Profiles of cancer stem cell subpopulations in cholangiocarcinomas

Felice Giuliante, Vincenzo Cardinale, Anastasia Renzi, Guido Carpino, Alessia Torrice, Maria C. Bragazzi, Alice Fraveto, Paolo Onori, Chiara Napoletano, Antonio Franchitto, Alfredo Cantafora, Gianluca Grazi, Nicola Caporaso, Giuseppe D'Argenio, Gianfranco Alpini, Lola M. Reid, Eugenio Gaudio, Domenico Alvaro

Risultato della ricerca: Contributo in rivistaArticolo in rivista

54 Citazioni (Scopus)

Abstract

Cholangiocarcinomas (CCAs) comprise a mucin-secreting form, intrahepatic or perihilar, and a mixed form located peripherally. We characterized cancer stem cells (CSCs) in CCA subtypes and evaluated their cancerogenic potential. CSC markers were investigated in 25 human CCAs in primary cultures and established cell lines. Tumorigenic potential was evaluated in vitro or in xenografted mice after s.c. or intrahepatic injection in normal and cirrhotic (carbon tetrachloride-induced) mice. CSCs comprised more than 30% of the tumor mass. Although the CSC profile was similar between mucin-intrahepatic and mucin-perihilar subtypes, CD13+ CSCs characterized mixed-intrahepatic, whereas LGR5+ characterized mucin-CCA subtypes. Many neoplastic cells expressed epithelial-mesenchymal transition markers and coexpressed mesenchymal and epithelial markers. In primary cultures, epithelial-mesenchymal transition markers, mesenchymal markers (vimentin, CD90), and CD13 largely predominated over epithelial markers (CD133, EpCAM, and LGR5). In vitro, CSCs expressing epithelial markers formed a higher number of spheroids than CD13+ or CD90+ CSCs. In s.c. tumor xenografts, tumors dominated by stromal markers were formed primarily by CD90+ and CD13+ cells. By contrast, in intrahepatic xenografts in cirrhotic livers, tumors were dominated by epithelial traits reproducing the original human CCAs. In conclusion, CSCs were rich in human CCAs, implicating CCAs as stem cell-based diseases. CSC subpopulations generate different types of cancers depending on the microenvironment. Remarkably, CSCs reproduce the original human CCAs when injected into cirrhotic livers.
Lingua originaleEnglish
pagine (da-a)1724-1739
Numero di pagine16
RivistaTHE AMERICAN JOURNAL OF PATHOLOGY
Volume185
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • 2734
  • Aged
  • Aged, 80 and over
  • Animals
  • Bile Duct Neoplasms
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cholangiocarcinoma
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver
  • Male
  • Mice
  • Middle Aged
  • Neoplastic Stem Cells
  • Transplantation, Heterologous

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