Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation.
OBJECTIVE
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 self-renewal in hepatic stem/progenitor cells and the relation between stem cell function and hepatocarcinogenesis.


METHODS
Functional analyses of polycomb-group protein Bmi1 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 Bmi1 and constitutively active beta-catenin mutant similarly promoted the self-renewal of hepatic stem/progenitor cells. The transplantation of Bmi1- or beta-catenin-transduced cells clonally expanded from 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 Bmi1 and the Wnt/beta-catenin pathway in regulating the self-renewal of normal or cancer stem cells in liver.
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Tetsuhiro
T
Chiba
Yun-Wen
YW
Zheng
Kaoru
K
Kita
Osamu
O
Yokosuka
Hiromitsu
H
Saisho
Masafumi
M
Onodera
Hiroyuki
H
Miyoshi
Masayuki
M
Nakano
Yoh
Y
Zen
Yasuni
Y
Nakanuma
Hiromitsu
H
Nakauchi
Atsushi
A
Iwama
Hideki
H
Taniguchi
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000502:physiology; D008099:Liver / Q000166:cytology; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000502:physiology
C489421:Bmi1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D063150:Polycomb Repressive Complex 1