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

被引：259

作者：

Arbelaiz, Ander ^{[1
]}

Azkargorta, Mikel ^{[2
,3
]}

Krawczyk, Marcin ^{[4
,5
]}

Santos-Laso, Alvaro ^{[1
]}

Lapitz, Ainhoa ^{[1
]}

Perugorria, Maria J. ^{[1
,3
,6
]}

Erice, Oihane ^{[1
]}

Gonzalez, Esperanza ^{[7
]}

Jimenez-Aguero, Raul ^{[1
]}

Lacasta, Adelaida ^{[1
]}

Ibarra, Cesar ^{[8
]}

Sanchez-Campos, Alberto ^{[8
]}

Jimeno, Juan P. ^{[9
]}

Lammert, Frank ^{[4
]}

Milkiewicz, Piotr ^{[10
,11
]}

Marzioni, Marco ^{[12
]}

Macias, Rocio I. R. ^{[3
,13
]}

Marin, Jose J. G. ^{[3
,13
]}

Patel, Tushar ^{[14
]}

Gores, Gregory J. ^{[15
]}

Martinez, Ibon ^{[16
]}

Elortza, Felix ^{[2
,3
]}

Falcon-Perez, Juan M. ^{[3
,6
,7
]}

Bujanda, Luis ^{[1
,3
]}

Banales, Jesus M. ^{[1
,3
,6
]}

机构：

[1] Univ Basque Country, UPV EHU, Donostia Univ Hosp, Biodonostia Res Inst,Dept Liver & Gastrointestina, San Sebastian, Spain

[2] ProteoRed ISCIII, CIBERehd, CIC bioGUNE, Prote Platform, Bizkaia Sci & Technol Pk, Derio, Spain

[3] Carlos III Natl Inst Hlth, Nat Inst Study Liver & Gastrointestinal Dis CIBER, Madrid, Spain

[4] Univ Saarland, Med Ctr, Dept Med 2, Homburg, Germany

[5] Med Univ Warsaw, Dept Gen Transplant & Liver Surg, Lab Metab Liver Dis, Warsaw, Poland

[6] Ikerbasque, Basque Fdn Sci, Bilbao, Spain

[7] CIBERehd, CIC bioGUNE, Metabol Unit, Derio, Spain

[8] Hosp Cruces, Bilbao, Spain

[9] Complejo Hosp Navarra, Pamplona, Spain

[10] Med Univ Warsaw, Dept Gen Transplant & Liver Surg, Liver & Internal Med Unit, Warsaw, Poland

[11] Pomeranian Med Univ, Translat Med Grp, Szczecin, Poland

[12] Univ Politecn Marche, Dept Gastroenterol, Ancona, Italy

[13] Univ Salamanca, Biomed Res Inst Salamanca IBSAL, Expt Hepatol & Drug Targeting HEVEFARM, Salamanca, Spain

[14] Mayo Clin, Dept Canc Biol, Jacksonville, FL USA

[15] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA

[16] OWL Metabol, Derio, Spain

来源：

HEPATOLOGY | 2017年 / 66卷 / 04期

关键词：

MASS-SPECTROMETRY; EXOSOMES; CANCER;

D O I：

10.1002/hep.29291

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 (similar to 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.

引用

页码：1125 / 1143

页数：19

共 45 条

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Mass spectrometry-based proteomics [J].