ; DOMAIN ; tumour ; CELL-LINES ; SEQUENCE ; PROGRESSION ; ASSAY ; Drosophila ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; LINE ; REGION ; MUTATIONS ; ADHESION ; MIGRATION ; cytoskeleton ; POLYMERASE-CHAIN-REACTION ; cell lines ; CELL-MIGRATION ; BINDS ; CELL POLARITY ; MAPS ; colon cancer ; TUMORIGENESIS ; cell adhesion ; cell migration ; ASSAYS ; SUPPRESSOR ; tumour suppressor ; APC ; 17P11.2 ; Hugl-1 ; II HEAVY-CHAIN ; LETHAL-GIANT-LARVAE ; lgl
    Abstract: The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal( 2) giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression
    Type of Publication: Journal article published
    PubMed ID: 15735678
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  • 5
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; proliferation ; CELL ; Germany ; IN-VIVO ; LUNG ; MODEL ; PATHWAY ; VITRO ; VIVO ; SAMPLE ; SAMPLES ; transcription ; DIFFERENTIATION ; LINES ; MICE ; IMPACT ; prognosis ; CELL-LINES ; PHOSPHORYLATION ; TARGET ; ASSAY ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; SIGNALING PATHWAY ; CANCER-CELLS ; MIGRATION ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; TARGETS ; cell lines ; AKT ; HOMEOBOX GENE ; signaling ; HUMAN PROSTATE ; development ; ASSAYS ; PROGENITORS ; colorectal ; TAIL ; MicroRNAs ; POLYMERASE ; CANCER-CELL-LINES ; RESTRICTION ; Homeobox ; HOXB8 ; HUMAN LUNG CANCERS ; Micro-RNA ; miR-196a
    Abstract: AIM: To analyze the relevance of the microRNA miR-196a for colorectal oncogenesis. METHODS: The impact of miR-196a on the restriction targets HoxA7, HoxB8, HoxC8 and HoxD8 was analyzed by reverse transcription polymerase chain reaction (RT-PCR) after transient transfection of SW480 cancer cells. The miR-196a transcription profile in colorectal cancer samples, mucosa samples and diverse cancer cell lines was quantified by RT-PCR. Transiently miR-196a-transfected colorectal cancer cells were used for diverse functional assays in vitro and for a xenograft lung metastasis model in vivo. RESULTS: HoxA7, HoxB8, HoxC8 and HoxD8 were restricted by miR-196a in a dose-dependent and gene-specific manner. High levels of miR-196a activated the AKT signaling pathway as indicated by increased phosphorylation of AKT. In addition, high levels of miR-196a promoted cancer cell detachment, migration, invasion and chemosensitivity towards platin derivatives but did not impact on proliferation or apoptosis. Furthermore, miR-196a increased the development of lung metastases in mice after tail vein injection. CONCLUSION: miR-196a exerts a pro-oncogenic influence in colorectal cancer.(C) 2009 The WIG Press and Baishideng. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19418581
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; proliferation ; CELL ; Germany ; IN-VIVO ; liver ; PROTEIN ; DIFFERENTIATION ; MICE ; ACTIVATION ; MECHANISM ; FAMILY ; T cells ; MEMBERS ; SUSCEPTIBILITY ; antibody ; DELETION ; MOUSE ; RATES ; DAMAGE ; B-CELLS ; INJURY ; FAMILIES ; development ; FULMINANT HEPATIC-FAILURE ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; MAINTENANCE ; GROWTH-FACTORS ; OCCURS ; 33 ; ANTI-FAS ; BCL-2 PROTEINS
    Abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. It interacts with proapoptotic Bcl-2 family members, thereby inhibiting mitochondrial activation and induction of apoptosis. Mcl-1 is essential for embryonal development and the maintenance of B cells, T cells, and hematopoietic stem cells. We have recently shown that induction of Mcl-1 by growth factors rescues primary human hepatocy-tes from CD95-mediated apoptosis. This prompted us to further analyze the relevance of Mcl-1 for hepatocellular homeostasis. Therefore, we generated a hepatocyte-specific Mcl-1 knockout mouse (Mcl-1(flox/flox)-AlbCre). Deletion of Mcl-1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl-1(flox/flox)-AlbCre mice are smaller compared to control littermates, due to higher apoptosis rates. As a compensatory mechanism, proliferation of hepatocytes is enhanced in the absence of Mcl-1. Importantly, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage. Furthermore, Mcl-1(flox/flox)-AlbCre mice are more susceptible to hepatocellular damage induced by agonistic anti-CD95 antibodies or concanavalin A. Conclusion: The present study provides in vivo evidence that Mcl-1 is a crucial antiapoptotic factor for the liver, contributing to hepatocellular homeostasis and protecting hepatocytes from apoptosis induction. (HEPATOLOGY 2009;49:627-636.)
    Type of Publication: Journal article published
    PubMed ID: 19127517
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  • 7
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; IN-VIVO ; PATHWAY ; VIVO ; DEATH ; DISEASE ; HEPATOCELLULAR-CARCINOMA ; liver ; PROTEIN ; TUMORS ; MICE ; MECHANISM ; FAMILY ; MARKER ; CARCINOGENESIS ; DELETION ; hepatocellular carcinoma ; CELL-DEATH ; AGE ; DAMAGE ; REGULATOR ; MITOSIS ; Bcl-2 ; INJURY ; HUMAN CANCER ; SURVIVIN ; cell death ; CANCERS ; HOMEOSTASIS ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; LIVER-REGENERATION
    Abstract: Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Delta hep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in 〉50% of Mcl-1(Delta hep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Delta hep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. (HEPATOLOGY 2010;51:1226-1236.)
    Type of Publication: Journal article published
    PubMed ID: 20099303
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  • 8
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; CELL ; Germany ; CLASSIFICATION ; SURGERY ; T-CELL ; T-CELLS ; BREAST-CANCER ; PROGRESSION ; immunohistochemistry ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; LYMPHOCYTES ; CANCER-PATIENTS ; IMMUNITY ; GASTRIC-CANCER ; inflammation ; CHEMOKINE RECEPTOR ; CCR5 ; PROGNOSTIC-FACTOR ; IMMUNE ; CCL5/RANTES ; T-cell infiltration
    Abstract: Chemokines and their receptors have been proposed to distinctly contribute to tumor growth, dissemination, and local immune escape. The aim of this study was to evaluate the relevance of the chemokine receptor CCR5 expression for the progression of human colorectal cancer. CCR5 expression was assessed by RT-PCR analysis in 103 colorectal cancer patients. Intensity of CCR5 expression was correlated with both tumor and patient characteristics. Infiltration of tumor margins with CD8(+) T cells in the context of CCR5 expression was analyzed by immunohistochemistry in additional 18 colorectal cancer specimens. Human colorectal cancer revealed variable intensities of CCR5 expression ranging from absent (48/103: 47%), weak (30/103: 29%), intermediate (13/103: 13%), to strong (12/103: 12%). Absent or weak CCR5 expression was significantly associated with advanced UICC stages (P = 0.02) and lymphatic metastasis (P = 0.05). In addition, CCR5 expression positively correlated with CD8(+) T-cell infiltration in tumor margins (P = 0.001). In summary, intermediate and strong CCR5 expression was significantly associated with nonmetastatic colorectal cancer and increased CD8(+) T-cell infiltration
    Type of Publication: Journal article published
    PubMed ID: 20054600
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  • 9
    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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  • 10
    Abstract: Background and Aims: p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and Delta N. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (Delta N) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of Delta Np73 in hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we investigated the molecular mechanisms accounting for the oncogenic role of Delta Np73 in HCC. Results:Delta Np73 beta can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of proapoptotic target genes. Interference of Delta Np73 beta with apoptosis-/chemosensitivity takes place at several levels of apoptosis signaling. Delta Np73 beta negatively regulates the genes encoding for the death receptors CD95, TNF-R1, TRAIL-R2 and TNFRSF18. Furthermore, Delta Np73 beta represses the genes encoding caspase-2, -3, -6, -8 and -9. Concomitantly, Delta Np73 beta inhibits apoptosis emanating from mitochondria. Conclusions: Thus, Delta Np73 expression in HCC selects against both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. Our data suggest that Delta Np73 isoforms repress apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways thereby contributing to chemoresistance. The clinical importance of these data is evidenced by our finding that the Delta Np73 beta target gene signature can predict the prognosis of patients suffering from HCC
    Type of Publication: Journal article published
    PubMed ID: 20581467
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