EpCAM+ Liver Cancer Stem-Like Cells Exhibiting Autocrine Wnt Signaling Potentially Originate in Cirrhotic Patients

Stem Cells Transl Med. 2017 Mar;6(3):807-818. doi: 10.1002/sctm.16-0248. Epub 2017 Jan 18.


Hepatocellular carcinoma (HCC) is believed to originate from cancer stem cells (CSCs). While epithelial cell adhesion molecule (EpCAM) is a marker of normal hepatic stem cells (HSCs), EpCAM+ cells from HCC behave like CSCs. Since HCC mostly develops on a cirrhotic background, we sought to determine whether CSC-like EpCAM+ cells exist in patients with advanced cirrhosis. Both flow cytometry and immunohistochemistry showed that frequency of EpCAM+ cells in advanced cirrhosis was increased as compared to control. To determine whether increased EpCAM population in advanced cirrhosis harbors any CSC-like cells, we compared molecular and functional features of EpCAM+ cells from advanced cirrhosis (Ep+CIR; n = 20) with EpCAM+ cells from both HCC (Ep+HCC; n = 20) and noncancerous/noncirrhotic (control) (Ep+NSC; n = 7) liver tissues. Ep+CIRs displayed similarity with Ep+HCC cells including upregulated expression of stemness and Notch pathway genes, enhanced self-renewal in serial spheroid assay and generation of subcutaneous tumors in nonobese diabetic/severe combined immunodeficiency mice. Moreover, transcriptome and miRNome of Ep+CIRs appeared closer to that of Ep+HCC cells than Ep+NSCs. Interestingly, more than 50% micro RNAs (miRNAs) and transcripts specifically expressed in Ep+HCCs were also expressed in Ep+CIRs. However, none of Ep+NSC specific miRNAs and only 7% Ep+NSC specific transcripts were expressed in Ep+CIRs. Further, according to gene expression and in vitro Wnt inhibition analysis, autocrine Wnt signaling appeared to be a distinct feature of Ep+CIR and Ep+HCC cells, which was absent from Ep+NSCs. EpCAM+ cells in advanced cirrhosis possibly include a population of CSC-like cells which can be explored for early diagnosis of HCC development. Stem Cells Translational Medicine 2017;6:807-818.

Keywords: Cancer stem cells; Cirrhosis; Epithelial cell adhesion molecule; Hepatocellular carcinoma; Wnt.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication*
  • Carcinogenesis / pathology
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Self Renewal
  • Epithelial Cell Adhesion Molecule / metabolism*
  • Female
  • Humans
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology*
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Middle Aged
  • Neoplastic Stem Cells / pathology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcriptome / genetics
  • Wnt Signaling Pathway*


  • Epithelial Cell Adhesion Molecule
  • MicroRNAs
  • RNA, Messenger