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  • 1
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; SURVIVAL ; CELL ; Germany ; human ; KINASE ; PATHWAY ; PATHWAYS ; DISEASE ; liver ; PROTEIN ; PROTEINS ; transcription ; TRANSDUCTION ; ACTIVATION ; FAMILY ; primary ; INDUCTION ; hepatocytes ; ACTIVATED PROTEIN-KINASE ; MEMBER ; SIGNAL ; CLEAVAGE ; CELL-SURVIVAL ; DAMAGE ; KAPPA-B ; RAT HEPATOCYTES ; CASPASE 8 ; Bcl-2 ; HUMAN HEPATOCYTES ; CD95 ; PHOSPHOINOSITIDE 3-KINASE ; MEDIATED APOPTOSIS ; SIGNAL TRANSDUCER ; ACID-INDUCED APOPTOSIS ; ACUTE LIVER-INJURY ; FULMINANT HEPATIC-FAILURE ; MITOCHONDRIAL RELEASE
    Abstract: CD95 (APO-1/Fas)-mediated apoptosis of hepatocytes plays a central role in the pathophysiology of various human liver diseases. Hepatocyte growth factor (HGF) was shown to exert antiapoptotic functions in rodent hepatocytes. We previously showed that primary human hepatocytes (PHH) are a valuable toot for the investigation of apoptotic processes in liver cells. In this study, we analyzed the influence of HGF on CD95-mediated apoptosis of PHH and its molecular determinants. HGF significantly inhibited CD95-mediated apoptosis of PHH as well as cleavage of caspase-8 and poly (ADP-ribose)polymerase. HGF transcriptionally induced the expression of the anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1). In contrary, HGF did not alter the expression levels of Bcl-2 or Bcl-(XL). HGF activated survival pathways such as the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK and the signal transducer and activator of transcription 3 (STAT3) pathway. Notably, HGF triggered serine(727)-but not tyrosine(705)-phosphorylation of STAT3. Pretreatment of PHH with the PI3K inhibitor LY294002 as well as adenoviral transduction of dominant negative Akt1 prevented HGF-mediated Mcl-1 induction and reversed the antiapoptotic effects of HGF. In conclusion, HGF confers survival of PHH by activation of the PI3K/Akt pathway. PI3K/Akt activation by HGF results in the induction of antiapoptotic proteins such as Mcl-1. Thus, application of HGF may be a therapeutic approach to prevent CD95-mediated hepatocellular damage in human liver diseases
    Type of Publication: Journal article published
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  • 2
    Keywords: RECEPTOR ; SPECTRA ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; tumor ; CELL ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; TYROSINE KINASE ; VIVO ; QUANTIFICATION ; DEATH ; DISEASE ; GENE ; PROTEIN ; cell line ; LINES ; PATIENT ; LIGAND ; FLOW ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; protein kinase ; PROTEIN-KINASE ; TYROSINE KINASE INHIBITOR ; TARGET ; PROGRESSION ; immunohistochemistry ; ASSAY ; CELL-DEATH ; MUTATION ; CELL-LINE ; LINE ; MUTATIONS ; CANCER-PATIENTS ; POLYMERASE-CHAIN-REACTION ; PROTEIN-KINASE-C ; CHAIN-REACTION ; RECEPTORS ; CANCER PATIENTS ; point mutation ; cell lines ; pancreatic cancer ; RANDOMIZED-TRIAL ; TUMOR ANGIOGENESIS ; MANAGEMENT ; CELL-CYCLE PROGRESSION ; INHIBITORS ; CELL-GROWTH ; CHAIN ; ONCOLOGY ; PANCREATIC-CANCER ; TUMOR-GROWTH ; flow cytometry ; THERAPIES ; ACUTE MYELOID-LEUKEMIA ; polymerase chain reaction ; REAL-TIME ; POINT MUTATIONS ; MURINE MODEL ; TYROSINE KINASES ; analysis ; methods ; pancreatic ; ASSAYS ; cell death ; BIOLOGICAL-ACTIVITY ; USA ; POTENTIAL ROLE ; vascular endothelial growth factor ; COMPOUND ; in vivo ; SPECTRUM ; SPECIMENS ; KINASE INHIBITOR ; GROWTH-FACTOR-RECEPTOR ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; - ; POINT ; modeling ; quantitative ; block ; ACTIVATING MUTATION ; ENDOTHELIAL GROWTH ; FLT3 ; FLT3 MUTATIONS ; INTERNATIONAL CONSENSUS ; PKC412 ; SOLID HUMAN TUMORS ; VEGF-RII
    Abstract: BACKGROUND. PKC412 is a kinase inhibitor that blocks protein kinase C (PKC), vascular endothelial growth factor receptors, platelet-derived growth factor receptor FLT3, and other class III receptor tyrosine kinases. The enthusiasm for this compound is based on its inhibitory effect even in the case of FLT3 mutations. The aim of this study was to analyze the role of FLT3 in pancreatic cancer and to study the biological activity of combined inhibition of neovascularization and mitogenesis in this disease. METHODS. FLT3 expression was analyzed in 18 pancreatic cancer specimens by real-time quantitative polymerase chain reaction (RTQ-PCR) and immunohistochemistry. Sixteen pancreatic cancer cell lines were screened for ITD and D835 point mutations of the FLT3 gene. MTT assays and anchorage-independent growth assays were used to study cell growth. Flow cytometry was used for cell cycle analysis and apoptosis quantification. In vivo AsPC-1 and HIAF-II cells were used for orthotopic tumor modeling. Immunohistochemistry was used to quantity tumor angiogenesis. RESULTS. FLT3 expression is down-regulated in pancreatic cancer. Activating FLT3 mutations (ITD, D835) were not detectable in any of the pancreatic cancer cell lines. Cell growth was significantly inhibited as cell-cycle progression was reduced and programmed cell death increased. In vivo PKC412 therapy resulted in a significant inhibition of orthotopic tumor growth with abrogation of tumor angiogenesis. CONCLUSIONS. These data highlight that PKC412 may be a new compound in target therapy of inoperable pancreatic cancer patients and suggest a potential role for the combined use of broad spectrum kinase inhibitors in the management of these patients
    Type of Publication: Journal article published
    PubMed ID: 17676584
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; tumor ; COMBINATION ; Germany ; human ; IN-VIVO ; TOXICITY ; VITRO ; DEATH ; liver ; DRUG ; DIFFERENTIATION ; MONOCLONAL-ANTIBODY ; TISSUE ; NF-KAPPA-B ; FAMILY ; MARKER ; INDUCTION ; treatment ; 5-FLUOROURACIL ; DESIGN ; INDUCED APOPTOSIS ; HUMAN LIVER ; sensitivity ; CISPLATIN ; TRAIL ; ETOPOSIDE ; HUMAN HEPATOCYTES ; APOPTOSIS-INDUCING LIGAND ; GEMCITABINE ; RE ; TUMORICIDAL ACTIVITY ; CHEMOTHERAPEUTIC DRUGS ; function ; BLOCKADE ; DRUGS ; CANCERS ; ANTITUMOR ; HEPATOCELLULAR-CARCINOMA CELLS
    Abstract: Purpose: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) exhibits potent antitumor activity on systemic administration in nonhuman primates without deleterious side effects for normal tissue. However, there is a controversy about the potential toxicity of TRAIL on human hepatocytes. The use of different recombinant TRAIL forms only partially explains the contradicting reports on FRAIL sensitivity in primary human hepatocytes (PHH). Experimental Design: To clarify this issue, we comprehensively tested four different recombinant forms of TRAIL for their apoptosis-inducing capacity on PHH obtained from a total of 55 human livers between day 1 and day 8 of in vitro culture. Results: One day after single-cell isolation, all but one recombinant form of TRAIL [i.e., an untagged form of TRAIL (TRAIL.0)] induced apoptosis in PHH. Apoptosis induction by TRAIL in these cells could only be fully inhibited by concomitant blockade of TRAIL receptor 1 and TRAIL receptor 2. At day 4 of in vitro culture, when surrogate markers indicated optimal hepatocyte in vitro function, only high doses of cross-linked FLAG-TRAIL killed PHH whereas the other three recombinant TRAIL forms did not. Strikingly, cotreatment of day 4 PHH with cisplatin sensitized for TRAIL-induced apoptosis whereas 5-fluorouracil, etoposide, gemcitabine, irinotecan, or oxaliplatin, which are commonly used in the treatment of gastrointestinal cancers, did not. Conclusion: Our data show that whereas TRAIL alone or together with selected chemotherapeutic drugs seems to be safe, the combination of TRAIL with cisplatin is toxic to PHH
    Type of Publication: Journal article published
    PubMed ID: 16638878
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  • 4
    Keywords: ANGIOGENESIS ; CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; BLOOD ; carcinoma ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; IN-VIVO ; MICROSCOPY ; VITRO ; VIVO ; DENSITY ; DIFFERENTIATION ; MICE ; fibroblasts ; BONE-MARROW ; NUDE-MICE ; CANCER-CELLS ; ADHESION ; MIGRATION ; STEM-CELLS ; RECRUITMENT ; VESSELS ; pancreatic cancer ; pancreatic carcinoma ; VEGF ; INHIBITORS ; ELISA ; ONCOLOGY ; pancreas ; PANCREATIC-CANCER ; fibroblast ; BLOOD-VESSELS ; stem cells ; analysis ; BONE ; ENGLAND ; tumor stroma ; VESSEL MATURATION ; STEM ; SMOOTH-MUSCLE-CELLS ; mesenchymal stem cells ; MARROW ; MARROW STROMAL CELLS ; EGF ; lentivirus ; MSC
    Abstract: Little is known about the factors that enable the mobilisation of human mesenchymal stem cells (MSC) from the bone marrow into the blood stream and their recruitment to and retention in the tumour. We found specific migration of MSC towards growth factors present in pancreatic tumours, such as PDGF, EGF, VEGF and specific inhibitors Glivec, Erbitux and Avastin interfered with migration. Within a few hours, MSC migrated into spheroids consisting of pancreatic cancer cells, fibroblasts and endothelial cells as measured by time-lapse microscopy. Supernatant from subconfluent MSC increased sprouting of HUVEC due to VEGF production by MSC itself as demonstrated by RT-PCR and ELISA. Only few MSCs were differentiated into endothelial cells in vitro, whereas in vivo differentiation was not observed. Lentiviral GFP-marked MSCs, injected in nude mice xenografted with orthotopic pancreatic tumours, preferentially migrated into the tumours as observed by FACS analysis of green fluorescent cells. By immunofluorescence and intravital microscopic studies, we found the interaction of MSC with the endothelium of blood vessels. Mesenchymal stem cells supported tumour angiogenesis in vivo, that is CD31(+) vessel density was increased after the transfer of MSC compared with siVEGF-MSC. Our data demonstrate the migration of MSC toward tumour vessels and suggest a supportive role in angiogenesis
    Type of Publication: Journal article published
    PubMed ID: 18665180
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  • 5
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; tumor ; CELL ; Germany ; human ; LUNG ; THERAPY ; TOOL ; liver ; POPULATION ; GENE ; GENES ; PROTEIN ; DIFFERENTIATION ; gene therapy ; MICE ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; kidney ; BONE-MARROW ; MOUSE ; NUMBER ; genetics ; NUDE-MICE ; FUSION ; MIGRATION ; STEM-CELLS ; PROGENITOR CELLS ; SELECTION ; GENE-THERAPY ; RETROVIRAL VECTORS ; pancreatic cancer ; heredity ; VELOCITY ; ONCOLOGY ; homing ; XENOGRAFTS ; THERAPIES ; EX-VIVO ; HUMAN BONE-MARROW ; stem cells ; BONE ; EXTENT ; microbiology ; ENGLAND ; STEM ; UMBILICAL-CORD BLOOD ; MEDICINE ; biotechnology ; modification ; mesenchymal stem cells ; DELIVERY VEHICLES ; INDUCIBLE RNA INTERFERENCE ; lentiviral transduction ; TARGETED-DELIVERY
    Abstract: Genetic modification of human bone marrow mesenchymal stem cells ( MSC) is highly valuable for their exploitation in basic science and therapeutic applications, for example in cancer. We present here a new, fast and easy-to-use method to enrich a functional population of lentiviral (LV)-transduced MSC expressing enhanced green fluorescent protein (eGFP). We replaced the eGFP gene by a fusion gene of puromycin acetyltransferase and eGFP. Upon LV gene transfer and puromycin selection, we quickly obtained a pure transduced MSC population, in which growth, differentiation capacity and migration preferences were not compromised. Furthermore, we are the first to report the migration velocity of MSC among which 30% were moving and velocity of about 15 mu mh(-1) was not altered by LV transduction. Manipulated MSC underwent senescence one passage earlier than non-transduced cells, suggesting the use for therapeutic intervention in early passage numbers. Upon tail vein application in nude mice, the majority of LV-transduced MSC could be detected in human orthotopic pancreatic tumor xenografts and to a minor extent in mouse liver, kidney and lung. Together, LV transduction of genes to MSC followed by puromycin selection is a powerful tool for basic research and improves the therapeutic prospects of MSC as vehicles in gene therapy
    Type of Publication: Journal article published
    PubMed ID: 18202717
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