Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation

Background& Aims: Transformed hematopoietic stem/progenitor cells with an enhanced or acquired self-renewal capability function as leukemic stem cells. In a variety of solid cancers, stem/progenitor cells could be also targets of carcinogenesis. However, it remains unclear whether disruption of stem cell function directly contributes to cancer initiation. We sought to elucidate the mechanisms of selfrenewal in hepatic stem/progenitor cells and the relation between stem cell function and hepatocarcinogenesis. Methods: Functional analyses of polycomb-group protein Bmil and Wnt/beta-catenin, the molecules that are responsible for the self-renewal capability of many types of stem cells, were conducted in c-Kit- CD29(+) CD49f(+)/(low)CD45 -Ter- 119- hepatic stem/ progenitor cells using retrovirus- or lentivirus-mediated gene transfer. The tumorigenicity of these cells transduced with the indicated retroviruses was also assessed by transplantation into nonobese diabetic/ severe combined immunodeficient mice. Results: Forced expression of Bmil and constitutively active beta-catenin mutant similarly promoted the self-renewal of hepatic stem/progenitor cells. The transplantation of Bmi1- or P-catenin-transduced cells clonally expanded froiii single hepatic stem/progenitor cells produced tumors, which exhibited the histologic features of combined hepatocellular and cholangiocarcinoma. Conclusions: These observations imply that the dysregulated self-renewal of hepatic stem/progenitor cells serves as an early event in hepatocarcinogenesis, and they highlight the important roles of Bmil and the Wnt/beta-catenin pathway in regulating the seff-renewal of normal or cancer stem cells in liver.