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Molecular features of hepatocellular carcinoma affect patient prognosis and treatment efficiency. This chapter provides an overview of the relevant studies conducted to identify the cell of origin of hepatocellular carcinoma with a special focus on the controversy of hepatocytes versus hepatic progenitors as the main tumor-initiating cell. Furthermore, we introduce the concept of cancer stem cells (CSCs) and highlight recent publications covering this topic in relation to liver cancer. More precisely, we concentrate on the origin of CSCs, discuss accepted markers and the need to define a consistent combination of them that can be utilized to clearly define this heterogeneous cell type, summarize important signaling pathways that govern the stemness, and describe state-of-the-art assays to isolate and evaluate CSCs. We focus on their contributions to oncogenesis and tumor heterogeneity, as well as their feature to resist chemo- and radiotherapy. Finally, the potential of using CSC markers for diagnostic purposes and therapeutic approaches targeting these cells is addressed.
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