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  • 1
    Keywords: EXPRESSION ; Germany ; MARKER ; PROSTATE-CANCER ; MASS-SPECTROMETRY ; BENIGN ; adenocarcinoma ; pancreatic cancer ; biomarker ; cachexia ; DIPEPTIDYL-PEPTIDASE-IV ; GLUCAGON-LIKE PEPTIDE-1 ; Glucagon-like peptide-1 (GLP-1) ; LIPID-MOBILIZING FACTOR ; Zinc-alpha 2-glycoprotein (ZAG) ; ZINC-ALPHA(2)-GLYCOPROTEIN ; ZINC-ALPHA-2-GLYCOPROTEIN
    Abstract: AIMS: Treatment of cachexia requires pharmacological intervention which, in turn, requires knowledge of the mediators and processes. Cachexia markers that are specifically expressed in pancreatic cancer and secreted into the blood circulation have yet to be identified. The aim of our study was to investigate the serum protein profiles and protein alterations associated with cachexia and to identify potential disease protein biomarkers indicative for this syndrome. MAIN METHODS: Serum samples from cachectic and non-cachectic patients undergoing pancreatic cancer (PaCa) surgery and controls were investigated by Surface Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS). The identity of detected discriminatory markers was determined by a combination of protein fractionation, chromatographic purification steps, gel electrophoresis, and mass spectrometry. KEY FINDINGS: Using Cu-IMAC array and CM-10 array based SELDI-TOF-MS. we identified eleven up- and four down-regulated proteins associated with cachexia. CiphergenExpress analysis revealed four disease-associated protein features (38559Da, 9138Da, 8925Da and 3358Da) that were elevated by a factor of 2.3, 1.7, 1.4 and 1.4, respectively. Zinc-alpha2-glycoprotein (ZAG), apolipoproteins apo C-II and apo C-III and glucagon-like peptide-1 (GLP-1) were identified as markers for PaCa-associated cachexia syndrome. ZAG levels were additionally evaluated in serum and tissue samples by ELISA and immunohistochemistry and the obtained data confirmed the SELDI-TOF-MS results. SIGNIFICANCE: The identified proteins could be routinely and reliably measured in the serum of patients and provide an elegant non-invasive approach for early diagnosis of cachectic pancreatic cancer patients. Controlling ZAG and GLP-1 activity could be beneficial in the management of cancers and cachexia-induced conditions.
    Type of Publication: Journal article published
    PubMed ID: 21094171
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  • 2
    Keywords: CELLS ; EXPRESSION ; carcinoma ; FACTOR RECEPTOR ; IN-VIVO ; PROTEIN ; HEAD ; NECK ; pancreatic cancer ; PROTEOMICS ; EPIDERMAL-GROWTH-FACTOR ; SERUM ; biomarker ; exosome ; METASTATIC BREAST-CANCER ; TARGETED THERAPY ; EGFR forms ; Secretome ; TUMOR AGGRESSIVENESS
    Abstract: Aims: Members of the epidermal growth factor receptor (EGFR) family represent validated targets for anticancer therapy and EGFR inhibitors have also shown efficacy in pancreatic carcinoma. We here described in detail molecular forms of the EGF receptor released by pancreatic cancer cells. We found peptides specific for the EGER in the secretomes of five pancreatic cancer cell lines. Secretomes from cultured cancer cells are widely used as sources for serum biomarker discovery. Main methods: The detailed analysis of EGFR forms in secretomes of human pancreatic cancer cells is a compilation of results from mass spectrometry (MS) and Western blotting with intracellular and extracellular domain specific antibodies. Key findings: Pancreatic cancer cells secrete a 110 kDa soluble form of the EGFR (sEGFR) representing the ligand binding extracellular EGFR domains and presumably released by ectodomain shedding. At the same time, as constituents of exosomes, the EGFR is released as full-length intact receptor (170 kDa) and as a 65 kDa processed form, the C-terminal remnant fragment that corresponds to the intracellular kinase domain. Significance: The detailed characterization of diverse EGER forms released by pancreatic cancer cells in vitro and presumably in vivo bears important implications for functional studies, for the validation of soluble EGFR as a serum biomarker and for the design of targeted therapies.
    Type of Publication: Journal article published
    PubMed ID: 21763319
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  • 3
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; MODEL ; SYSTEM ; DISEASE ; DISEASES ; LONG-TERM ; DIFFERENTIATION ; EPITHELIA ; CONTRAST ; SKIN ; BIOLOGY ; ALPHA ; culture ; smoking ; PATHOGENESIS ; MORPHOLOGY ; RECEPTORS ; epidermis ; physiology ; LAYER ; LIFE ; analysis ; EPITHELIUM ; pharmacology ; UNIT ; NICOTINE ; coculture ; acetylcholine ; acne inversa ; epidermis equivalent ; EXTRANEURONAL CHOLINERGIC SYSTEM ; hidradenitis ; HIDRADENITIS-SUPPURATIVA
    Abstract: In recent years, the physiological role of non-neuronal acetylcholine (ACh) and its receptors (AChR) in epidermal physiology has been under intense investigation. However, little is known about the role of the non-neuronal cholinergic system in inflammatory skin diseases. We chose the clinically nicotine-dependent skin disease hidradenitis suppurativa (HS) as model to study the influence of long term nicotine ingestion on epidermal morphology and AChR expression. HS is a chronic inflammatory, disabling disease of unknown pathogenesis emerging from the pilosebaceous unit of the intertriginous areas. In order to correlate our findings to specific nicotine effects, we used the organotypical coculture system (OTC) and raised artificial epidermis in the presence of nicotine. After 12 days in culture control OTC showed a mature epithelium, while nicotine treated OTCs were significantly thicker. Using immunofluorescence analysis, nicotine treated OTCs produced significantly stronger immunoreactivity (IR) for the alpha 3, M-3 and M-5 AChR antisera than control. In contrast, the alpha 7 nAChR antiserum showed a slightly reduced IR in the granular layer and the alpha 9 nAChR IR retracted to the lower suprabasal layers. In HS epidermis we found the strongest IR for all AChR around the follicular infundibulum while in the sinus epithelia it was only weak. In contrast to the nicotine treated OTC, the alpha 7 nAChR IR in the hyperplastic HS epidermis was clearly extended to all living layers. Altogether we provide first hints for a causative role of the non-neuronal cholinergic system in the pathogenesis of HS by promoting infundibular epithelial hyperplasia and thus follicular plugging. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17363005
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  • 4
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; proliferation ; SURVIVAL ; tumor ; CELL ; human ; KINASE ; PATHWAY ; PATHWAYS ; SUPPORT ; EXPOSURE ; SITE ; DIFFERENTIATION ; MONOCLONAL-ANTIBODY ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; BINDING ; PHOSPHORYLATION ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; antibodies ; MEMBRANE ; METASTASIS ; REGION ; CANCER-CELLS ; EXTRACELLULAR-MATRIX ; BETA ; ADHESION ; MIGRATION ; FACTOR-KAPPA-B ; INTEGRIN ; NF-kappa B ; RECEPTORS ; MMP ; FIBRONECTIN ; TUMOR-METASTASIS ; SERUM ; FAMILIES ; basement membrane ; cell adhesion ; GELATINASE-A ; MMP-2 ; INTEGRINS ; RGD ; NUCLEAR ; EVENTS ; ERK ; MMP-9 ; pharmacology ; MT1-MMP ; TISSUE INHIBITOR ; ENGLAND ; matrix metalloproteinase ; MATRIX-METALLOPROTEINASE ; MEDICINE ; MEDIA ; interactions ; MT1-MMP MMP-14 ; PI-3K
    Abstract: Interactions between tumour cells and the extracellular matrix (ECM) strongly influence tumour development, affecting cell survival, proliferation and migration. Many of these interactions are mediated through a family of cell surface receptors named integrins. Fibronectin and its integrin receptors play important roles in tumour development. The alpha 5 beta 1 integrin interacts with the central cell adhesive region of fibronectin and requires both the RGD and synergy sites for maximal binding. Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases. They are capable of digesting the different components of the ECM and basement membrane. The ECM gives structural support to cells and plays a central role in cell adhesion, differentiation, proliferation and migration. Binding of ECM to integrins modulates expression and activity of the different MMPs. Our experimental findings demonstrate that cultivation of human breast cancer cells, MCF-7, in serum free medium in the presence of fibronectin upregulates the activity of MMP-2 and MMP-9. Blocking of alpha 5 beta 1 integrin with anti-alpha 5 monoclonal antibody inhibits the fibronectin-induced MMP activation response appreciably. This strongly indicates alpha 5 beta 1 mediated signalling events in activation of MMP-2 and MMP-9. Phosphorylation of FAK and PI-3 kinase and the nuclear translocation of ERK and NF-kappa B upon fibronectin binding demonstrate possible participation of the FAK/PI-3K/ERK signalling pathways in the regulation of MMP-2 activity. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18243246
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