Hepatocellular carcinoma is the fifth most common malignancy worldwide. Recent trends indicate a rising incidence in the United States, with a 5-year survival rate of less than 5%. New therapeutics targeting advanced-stage hepatocellular carcinoma, such as sorafenib, have marginally improved the median overall survival by 3 months. There is an urgent need for new targeted agents that are associated with minimal local and systemic toxicities. Up to 40% of hepatocellular carcinomas are clonal, potentially arising from stem cells and increased activation of multiple pathways including IL-6/STAT3, WNT, CDK4, and hedgehog, as well as loss of response to the transforming growth factor-beta (TGF-β) signaling pathway. Our hypothesis has been that these “cancer stem cells” or cancer sustaining cells may prove to be strong genetic and therapeutic targets. Modulating stem cell renewal factors such as STAT3, NANOG, and OCT4 may reduce hepatocellular carcinoma formation. These points are discussed in detail in this review
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