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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
    Keywords: CANCER ; IN-VITRO ; Germany ; COHORT ; LONG-TERM ; RISK ; PATIENT ; colon ; CONTRAST ; NO ; ADENOMAS ; prevention ; colorectal cancer ; PROSPECTIVE COHORT ; COLORECTAL-CANCER ; GREEN TEA ; RECURRENCE ; COLON-CANCER ; SURVEILLANCE ; QUESTIONNAIRE ; RANDOMIZED-TRIAL ; colonoscopy ; FLAVONOIDS ; methods ; PEOPLE ; comparison ; WORLD ; DIETARY FLAVONOIDS ; BLACK TEA ; colon polyps ; COLONOSCOPY SURVEILLANCE ; CONSENSUS UPDATE ; flavonoid ; intestinal neoplasia ; recurrence risk ; VITAMIN-D INTAKE
    Abstract: AIM: To investigate biological prevention with flavonoids the recurrence risk of neoplasia was studied in patients with resected colorectal cancer and after adenoma polypectomy. METHODS: Eighty-seven patients, 36 patients with resected colon cancer and 51 patients after polypectomy, were divided into 2 groups: one group was treated with a flavonoid mixture (daily standard dose 20 mg apigenin and 20 mg epigallocathechin-gallat, n = 31) and compared with a matched control group (n = 56). Both groups were observed for 3-4 years by surveillance colonoscopy and by questionnaire. RESULTS: Of 87 patients enrolled in this study, 36 had resected colon cancer and 29 of these patients had surveillance colonoscopy. Among the flavonoid-treated patients with resected colon cancer (n = 14), there was no cancer recurrence and one adenoma developed. In contrast the cancer recurrence rate of the 15 matched untreated controls was 20% (3 of 15) and adenomas evolved in 4 of those patients (27%). The combined recurrence rate for neoplasia was 7% (1 of 14) in the treated patients and 47% (7 of 15) in the controls (P = 0.027). CONCLUSION: Sustained long-term treatment with a flavonoid mixture could reduce the recurrence rate of colon neoplasia in patients with resected colon cancer. (C) 2008 WJG. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18407592
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  • 3
    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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  • 4
  • 5
    Keywords: ELDERLY-PATIENTS ; SUPPORTIVE CARE ; COOPERATIVE-ONCOLOGY-GROUP ; PHASE-III TRIAL ; ADVANCED GASTRIC-CANCER ; 1ST-LINE THERAPY ; ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE ; COMPREHENSIVE GERIATRIC ASSESSMENT ; ESOPHAGOGASTRIC CANCER ; YOUNGER PATIENTS
    Abstract: AIM: To investigate the outcome of palliative chemotherapy in old patients with gastroesophageal cancer at the National Center for Tumor Diseases, Heidelberg. METHODS: Using a prospectively generated database, we retrospectively analyzed 55 patients 〉= 70 years under palliative chemotherapy for advanced gastroesophageal cancer at the outpatient clinic of the National Center for Tumor Diseases Heidelberg, Germany between January 2006 and December 2013. Further requirements for inclusion were (1) histologically proven diagnosis of gastroesophageal cancer; (2) advanced (metastatic or inoperable) disease; and (3) no history of radiation or radiochemotherapy. The clinical information included Eastern Cooperative Oncology Group performance status (ECOG PS), presence and site of metastases at diagnosis, date of previous surgery and perioperative chemotherapy, start and stop date of first-line treatment, toxicities and consecutive dosage reductions of first- line treatment, response to first- line therapy, date of progression, usage of second- line therapies and date and cause of death. Survival times [progression- free survival (PFS), overall survival (OS) and residual survival (RS)] were calculated. Toxicity and safety were examined. Prognostic factors including ECOG PS, age and previous perioperative treatment were analyzed. RESULTS: Median age of our cohort was 76 years. 86% of patients received a combination of two cytotoxic drugs. 76 percent of patients had an oxaliplatin-based first-line therapy with the oxaliplatin and 5-fluorouracil regimen being the predominantely chosen regimen (69%). Drug modifications due to toxicity were necessary in 56% of patients, and 11% of patients stopped treatment due to toxicities. Survival times of our cohort are in good accordance with the major phase. trials that included mostly younger patients: PFS and OS were 5.8 and 9.5 mo, respectively. Survival differed significantly between patient groups with low (〈= 1) and high (〉= 2) ECOG PS (12.7 mo vs 3.8 mo, P 〈 0.001). Very old patients (〉= 75 years) did not show a worse outcome in terms of survival. Patients receiving second-ine treatment (51%) had a significantly longer RS than patients with best supportive care (6.8 vs 1.4 mo, P = 0.001). Initial ECOG PS was a strong prognostic factor for PFS, OS and RS. CONCLUSION: Old patients with non-curable gastroesophageal cancer should be offered chemotherapy, and ECOG PS is a tool for balancing benefit and harm upfront. Second-line treatment is reasonable.
    Type of Publication: Journal article published
    PubMed ID: 25945004
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  • 6
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; TUMOR-CELLS ; carcinoma ; Germany ; human ; SYSTEM ; PROTEIN ; DIFFERENTIATION ; TISSUE ; LINES ; PATIENT ; ACTIVATION ; COMPLEX ; COMPLEXES ; MARKER ; TISSUES ; CELL-LINES ; PLASMA ; COLORECTAL-CANCER ; CELL-LINE ; LINE ; TISSUE FACTOR ; adenocarcinoma ; cell lines ; pancreatic cancer ; pancreatic carcinoma ; chronic pancreatitis ; PANCREATIC-CANCER ; THROMBOSIS ; LEVEL ; pancreatic ; EXTRACELLULAR-MATRIX PROTEINS ; FRAGMENT ; PULMONARY-EMBOLISM ; CLINICAL COURSE ; coagulation activation ; HUMAN DUCTAL ADENOCARCINOMAS ; NORTHERN ; thromboembolism ; VENOUS THROMBOEMBOLISM
    Abstract: AIM: To study expression of tissue factor (TF) in pancreatic cancer and its role in the development of thromboembolism. METHODS: TF expression was studied in eight human pancreatic carcinoma cell lines by Northern blot and indirect immunofluorescence. Expression of alternatively spliced TF (asTF) was assessed by RTPCR. In addition, TF expression was determined by immunofluorescence in pancreatic tissues of 19 patients with pancreatic adenocarcinoma (PCa), 9 patients with chronic pancreatitis (CP) and 20 normal controls. Plasma samples (30 PCa-patients, 13 CP-patients and 20 controls) were investigated for soluble TF levels and coagulation activation markers [thrombin-antithrombin III complex (TAT), prothrombin fragment 1 + 2 (F1 + 2)]. RESULTS: All pancreatic carcinoma cell lines expressed TF (8/8) and most of them expressed asTF (6/8). TF expression at the protein level did not correlate with the differentiation of the carcinoma cell line. All but two pancreatic cancer tissue samples stained positive for TF (17/19). In all samples of CP weak staining was restricted to pancreatic duct cells, whereas only a few subendothelial cells were positive in 9/20 of normal controls. TF and TAT levels in PCa patients were significantly elevated compared to controls whereas elevated F1 + 2 levels did not reach statistical significance compared to controls. In CP patients TAT and F1 + 2 levels proved to be significantly elevated compared to controls, although TAT elevation was less pronounced than in PCa patients. CONCLUSION: We conclude that in addition to the upregulated expression of TF on the cell membrane, soluble TF might contribute to activation of the coagulation system in pancreatic cancer. (C) 2006 The WJG Press. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16937466
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  • 7
    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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  • 8
    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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  • 9
    Keywords: ENDOTHELIAL GROWTH-FACTOR ; GENE-EXPRESSION ; SIGNALING PATHWAYS ; EXTRACELLULAR-MATRIX ; OSTEOPONTIN EXPRESSION ; MESENCHYMAL TRANSITION ; DUCTAL ADENOCARCINOMA CELLS ; BONE SIALOPROTEIN-II ; MATRICELLULAR GLYCOPROTEIN ; BIOLOGICAL FUNCTIONS
    Abstract: Pancreatic cancer has a considerably poor prognosis with a 5-year survival probability of less than 5% when all stages are combined. Pancreatic cancer is characterized by its dense stroma, which is involved in the critical interplay with the tumor cells throughout tumor progression and furthermore, creates a barrier restricting efficient penetration of therapeutics. Alterations in a large number of genes are reflected by a limited number of signaling pathways, which are potential targets. Understanding more about the molecular basis of this devastating cancer type regarding tumor microenvironment, distinct subpopulations of cells, epithelial-to-mesenchymal transition and inflammation will lead to the development of various targeted therapies for controlling tumor growth and metastasis. In this complex scenario of pancreatic cancer, especially members of the "small integrin binding ligand N-linked glycoproteins" (SIBLINGs) and "secreted protein acidic and rich in cysteine" (SPARC) families have emerged due to their prominent roles in properties including proliferation, differentiation, apoptosis, adhesion, migration, angiogenesis, wound repair and regulation of extracellular matrix remodeling. SIBLINGs consist of five members, which include osteopontin (OPN), bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein. The SPARC family of modular extracellular proteins is comprised of SPARC/osteonectin (ON) and SPARC-like 1 (hevin); secreted modular calcium binding proteins; testicans and follistatin-like protein. In this review, we especially focus on OPN and ON, elaborating on their special and growing importance in pancreatic cancer diagnosis and prognosis.
    Type of Publication: Journal article published
    PubMed ID: 25356037
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  • 10
    Keywords: ENDOTHELIAL GROWTH-FACTOR ; DUCTAL ADENOCARCINOMA ; RANDOMIZED CONTROLLED-TRIAL ; CURATIVE RESECTION ; COOPERATIVE-ONCOLOGY-GROUP ; PHASE-III TRIAL ; PLUS GEMCITABINE ; ALGENPANTUCEL-L IMMUNOTHERAPY ; STANDARD ADJUVANT THERAPY ; LONG-TERM OUTCOMES
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and, in most cases, PDAC is diagnosed at advanced disease stages, when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize, which involve essential adaptive changes in cellular metabolism, signaling, adhesion and immunoediting. In addition, PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades, gemcitabine has been the reference for the systemic treatment of PDAC. However, recently, a regimen combining fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC, with survival outcomes of 11.3 and 8.5 mo on phase III trials, respectively, over single-agent gemcitabine. With the pending issue of their higher toxicities, these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition, the efficacy of oral fluoropyrimidine (S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past, with only one drug (erlotinib) approved to date. Besides, a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise, immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.
    Type of Publication: Journal article published
    PubMed ID: 26309356
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