Sabine K Urban1,2, Hanna Sänger2,3, Marcin Krawczyk2,4, Henrike Julich-Haertel2, Arnulf Willms5, Joanna Ligocka6, Mikel Azkargorta7, Tudor Mocan8, Christoph Kahlert9, Beata Kruk4, Krzysztof Jankowski10, Waldemar Patkowski6, Marek Krawczyk6, Krzysztof Zieniewicz6, Wacław Hołówko6, Łukasz Krupa11, Mateusz Rzucidło11, Krzysztof Gutkowski11, Wojciech Wystrychowski12, Robert Król12, Joanna Raszeja-Wyszomirska13, Artur Słomka14, Robert Schwab5, Aliona Wöhler5, Maria A Gonzalez-Carmona1, Sebastian Gehlert15, Zeno Sparchez8, Jesus M Banales16, Christian P Strassburg1, Frank Lammert2, Piotr Milkiewicz13,17, Miroslaw Kornek1,2. 1. Department of Internal Medicine I, University Medical Center Bonn, Bonn, Germany. 2. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany. 3. Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. 4. Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland. 5. Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany. 6. Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland. 7. Proteomics Platform, Bizkaia Science and Technology Park, Derio, Spain. 8. Octavian Fodor Institute for Gastroenterology and Hepatology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania. 9. Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 10. Department of Internal Medicine and Cardiology, Medical University of Warsaw, Warsaw, Poland. 11. Department of Gastroenterology and Hepatology with Internal Disease Unit, Specialist District Hospital in Rzeszow, Rzeszow, Poland. 12. Department of General, Vascular and Transplant Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. 13. Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland. 14. Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Poland. 15. Department for Biosciences of Sports, Institute of Sports Science, University of Hildesheim, Hildesheim, Germany. 16. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain. 17. Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.
Abstract
BACKGROUND: Biliary cancer, comprising cholangio- and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation. METHODS: Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer patients, as well as from healthy individuals, were isolated by sequential two-step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis. RESULTS: Two directly tumour-related antigen combinations (AnnV+ CD44v6+ and AnnV+ CD44v6+ CD133+ ) and two combinations related to progenitor cells from the tumour microenvironment (AnnV+ CD133+ gp38+ and AnnV+ EpCAM+ CD133+ gp38+ ) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV+ CD44v6+ EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively. CONCLUSIONS: EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies.
BACKGROUND:Biliary cancer, comprising cholangio- and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation. METHODS: Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancerpatients, as well as from healthy individuals, were isolated by sequential two-step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis. RESULTS: Two directly tumour-related antigen combinations (AnnV+ CD44v6+ and AnnV+ CD44v6+ CD133+ ) and two combinations related to progenitor cells from the tumour microenvironment (AnnV+ CD133+ gp38+ and AnnV+ EpCAM+ CD133+ gp38+ ) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV+ CD44v6+ EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively. CONCLUSIONS: EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies.
Authors: Artur Słomka; Bingduo Wang; Tudor Mocan; Adelina Horhat; Arnulf G Willms; Ingo G H Schmidt-Wolf; Christian P Strassburg; Maria A Gonzalez-Carmona; Veronika Lukacs-Kornek; Miroslaw T Kornek Journal: Theranostics Date: 2022-08-01 Impact factor: 11.600