EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features.
OBJECTIVE
Cancer progression/metastases and embryonic development share many properties including cellular plasticity, dynamic cell motility, and integral interaction with the microenvironment. We hypothesized that the heterogeneous nature of hepatocellular carcinoma (HCC), in part, may be owing to the presence of hepatic cancer cells with stem/progenitor features.


METHODS
Gene expression profiling and immunohistochemistry analyses were used to analyze 235 tumor specimens derived from 2 recently identified HCC subtypes (EpCAM(+) alpha-fetoprotein [AFP(+)] HCC and EpCAM(-) AFP(-) HCC). These subtypes differed in their expression of AFP, a molecule produced in the developing embryo, and EpCAM, a cell surface hepatic stem cell marker. Fluorescence-activated cell sorting was used to isolate EpCAM(+) HCC cells, which were tested for hepatic stem/progenitor cell properties.


RESULTS
Gene expression and pathway analyses revealed that the EpCAM(+) AFP(+) HCC subtype had features of hepatic stem/progenitor cells. Indeed, the fluorescence-activated cell sorting-isolated EpCAM(+) HCC cells displayed hepatic cancer stem cell-like traits including the abilities to self-renew and differentiate. Moreover, these cells were capable of initiating highly invasive HCC in nonobese diabetic, severe combined immunodeficient mice. Activation of Wnt/beta-catenin signaling enriched the EpCAM(+) cell population, whereas RNA interference-based blockage of EpCAM, a Wnt/beta-catenin signaling target, attenuated the activities of these cells.


CONCLUSIONS
Taken together, our results suggest that HCC growth and invasiveness is dictated by a subset of EpCAM(+) cells, opening a new avenue for HCC cancer cell eradication by targeting Wnt/beta-catenin signaling components such as EpCAM.
Yamashita
Taro
T
Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Ji
Junfang
J
Budhu
Anuradha
A
Forgues
Marshonna
M
Yang
Wen
W
Wang
Hong-Yang
HY
Jia
Huliang
H
Ye
Qinghai
Q
Qin
Lun-Xiu
LX
Wauthier
Elaine
E
Reid
Lola M
LM
Minato
Hiroshi
H
Honda
Masao
M
Kaneko
Shuichi
S
Tang
Zhao-You
ZY
Wang
Xin Wei
XW
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002469:Cell Separation; D000071858:Epithelial Cell Adhesion Molecule; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011379:Prognosis; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000473:pathology / Q000502:physiology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D034741:RNA, Small Interfering; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3