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Cancer-associated circulating large extracellular vesicles in cholangiocarcinoma and hepatocellular carcinoma

  • Author Footnotes
    † These authors contributed equally and shared first co-authorship.
    Henrike Julich-Haertel
    Footnotes
    † These authors contributed equally and shared first co-authorship.
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Author Footnotes
    † These authors contributed equally and shared first co-authorship.
    Sabine K. Urban
    Footnotes
    † These authors contributed equally and shared first co-authorship.
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Author Footnotes
    † These authors contributed equally and shared first co-authorship.
    Marcin Krawczyk
    Footnotes
    † These authors contributed equally and shared first co-authorship.
    Affiliations
    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
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  • Author Footnotes
    † These authors contributed equally and shared first co-authorship.
    Arnulf Willms
    Footnotes
    † These authors contributed equally and shared first co-authorship.
    Affiliations
    Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
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  • Krzysztof Jankowski
    Affiliations
    Department Internal Medicine and Cardiology, Medical University of Warsaw, Warsaw, Poland
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  • Waldemar Patkowski
    Affiliations
    Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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  • Beata Kruk
    Affiliations
    Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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  • Maciej Krasnodębski
    Affiliations
    Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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  • Joanna Ligocka
    Affiliations
    Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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  • Robert Schwab
    Affiliations
    Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
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  • Ines Richardsen
    Affiliations
    Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
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  • Sebastian Schaaf
    Affiliations
    Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
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  • Angelina Klein
    Affiliations
    Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
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  • Sebastian Gehlert
    Affiliations
    Department of Molecular and Cellular Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne, Cologne, Germany
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  • Hanna Sänger
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Markus Casper
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Jesus M. Banales
    Affiliations
    Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain
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  • Detlef Schuppan
    Affiliations
    Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
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  • Piotr Milkiewicz
    Affiliations
    Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland

    Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
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  • Frank Lammert
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Marek Krawczyk
    Affiliations
    Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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  • Author Footnotes
    ‡ These authors contributed equally and shared last authorship.
    Veronika Lukacs-Kornek
    Footnotes
    ‡ These authors contributed equally and shared last authorship.
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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  • Author Footnotes
    ‡ These authors contributed equally and shared last authorship.
    Miroslaw Kornek
    Correspondence
    Corresponding author. Address: Department of Medicine II, Saarland University Medical Center, Saarland University, Kirrberger Str., 100, Homburg 66421, Germany.
    Footnotes
    ‡ These authors contributed equally and shared last authorship.
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany

    Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally and shared first co-authorship.
    ‡ These authors contributed equally and shared last authorship.
Published:March 04, 2017DOI:https://doi.org/10.1016/j.jhep.2017.02.024

      Background & Aims

      Large extracellular vesicles, specifically AnnexinV+ EpCAM+ CD147+ tumour-associated microparticles (taMPs), facilitate the detection of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) as well as pancreas carcinoma (PaCa). Here we assess the diagnostic value of taMPs for detection and monitoring of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Specifically, the aim of this study was to differentiate liver taMPs from other cancer taMPs, such as CRC and NSCLC.

      Methods

      Fluorescence-activated cell scanning (FACS) was applied to detect various taMP populations in patients’ sera that were associated with the presence of a tumour (AnnexinV+ EpCAM+ CD147+ taMPs) or could discriminate between cirrhosis (due to HCV or HBV) and liver cancers (AnnexinV+ EpCAM+ ASGPR1+ taMPs). In total 172 patients with liver cancer (HCC or CCA), 54 with cirrhosis and no liver neoplasia, and 202 control subjects were enrolled.

      Results

      The results indicate that AnnexinV+ EpCAM+ CD147+ taMPs were elevated in HCC and CCA. Furthermore, AnnexinV+ EpCAM+ ASGPR1+ CD133+ taMPs allowed the distinction of liver malignancies (HCC or CCA) and cirrhosis from tumour-free individuals and, more importantly, from patients carrying other non-liver cancers. In addition, AnnexinV+ EpCAM+ ASGPR1+ taMPs were increased in liver cancer-bearing patients compared to patients with cirrhosis that lacked any detectable liver malignancy. The smallest sizes of successfully detected cancers were ranging between 11–15 mm. AnnexinV+ EpCAM+ ASGPR1+ taMPs decreased at 7 days after curative R0 tumour resection suggesting close correlations with tumour presence. ROC values, sensitivity/specificity scores and positive/negative predictive values (>78%) indicated a potent diagnostic accuracy of AnnexinV+ EpCAM+ ASGPR1+ taMPs.

      Conclusion

      These data provide strong evidence that AnnexinV+ EpCAM+ ASGPR1+ taMPs are a novel biomarker of HCC and CCA liquid biopsy that permit a non-invasive assessment of the presence and possible extent of these cancers in patients with advanced liver diseases.

      Lay summary

      Microparticles (MPs) are small vesicles that bleb from the membrane of every cell, including cancer cells, and are released to circulate in the bloodstream. Since their surface composition is similar to the surface of their underlying parental cell, MPs from the bloodstream can be isolated and by screening their surface components, the presence of their parental cells can be identified. This way, it was possible to detect and discriminate between patients bearing liver cancer and chronic liver cirrhosis.

      Graphical abstract

      Keywords

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