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  • Title: Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells.
    Author: Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, Huang DD, Tang L, Kong XN, Chen C, Liu SQ, Wu MC, Wang HY.
    Journal: Cancer Res; 2008 Jun 01; 68(11):4287-95. PubMed ID: 18519688.
    Abstract:
    Adult hepatic progenitor (oval) cells are facultative stem cells in liver, which participate in a range of human liver diseases, including hepatocellular carcinoma (HCC). However, the molecular pathways regulating the expansion and differentiation of these cells are poorly understood. We show that active Wnt/beta-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively active beta-catenin mutant promotes expansion of the oval cell population in the regenerated liver. More importantly, we identify a subpopulation of less differentiated progenitor-like cells in HCC cell lines and primary HCC tissues, which are defined by expression of the hepatic progenitor marker OV6 and endowed with endogenously active Wnt/beta-catenin signaling. These OV6(+) HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy compared with OV6(-) tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation, whereas inhibition of beta-catenin signaling leads to a decrease in the proportion of OV6(+) cells. In addition, the chemoresistance of OV6(+) HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targeting beta-catenin. These results highlight the importance of the Wnt/beta-catenin pathway in activation and expansion of oval cells in normal rodent models and human HCCs. OV6(+) tumor cells may represent the cellular population that confers HCC chemoresistance, and therapies targeted to the Wnt/beta-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy.
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