Histological and culture studies with respect to ABCG2 expression support the existence of a cancer cell hierarchy in human hepatocellular carcinoma

Am J Pathol. 2007 May;170(5):1750-62. doi: 10.2353/ajpath.2007.060798.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / biosynthesis*
  • Adult
  • Aged
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Female
  • Fluorescent Antibody Technique
  • Hepatocytes / metabolism
  • Hepatocytes / pathology*
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Male
  • Middle Aged
  • Neoplasm Proteins / biosynthesis*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Reverse Transcriptase Polymerase Chain Reaction


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Neoplasm Proteins