Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis

Hepatology. 2014 Sep;60(3):896-907. doi: 10.1002/hep.27050. Epub 2014 Jul 25.

Abstract

Cholangiocarcinoma (CCA) presents significant diagnostic challenges, resulting in late patient diagnosis and poor survival rates. Primary sclerosing cholangitis (PSC) patients pose a particularly difficult clinical dilemma because they harbor chronic biliary strictures that are difficult to distinguish from CCA. MicroRNAs (miRs) have recently emerged as a valuable class of diagnostic markers; however, thus far, neither extracellular vesicles (EVs) nor miRs within EVs have been investigated in human bile. We aimed to comprehensively characterize human biliary EVs, including their miR content. We have established the presence of extracellular vesicles in human bile. In addition, we have demonstrated that human biliary EVs contain abundant miR species, which are stable and therefore amenable to the development of disease marker panels. Furthermore, we have characterized the protein content, size, numbers, and size distribution of human biliary EVs. Utilizing multivariate organization of combinatorial alterations (MOCA), we defined a novel biliary vesicle miR-based panel for CCA diagnosis that demonstrated a sensitivity of 67% and specificity of 96%. Importantly, our control group contained 13 PSC patients, 16 with biliary obstruction of varying etiologies (including benign biliary stricture, papillary stenosis, choledocholithiasis, extrinsic compression from pancreatic cysts, and cholangitis), and 3 with bile leak syndromes. Clinically, these types of patients present with a biliary obstructive clinical picture that could be confused with CCA.

Conclusion: These findings establish the importance of using extracellular vesicles, rather than whole bile, for developing miR-based disease markers in bile. Finally, we report on the development of a novel bile-based CCA diagnostic panel that is stable, reproducible, and has potential clinical utility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Bile / chemistry*
  • Bile Duct Neoplasms / diagnosis*
  • Bile Duct Neoplasms / metabolism
  • Bile Ducts, Intrahepatic*
  • Biomarkers / analysis
  • Case-Control Studies
  • Cholangiocarcinoma / diagnosis*
  • Cholangiocarcinoma / metabolism
  • Cytoplasmic Vesicles / chemistry
  • Cytoplasmic Vesicles / metabolism
  • Female
  • Humans
  • Male
  • MicroRNAs / analysis*
  • MicroRNAs / metabolism
  • Middle Aged
  • Support Vector Machine
  • Young Adult

Substances

  • Biomarkers
  • MicroRNAs