title: Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma.
abstract: Recent evidence suggests that hepatocellular carcinoma (HCC) is organized by a subset of cells with stem cell features (cancer stem cells; CSCs). CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been identified by the use of various stem cell markers. However, little information is known about the expression patterns and characteristics of marker-positive CSCs, hampering the development of personalized CSC-targeted therapy. Here, we show that CSC markers EpCAM and CD90 are independently expressed in liver cancer. In primary HCC, EpCAM+ and CD90+ cells resided distinctively, and gene-expression analysis of sorted cells suggested that EpCAM+ cells had features of epithelial cells, whereas CD90+ cells had those of vascular endothelial cells. Clinicopathological analysis indicated that the presence of EpCAM+ cells was associated with poorly differentiated morphology and high serum alpha-fetoprotein (AFP), whereas the presence of CD90+ cells was associated with a high incidence of distant organ metastasis. Serial xenotransplantation of EpCAM+ /CD90+ cells from primary HCCs in immune-deficient mice revealed rapid growth of EpCAM+ cells in the subcutaneous lesion and a highly metastatic capacity of CD90+ cells in the lung. In cell lines, CD90+ cells showed abundant expression of c-Kit and in vitro chemosensitivity to imatinib mesylate. Furthermore, CD90+ cells enhanced the motility of EpCAM+ cells when cocultured in vitro through the activation of transforming growth factor beta (TGF-β) signaling, whereas imatinib mesylate suppressed TGFB1 expression in CD90+ cells as well as CD90+ cell-induced motility of EpCAM+ cells.
  
  
  CONCLUSIONS
  Our data suggest the discrete nature and potential interaction of EpCAM+ and CD90+ CSCs with specific gene-expression patterns and chemosensitivity to molecular targeted therapy. The presence of distinct CSCs may determine the clinical outcome of HCC.
authors.affiliation: Liver Center, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan. taroy@m-kanazawa.jp
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nakamoto
authors.forename: Masayo
authors.initials: M
authors.lastname: Baba
authors.forename: Kouki
authors.initials: K
authors.lastname: Nio
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Hara
authors.forename: Sha Sha
authors.initials: SS
authors.lastname: Zeng
authors.forename: Takehiro
authors.initials: T
authors.lastname: Hayashi
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Kondo
authors.forename: Hajime
authors.initials: H
authors.lastname: Takatori
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamashita
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000368:Aged; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D010879:Piperazines; D011743:Pyrimidines; D018800:Thy-1 Antigens; D000068877:Imatinib Mesylate