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  • 1
    Keywords: EXPRESSION ; PROTEINS ; COLORECTAL-CANCER ; EPITHELIAL-CELLS ; PROTEOMICS ; TUMOR-DERIVED EXOSOMES ; DIAGNOSTIC BIOMARKERS ; MICROVESICLES ; COMMUNICATION ; CD73
    Abstract: BACKGROUND: Pancreatic cancer development is associated with characteristic alterations like desmoplastic reaction and immune escape which are mediated by the cell-cell communication mechanism and by the microenvironment of the cells. The whole of released components are important determinants in these processes. Especially the extracellular vesicles released by pancreatic cancer cells play a role in cell communication and modulate cell growth and immune responses. RESULTS: Here, we present the proteomic description of affinity purified extracellular vesicles from pancreatic tumour cells, compared to the secretome, defined as the whole of the proteins released by pancreatic cancer cells. The proteomic data provide comprehensive catalogues of hundreds of proteins, and the comparison reveals a special proteomic composition of pancreatic cancer cell derived extracellular vesicles. The functional analysis of the protein composition displayed that membrane proteins, glycoproteins, small GTP binding proteins and a further, heterogeneous group of proteins are enriched in vesicles, whereas proteins derived from proteasomes and ribosomes, as well as metabolic enzymes, are not components of the vesicles. Furthermore proteins playing a role in carcinogenesis and modulators of the extracellular matrix (ECM) or cell-cell interactions are components of affinity purified extracellular vesicles. CONCLUSION: The data deepen the knowledge of extracellular vesicle composition by hundreds of proteins that have not been previously described as vesicle components released by pancreatic cancer cells. Extracellular vesicles derived from pancreatic cancer cells show common proteins shared with other vesicles as well as cell type specific proteins indicating biomarker candidates and suggesting functional roles in cancer cell stroma interactions.
    Type of Publication: Journal article published
    PubMed ID: 25469109
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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
  • 4
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; VITRO ; VIVO ; SYSTEM ; GENE ; GENE-EXPRESSION ; GENES ; cell line ; TRANSDUCTION ; RESPONSES ; IMPACT ; INDUCTION ; tumour ; DOWN-REGULATION ; SUPPRESSION ; SIGNAL ; cytokines ; TARGET ; gene expression ; resistance ; CARCINOMA CELLS ; colorectal cancer ; COLORECTAL-CANCER ; cervical cancer ; CERVICAL-CANCER ; CELL-LINE ; LINE ; SIGNALING PATHWAY ; CANCER-CELLS ; COLORECTAL CANCERS ; EXTRACELLULAR-MATRIX ; CARCINOMA-CELLS ; SUPERFAMILY ; CERVICAL-CARCINOMA ; cervical carcinoma ; GROWTH-FACTOR-BETA ; TARGETS ; C-MYC ; OVEREXPRESSION ; pancreatic carcinoma ; HIGH-LEVEL ; CELL-GROWTH ; CYTOKINE ; MATRIX ; ONCOLOGY ; TUMOR SUPPRESSION ; LIGHT ; extracellular matrix ; RESTORATION ; regulation ; TGF-BETA ; interaction ; LEVEL ; TARGET GENES ; methods ; pancreatic ; SUPPRESSOR ; EVENTS ; tumour suppressor ; function ; LOSSES ; CANCERS ; in vivo ; SIGNALS ; carcinogenic ; COLON-CARCINOMA CELLS ; ENGLAND ; PREDICT ; colorectal ; NOV ; evidence ; cell growth ; BETAIG-H3 GENE ; BRONCHIAL EPITHELIAL-CELLS ; Smad4 ; STABLE RNA INTERFERENCE ; SUPPRESSOR E-CADHERIN ; tumour suppression
    Abstract: Background: Smad4 is a tumour suppressor frequently inactivated in pancreatic and colorectal cancers. We have recently reported loss of Smad4 in every fourth carcinoma of the uterine cervix. Smad4 transmits signals from the TGF-beta superfamily of cytokines and functions as a versatile transcriptional co-modulator. The prevailing view suggests that the tumour suppressor function of Smad4 primarily resides in its capability to mediate TGF-beta growth inhibitory responses. However, accumulating evidence indicates, that the acquisition of TGF-beta resistance and loss of Smad4 may be independent events in the carcinogenic process. Through inducible reexpression of Smad4 in cervical cancer cells we wished to shed more light on this issue and to identify target genes implicated in Smad4 dependent tumor suppression. Methods: Smad4-deficient human C4-II cervical carcinoma cells were used to establish inducible Smad4 reexpression using the commercial Tet-on (TM) system (Clontech). The impact of Smad4 reexpression on cell growth was analysed in vitro and in vivo. Transcriptional responses were assessed through profiling on cDNA macroarrays (Clontech) and validated through Northern blotting. Results: Clones were obtained that express Smad4 at widely varying levels from approximately physiological to 50-fold overexpression. Smad4-mediated tumour suppression in vivo was apparent at physiological expression levels as well as in Smad4 overexpressing clones. Smad4 reexpression in a dose-dependent manner was associated with transcriptional induction of the extracellular matrix-associated genes, BigH3, fibronectin and PAI-I, in response to TGF-beta. Smad4-dependent regulation of these secreted Smad4 targets is not restricted to cervical carcinoma cells and was confirmed in pancreatic carcinoma cells reexpressing Smad4 after retroviral transduction and in a stable Smad4 knockdown model. On the other hand, the classical cell cycle-associated TGF-beta target genes, c-myc, p21 and p15, remained unaltered. Conclusion: Our results show that Smad4-mediated tumour suppression in cervical cancer cells is not due to restoration of TGF-beta growth inhibitory responses. Rather, tumour cell-ECM interactions may be more relevant for Smad4-mediated tumour suppression. C4-II cells with a high level inducible Smad4 expression may serve as a model to indicate further Smad4 targets responsive to diverse environmental stimuli operative in vivo
    Type of Publication: Journal article published
    PubMed ID: 17997817
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  • 5
    Keywords: EXPRESSION ; PROTEINS ; BIOMARKERS ; Drosophila ; TUMOR-SUPPRESSOR GENE ; SIGNALING PATHWAY ; beta-catenin ; ADHESION MOLECULE ; SERUM ; PROTOCADHERIN FAT1
    Abstract: In pancreatic cancer, there is a clear unmet need to identify new serum markers for either early diagnosis, therapeutic stratification or patient monitoring. Proteomic analysis of tumor cell secretomes is a promising approach to indicate proteins released from tumor cells in vitro. Ectodomain shedding of transmembrane proteins has previously been shown to contribute significant fractions the tumor cell secretomes and to generate valuable serum biomarkers. Here we introduce a soluble form of the giant cadherin Fat1 as a novel biomarker candidate. Fat1 expression and proteolytic processing was analyzed by mass spectrometry and Western blotting using pancreatic cancer cell lines as compared to human pancreatic ductal epithelial cells. RNA expression in cancer tissues was assessed by in silico analysis of publically available microarray data. Involvement of ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in Fat1 ectodomain shedding was analyzed by chemical inhibition and knockdown experiments. A sandwich ELISA was developed to determine levels of soluble Fat1 in serum samples. In the present report we describe the release of high levels of the ectodomain of Fat1 cadherin into the secretomes of human pancreatic cancer cells in vitro, a process that is mediated by ADAM10. We confirm the full-length and processed heterodimeric form of Fat1 expressed on the plasma membrane and also show the p60 C-terminal transmembrane remnant fragment corresponding to the shed ectodomain. Fat1 and its sheddase ADAM10 are overexpressed in pancreatic adenocarcinomas and ectodomain shedding is also recapitulated in vivo leading to increased Fat1 serum levels in some pancreatic cancer patients. We suggest that soluble Fat1 may find an application as a marker for patient monitoring complementing carbohydrate antigen 19-9 (CA19-9). In addition, detailed analysis of the diverse processed protein isoforms of the candidate tumor suppressor Fat1 can also contribute to our understanding of cell biology and tumor behavior.
    Type of Publication: Journal article published
    PubMed ID: 24625754
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