Emerging signals regulating liver tumor initiating cells

Tumor initiating cells (TICs) have been identified as cells that account for tumor heterogeneity. Recent studies demonstrated that genes controlling stem cell biology play key roles in maintaining TICs and promote their development into cancer. In this review, we summarize findings from human and animal studies that indicate the presence of TICs during liver cancer development. Markers identified for liver development and regeneration are used to identify liver cancer TICs. Expression of these markers is often upregulated in human hepatocellular carcinoma (HCC) specimen. Using flow cytometry analysis and lineage tracing approaches, the presence of TICs is confirmed. Expression of TIC markers and the presence of TICs are also observed in genetically modified animals that target genes that are frequently altered in human HCC. The presence of these TICs represents a major challenge for therapeutic development. Elucidating signals that can regulate the fate, transformation and growth of liver TICs is an emerging need in liver research. Sex-determining region Y-box 9 (SOX9) has recently become an important marker for liver TICs. Here, we summarize the role of SOX9 in TICs and its potential interaction with other signals. This includes the Notch-Numb signal that controls asymmetrical-symmetrical cell division, Wnt-β-catenin signal that maintains cell fate and transforming growth factor (TGF)-β signal that acts as upstream inducers. Keywords: Liver cancer, Hepatocellular carcinoma (HCC), Tumor initiating cells (TICs), Sex-determining region Y-box 9 (SOX9), β-catenin, Notch, Numb, Transforming growth factor (TGF)-β