Clinical implications of cancer stem cell biology in hepatocellular carcinoma

Solid tumors are thought to contain cancer stem cells (CSCs) as a distinct population responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to a new tumor in local or distant organs. CSCs have been identified in many tumor types, including hepatocellular carcinoma (HCC), the fifth most common and third most deadly malignancy with observable heterogeneity. Numerous studies have shown that hepatic CSCs could be enriched via different cell surface markers, eg, CD13, CD24, CD44, CD90, CD133, EpCAM (CD326), and OV6. They also could be identified through functional assays such as isolating the side population cells by Hoechst dye staining or screening cells with a high activity of aldehyde dehydrogenase. Functional characterization of hepatic CSCs has revealed several deregulated signaling pathways, such as Wnt/β-catenin, AKT, transforming growth factor-beta (TGF-β), interleukin (IL)-6/STAT3 pathways to be critical in inducing "stemness" of HCC and in promoting self-renewal, tumorigenicity, and chemoresistance. An increased understanding of hepatic CSC biology facilitated the development of new diagnostic, prognostic, and therapeutic strategies for improving HCC clinical management. In this review, we summarize recent evidence including the identification of the hepatic CSC and its underlying biological mechanisms, and discuss the potential clinical implications in HCC.