EpCAM+ Liver Cancer Stem-Like Cells Exhibiting Autocrine Wnt Signaling Potentially Originate in Cirrhotic Patients.
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.
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Ritu
R
Khosla
Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India.
Archana
A
Rastogi
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Gayatri
G
Ramakrishna
Department of Liver Transplant and Hepato Pancreato Biliary Surgery, Institute of Liver and Biliary Sciences, New Delhi, India.
Viniyendra
V
Pamecha
Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
Ashok
A
Mukhopadhyay
Bionivid Technology Pvt Ltd, Bangalore, India.
Madavan
M
Vasudevan
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Shiv Kumar
SK
Sarin
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Nirupma
N
Trehanpati
D000818:Animals; D019898:Autocrine Communication; D063646:Carcinogenesis / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D000066673:Cell Self Renewal; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D060449:Wnt Signaling Pathway
D000071858:Epithelial Cell Adhesion Molecule; D035683:MicroRNAs; D012333:RNA, Messenger
Cancer stem cells; Cirrhosis; Epithelial cell adhesion molecule; Hepatocellular carcinoma; Wnt