Characterization of the epithelial cell adhesion molecule (EpCAM)+ cell population in hepatocellular carcinoma cell lines.
Accumulating evidence suggests that cancer stem cells (CSC) play an important role in tumorigenicity. Epithelial cell adhesion molecule (EpCAM) is one of the markers that identifies tumor cells with high tumorigenicity. The expression of EpCAM in liver progenitor cells prompted us to investigate whether CSC could be identified in hepatocellular carcinoma (HCC) cell lines. The sorted EpCAM(+) subpopulation from HCC cell lines showed a greater colony formation rate than the sorted EpCAM(-) subpopulation from the same cell lines, although cell proliferation was comparable between the two subpopulations. The in vivo evaluation of tumorigenicity, using supra-immunodeficient NOD/scid/γc(null) (NOG) mice, revealed that a smaller number of EpCAM(+) cells (minimum 100) than EpCAM(-) cells was necessary for tumor formation. The bifurcated differentiation of EpCAM(+) cell clones into both EpCAM(+) and EpCAM(-) cells was obvious both in vitro and in vivo, but EpCAM(-) clones sustained their phenotype. These clonal analyses suggested that EpCAM(+) cells may contain a multipotent cell population. Interestingly, the introduction of exogenous EpCAM into EpCAM(+) clones, but not into EpCAM(-) clones, markedly enhanced their tumor-forming ability, even though both transfectants expressed a similar level of EpCAM. Therefore, the difference in the tumor-forming ability between EpCAM(+) and EpCAM(-) cells is probably due to the intrinsic biological differences between them. Collectively, our results suggest that the EpCAM(+) population is biologically quite different from the EpCAM(-) population in HCC cell lines, and preferentially contains a highly tumorigenic cell population with the characteristics of CSC.
Kimura
Osamu
O
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Takahashi
Takeshi
T
Ishii
Naoto
N
Inoue
Yuki
Y
Ueno
Yoshiyuki
Y
Kogure
Takayuki
T
Fukushima
Koji
K
Shiina
Masaaki
M
Yamagiwa
Yoko
Y
Kondo
Yasuteru
Y
Inoue
Jun
J
Kakazu
Eiji
E
Iwasaki
Takao
T
Kawagishi
Naoki
N
Shimosegawa
Tooru
T
Sugamura
Kazuo
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000502:physiology*; D017434:Protein Structure, Tertiary
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule