Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity.

Jong Ryeol Eun,Yanling Zhang,Mark A Zern,Yanhong Zhang,Benjamin Tschudy-Seney,Rajen Ramsamooj,Yong Jin Jung,Yu-Jui Yvonne Wan,Yuyou Duan,Neil D Theise

doi:10.1371/journal.pone.0110744

Abstract

BackgroundSK Hep-1 cells (SK cells) derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, however, SK cells do not express liver genes and exhibit liver function, thus, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers. Here, we characterized SK cells and its tumourigenicity.Methods and Principal FindingsWe found that classical mesenchymal stem cell (MSC) markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative. SK cells are capable of differentiate into adipocytes and osteoblasts as adipose-derived MSC (Ad-MSC) and bone marrow-derived MSC (BM-MSC) do. Importantly, a single SK cell exhibited a substantial tumourigenicity and metastatic capacity in immunodefficient mice. Metastasis not only occurred in circulating organs such as lung, liver, and kidneys, but also in muscle, outer abdomen, and skin. SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC. The xenograft cells from subcutaneous and metastatic tumors exhibited a similar tumourigenicity and metastatic capacity, and showed the same relatively homogenous population with MSC characteristics when compared to parental SK cells. SK cells could unlimitedly expand in vitro without losing MSC characteristics, its tumuorigenicity and metastatic capacity, indicating that SK cells are oncogenic MSC with enhanced self-renewal capacity. We believe that this is the first report that human MSC appear to be transformed into cancer stem cells (CSC), and that their derivatives also function as CSCs.ConclusionOur findings demonstrate that SK cells represent a transformation mechanism of normal MSC into an enhanced self-renewal CSC with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity. Thus, it represents a novel mechanism of tumor initiation, development and metastasis by CSCs of non-epithelial and endothelia origin.

Highlights

Carcinomas are a heterogeneous population of a series of cells with different phenotypes; the origin of many cancers remains unknown
Our findings demonstrate that SK cells represent a transformation mechanism of normal mesenchymal stem cell (MSC) into an enhanced self-renewal cancer stem cells (CSC) with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity
Liver cancers can be divided into well, moderate, and poorly-differentiated carcinomas, and liver-specific genes can be detected in well- and moderately-differentiated liver cancer cells, indicating that these cancers originated from hepatocytes and cholangiocytes; liver specific genes cannot be detected in poorly-differentiated liver cancer cells, suggesting that these cancers might originate from other cell types rather than hepatocytes and cholangiocytes

Summary

Introduction

Carcinomas are a heterogeneous population of a series of cells with different phenotypes; the origin of many cancers remains unknown. 78% of the cells are hepatocytes; and the majority of non-hepatocytes are thought to be cholangiocytes [4], sinusoidal endothelia cells, Kupffer cells, hepatobiliary stem/progenitor cells, hepatic stellate cells, myofibroblasts, and pit cells [5,6,7,8,9]. SK Hep-1 cells (SK cells) derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, SK cells do not express liver genes and exhibit liver function, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers.

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Results

Discussion

Conclusion