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

Abstract

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

miR‐26b‐5p helps in EpCAM+cancer stem cells maintenance via HSC71/HSPA8 and augments malignant features in HCC

“…In an earlier study we had performed both mRNA and miRNA profiling in Ep+HCC (Ep + CSC), paired Ep − HCC and Ep+NSC cells . For our data to be more representative, we tried to map the protein profiling results with the NGS based mRNA and miRNA profiling data.…”

“…In an earlier study we had performed both mRNA and miRNA profiling in Ep+HCC (Ep + CSC), paired Ep − HCC and Ep+NSC cells. 28 For our data to be more representative, we tried to map the protein profiling results with the NGS based mRNA and miRNA profiling data. According to the transcriptome analysis, among the 11 Ep+CSC specific proteins, the corresponding genes of only four proteins (GAPDH, HSPA8, HNRNPC and MPST) were significantly (>2 fold) overexpressed in Ep+CSCs (Figure 2A).…”

A Preview of Selected Articles

“…Given the existence of EpCAM‐positive CSC‐like cells in hepatocellular carcinoma, the most common type of primary liver cancer, and studies hinting that CSCs may arise in the livers of cirrhotic patients , researchers led by Nirupma Trehanpati and Shiv Kumar Sarin (Institute of Liver & Biliary Sciences, New Delhi, India) aimed to determine whether EpCAM‐positive CSC‐like cells do arise in the livers of cirrhotic patients. In their Stem Cells Translational Medicine article , Khosla et al first discovered an increase in the frequency of EpCAM‐positive CSC‐like cells in cirrhotic patients over time. Their subsequent comparisons discovered that EpCAM‐positive CSC‐like cells from cirrhotic patients more closely resembled EpCAM‐positive CSC‐like cells from hepatocellular carcinoma patients than those from healthy tissues (presumed normal hepatic stem cells).…”

“…In our first Featured Article this month from Stem Cells , Du et al report that intracellular Notch1 signaling in cancer‐associated fibroblasts modulates the plasticity and stemness of melanoma CSCs, thereby regulating the aggressiveness and metastatic nature of melanoma . In a related Article from Stem Cells Translational Medicine , Khosla et al provide evidence for the emergence of an epithelial cell adhesion molecule (EpCAM)‐expressing CSC population in patients with advanced cirrhosis that displays increased autocrine activation of Wnt signaling, self‐renewal properties, and tumor‐forming potential .…”

A Preview of Selected Articles

“…Liver cirrhosis, the late stage of scarring caused by liver diseases or conditions such as hepatitis and chronic alcoholism, often leads to the development of HCC, with CSC‐like cells expressing the epithelial cell adhesion molecule (EpCAM) gene thought to represent the cell of origin. A S tem C ells T ranslational M edicine study from the laboratories of Nirupma Trehanpati and Shiv Kumar Sarin (Institute of Liver & Biliary Sciences, New Delhi, India) sought to assess the prevalence and characteristics of EpCAM‐expressing CSC‐like cells in advanced cirrhosis in the hopes of discerning a link . Interestingly, liver samples from cirrhotic human patients displayed elevated numbers of EpCAM‐expressing CSC‐like cells, which displayed upregulated expression of stemness and Notch pathway genes and enhanced self‐renewal/tumor‐initiating activity.…”