title: Histological and culture studies with respect to ABCG2 expression support the existence of a cancer cell hierarchy in human hepatocellular carcinoma.
abstract: In this study, we examined the possible involvement of progenitor cells in the carcinogenesis of human hepatocellular carcinoma (HCC) using tissue specimens and cell lines. We used ATP-binding cassette transporter ABCG2 as a progenitor cell marker. Immunohistochemically, ABCG2(+) hepatocytes were observed in the periportal areas of the dysplastic nodule, and ABCG2(+) cancer cells were also scattered or focally clustered in HCC. We sorted the cultured HCC cells (HuH7 and PLC5) into ABCG2(+) and ABCG2(-) subpopulations and then subcultured them for 4 weeks. ABCG2(+) cells could generate ABCG2(+) and ABCG2(-) progenies during subculture, whereas ABCG2(-) cells bore only ABCG2(-) cells, suggesting that a cancer cell hierarchy with reference to ABCG2 exists in HCC cells and that ABCG2(+) cells reside at the higher rank in that hierarchy. Interestingly, other progenitor cell markers including cytokeratin 19 and alpha-fetoprotein were mainly expressed in ABCG2(+) subpopulations. Conversely, albumin expression was more intense in ABCG2(-) cells. In addition, the expression patterns of transcription factors (GATA6, CCAAT/enhancer-binding protein alpha, and CCAAT/enhancer-binding protein beta) in ABCG2(+) and ABCG2(-) cells resembled those during normal liver development. In conclusion, this study suggests that cancer cells with ABCG2 expression might play a central role in hepatocarcinogenesis and the maintenance of the cancer cell hierarchy of human HCC.
authors: Department of Human Pathology, Kanazawa University Graduate School of Medicine, 13-1 Takaramachi, Kanazawa 920-8640, Japan.
authors: Yoh
authors: Y
authors: Zen
authors: Takahiko
authors: T
authors: Fujii
authors: Seiichi
authors: S
authors: Yoshikawa
authors: Hiroyuki
authors: H
authors: Takamura
authors: Takashi
authors: T
authors: Tani
authors: Tetsuo
authors: T
authors: Ohta
authors: Yasuni
authors: Y
authors: Nakanuma
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins