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Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma.

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Affiliations

  • 1. Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
      Authors
    • Arbelaiz A 1
    • Santos-Laso A 1
    • Lapitz A 1
    • Perugorria MJ 1, 9
    • Erice O 1
    • Jimenez-Agüero R 1
    • Lacasta A 1
    • Bujanda L 1, 9
    • Banales JM 1, 9
    (9 authors)
  • 2. Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain.
      Authors
    • Azkargorta M 2, 9
    • Elortza F 2, 9
    (2 authors)
  • 3. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
      Authors
    • Krawczyk M 3
    • Lammert F 3
    (2 authors)
  • 4. Metabolomics Unit, CIC bioGUNE, CIBERehd, Derio, Spain.
      Authors
    • Gonzalez E 4
    • Falcon-Perez JM 4, 9
    (2 authors)
  • 5. Hospital of Cruces, Bilbao, Spain.
      Authors
    • Ibarra C 5
    • Sanchez-Campos A 5
    (2 authors)
    • Show all (12)

ORCIDs linked to this article

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Hepatology (Baltimore, Md.), 26 Aug 2017, 66(4):1125-1143
https://doi.org/10.1002/hep.29291 PMID: 28555885 

A comment on this article appears in "The Changing Face of the Diagnosis of Chronic and Malignant Liver Diseases: Potential New Biomarkers." Ann Hepatol. 2017 Dec 27;17(1):14-17. A comment on this article appears in "The challenge of cholangiocarcinoma diagnosis: The turning point is in extracellular vesicles?" Hepatology. 2017 Oct;66(4):1029-1031.

Abstract 

Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions, such as primary sclerosing cholangitis (PSC), are risk factors. Noninvasive differential diagnosis between intrahepatic CCA and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate noninvasive biomarkers for PSC, CCA, and HCC are not available. In the search for novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n = 43), PSC (n = 30), or HCC (n = 29) patients and healthy individuals (control, n = 32); and their protein content was characterized. By using nanoparticle tracking analysis, serum EV concentration was found to be higher in HCC than in all the other groups. Round morphology (by transmission electron microscopy), size (∼180 nm diameter by nanoparticle tracking analysis), and markers (clusters of differentiation 9, 63, and 81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the receiver operating characteristic curve of 0.878 for CCA versus control, 0.905 for CCA stage I-II versus control, 0.789 for PSC versus control, 0.806 for noncirhottic PSC versus control, 0.796 for CCA versus PSC, 0.956 for CCA stage I-II versus PSC, 0.904 for HCC versus control, and 0.894 for intrahepatic CCA versus HCC. Proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins.

Conclusion

Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools. (Hepatology 2017;66:1125-1143).

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Read article at publisher's site: https://doi.org/10.1002/hep.29291

Read article for free, from open access legal sources, via Unpaywall: https://aasldpubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hep.29291Unpaywall

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Funding 

Funders who supported this work.

Basque Foundation for Innovation and Health Research: EiTB Maratoia (1)

Departments of Industry, Tourism, Trade and Health of the Basque Country (2)

Diputación Foral Gipuzkoa (3)

German Federal Ministry of Education and Research (1)

Instituto de Salud Carlos III (1)

Junta de Castilla y Leon (2)

Spanish Ministries of Economy and Competitiveness (9)