CIC bioGUNE
Published October 2, 2017 | Version v1
Journal article Open

Serum Extracellular Vesicles Contain Protein Biomarkers for Primary Sclerosing Cholangitis and Cholangiocarcinoma

Creators

  • 1. Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
  • 2. Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
  • 3. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
  • 4. Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
  • 5. Metabolomics Unit, CIC bioGUNE, CIBERehd, Derio, Spain.
  • 6. Hospital of Cruces, Bilbao, Spain.
  • 7. Complejo Hospitalario de Navarra, Pamplona, Spain.
  • 8. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
  • 9. Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
  • 10. Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
  • 11. National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
  • 12. Department of Cancer Biology, Mayo Clinic, Jacksonville, FL.
  • 13. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
  • 14. OWL Metabolomics, Derio, Spain.
  • 15. National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Metabolomics Unit, CIC bioGUNE, CIBERehd, Derio, Spain.
  • 16. Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.

Description

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 5 43), PSC (n 5 30), or HCC (n 5 29) patients and healthy individuals (control, n 5 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.

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