TY - JOUR
T1 - Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma
AU - Arbelaiz, Ander
AU - Azkargorta, Mikel
AU - Krawczyk, Marcin
AU - Santos-Laso, Alvaro
AU - Lapitz, Ainhoa
AU - Perugorria, Maria J.
AU - Erice, Oihane
AU - Gonzalez, Esperanza
AU - Jimenez-Agüero, Raul
AU - Lacasta, Adelaida
AU - Ibarra, Cesar
AU - Sanchez-Campos, Alberto
AU - Jimeno, Juan P.
AU - Lammert, Frank
AU - Milkiewicz, Piotr
AU - Marzioni, Marco
AU - Macias, Rocio I.R.
AU - Marin, Jose J.G.
AU - Patel, Tushar
AU - Gores, Gregory J.
AU - Martinez, Ibon
AU - Elortza, Félix
AU - Falcon-Perez, Juan M.
AU - Bujanda, Luis
AU - Banales, Jesus M.
N1 - Funding Information:
Supported by the Spanish Ministries of Economy and Competitiveness (FIS PI12/00380, FIS PI15/01132, and Miguel Servet Program CON14/ 00129, to J.M.B.; FIS PI14/00399, to M.J.P.; PI12-01604 and SAF2015-66312-R, to J.M.F.-P.; FIS PI16/00598 and SAF2013-40620-R, to J.J.G.M.; SAF2016-75197-R, to R.I.R.M.), cofinanced by Fondo Europeo de Desarrollo Regional; Instituto de Salud Carlos III (CIBERehd) (EHD15PI05, to J.M.B., R.I.R.M., L.B., and J.J.G.M.); Junta de Castilla y Leon (SA015U13 and BIO/SA52/15, to J.J.G.M.); Diputación Foral Gipuzkoa (DFG14/007, to L.B.; DFG15/010 and DFG16/004, to J.M.B.); Departments of Industry, Tourism, Trade and Health of the Basque Country (2013111173, to L.B.; 2012111086 Etortek, to J.M.F.-P.); Basque Foundation for Innovation and Health Research: EiTB Maratoia (BIO15/CA/016/ BD, to J.M.B.); German Federal Ministry of Education and Research (core grant Liver Systems Medicine LiSyM 031L005, to F.L.); and Asociación Espa-ola Contra el Cancer (to J.M.B. and O.E.) and the Basque government (to A.S.-L.).
Publisher Copyright:
© 2017 by the American Association for the Study of Liver Diseases.
PY - 2017/10
Y1 - 2017/10
N2 - 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).
AB - 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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U2 - 10.1002/hep.29291
DO - 10.1002/hep.29291
M3 - Article
C2 - 28555885
AN - SCOPUS:85028330245
SN - 0270-9139
VL - 66
SP - 1125
EP - 1143
JO - Hepatology
JF - Hepatology
IS - 4
ER -