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  • Exosomes
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  • 1
    Language: English
    In: Life Sciences, 2011, Vol.89(9), pp.304-312
    Description: Members of the epidermal growth factor receptor (EGFR) family represent validated targets for anti-cancer 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 EGFR in the secretomes of five pancreatic cancer cell lines. Secretomes from cultured cancer cells are widely used as sources for serum biomarker discovery. 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. 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. The detailed characterization of diverse EGFR 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.
    Keywords: Egfr Forms ; Secretome ; Exosome ; Proteomics ; Targeted Therapy ; Biomarker ; Pancreatic Cancer ; Sciences (General) ; Biology
    ISSN: 0024-3205
    E-ISSN: 1879-0631
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  • 2
    Language: English
    In: Cell Communication and Signaling, 01 April 2017, Vol.15(1), pp.1-14
    Description: Abstract Background Colorectal cancers (CRCs) that lack DNA mismatch repair function exhibit the microsatellite unstable (MSI) phenotype and are characterized by the accumulation of frameshift mutations at short repetitive DNA sequences (microsatellites). These tumors recurrently show inactivating...
    Keywords: Exosomes ; Intercellular Communication ; Proteomics ; Transforming Growth Factor Beta Receptor Type 2 ; DNA Mismatch Repair Deficiency ; Microsatellite Instability ; Biology
    E-ISSN: 1478-811X
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  • 3
    Language: English
    In: TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells. Cell Communication and Signaling, 15(1), 14., United Kingdom. (2017).
    Description: BACKGROUND: Colorectal cancers (CRCs) that lack DNA mismatch repair function exhibit the microsatellite unstable (MSI) phenotype and are characterized by the accumulation of frameshift mutations at short repetitive DNA sequences (microsatellites). These tumors recurrently show inactivating frameshift mutations in the tumor suppressor Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) thereby abrogating downstream signaling. How altered TGFBR2 signaling affects exosome-mediated communication between MSI tumor cells and their environment has not been resolved. Here, we report on molecular alterations of exosomes shed by MSI cells and the biological response evoked in recipient cells. METHODS: Exosomes were isolated and characterized by electron microscopy, nanoparticle tracking, and western blot analysis. TGFBR2-dependent effects on the cargo and functions of exosomes were studied in a MSI CRC model cell line enabling reconstituted and inducible TGFBR2 expression and signaling. Microsatellite frameshift mutations in exosomal and cellular DNA were examined by PCR-based DNA fragment analysis and exosomal protein profiles were identified by mass spectrometry. Uptake of fluorescent-labeled exosomes by hepatoma recipient cells was monitored by confocal microscopy. TGFBR2-dependent exosomal effects on secreted cytokine levels of recipient cells were analyzed by Luminex technology and ELISA. RESULTS: Frameshift mutation patterns in microsatellite stretches of TGFBR2 and other MSI target genes were found to be reflected in the cargo of MSI CRC-derived exosomes. At the proteome level, reconstituted TGFBR2 expression and signaling uncovered two protein subsets exclusively occurring in exosomes derived from TGFBR2-deficient (14 proteins) or TGFBR2-proficient (five proteins) MSI donor cells. Uptake of these exosomes by recipient cells caused increased secretion (2-6 fold) of specific cytokines (Interleukin-4, Stem Cell Factor, Platelet-derived Growth Factor-B), depending on the TGFBR2 expression status of the tumor cell. CONCLUSION: Our results indicate that the coding MSI phenotype of DNA mismatch repair-deficient CRC cells is maintained in their exosomal DNA. Moreover, we uncovered that a recurrent MSI tumor driver mutation like TGFBR2 can reprogram the protein content of MSI cell-derived exosomes and in turn modulate the cytokine secretion profile of recipient cells. Apart from its diagnostic potential, these TGFBR2-dependent exosomal molecular and proteomic signatures might help to understand the signaling routes used by MSI tumors. Fricke et al. uncovered coding microsatellite instability-associated mutations of colorectal tumor driver genes like TGFBR2 in MSI tumor cellderived exosomes. Depending on the TGFBR2 expression status of their donor cells, shed exosomes show distinct proteomic signatures and promote altered cytokine secretion profiles in recipient cells.
    Description: Peer reviewed
    Keywords: Chemokines/Metabolism ; Colorectal Neoplasms/Metabolism ; Dna Mismatch Repair ; Enzyme-Linked Immunosorbent Assay ; Exosomes/Metabolism/Ultrastructure ; Frameshift Mutation/Genetics ; Hct116 Cells ; Hep G2 Cells ; Humans ; Microsatellite Instability ; Platelet-Derived Growth Factor/Metabolism ; Protein-Serine-Threonine Kinases/Metabolism ; Proteome/Metabolism ; Receptor, Transforming Growth Factor-Beta Type Ii ; Receptors, Transforming Growth Factor Beta/Metabolism ; Reproducibility Of Results ; Colorectal Cancer ; Dna Mismatch Repair Deficiency ; Exosomes ; Intercellular Communication ; Microsatellite Instability ; Proteomics ; Transforming Growth Factor Beta Receptor Type 2 ; Human Health Sciences :: Oncology ; Sciences De La Santé Humaine :: Oncologie
    Source: ORBi (Open Repository and Bibliography), University of Liège
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  • 4
    Language: English
    In: International Journal of Molecular Sciences, 01 August 2019, Vol.20(17), p.4162
    Description: Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by mutational inactivation of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2). TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived...
    Keywords: Extracellular Vesicles ; Exosomes ; Proteomics ; Stable Isotope Labeling With Amino Acids in Cell Culture (Silac) ; Tgfbr2 ; Microsatellite Instability ; DNA Mismatch Repair ; Colorectal Cancer ; Biology
    ISSN: 16616596
    E-ISSN: 1422-0067
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