title: CD34(+) Liver Cancer Stem Cells Were Formed by Fusion of Hepatobiliary Stem/Progenitor Cells with Hematopoietic Precursor-Derived Myeloid Intermediates.
abstract: A large number of cancer stem cells (CSCs) were identified and characterized; however, the origins and formation of CSCs remain elusive. In this study, we examined the origination of the newly identified CD34(+) liver CSC (LCSC). We found that CD34(+) LCSC coexpressed liver stem cell and myelomonocytic cell markers, showing a mixed phenotype, a combination of hepatobiliary stem/progenitor cells (HSPCs) and myelomonocytic cells. Moreover, human xenografts produced by CD34(+) LCSCs and the parental cells, which CD34(+) LCSC was isolated from, coexpressed liver cancer and myelomonocytic markers, also demonstrating mixed phenotypes. The xenografts and the parental cells secreted albumin demonstrating their hepatocyte origin and also expressed cytokines [interleukin (IL)-1b, IL-6, IL-12A, IL-18, tumor necrosis factor-alpha (TNF-α), and CSF1] and chemokines (IL-8, CCL2, and CCL5). Expression of these cytokines and chemokines responded to the stimuli [interferon-γ (INF-γ), IL-4, and lipopolysaccharide (LPS)]. Furthermore, human xenografts and the parental cells phagocytized Escherichia coli. CD34(+) LCSC coexpressed CD45, demonstrating that its origin appears to be from a hematopoietic precursor. The percentage of cells positive for OV6, CD34, and CD31, presenting the markers of HSPC, hematopoietic, and myelomonocytic cells, increased under treatment of CD34(+) LCSC with a drug. Cytogenetic analysis showed that CD34(+) LCSC contained a greater number of chromosomes. HBV DNA integrations and mutations in CD34(+) LCSC and the parental cells were identical to those in the literature or the database. Thus, these results demonstrated that CD34(+) LCSCs were formed by fusion of HSPC with CD34(+) hematopoietic precursor-derived myeloid intermediates; it appears that this is the first report that human CSCs have been formed by the fusion. Therefore, it represents a significant step toward better understanding of the formation of human CSC and the diverse origins of liver cancers.
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.|3 College of Animal Science and Technology, Sichuan Agricultural University , Ya'an, China .
authors.forename: Changjun
authors.initials: C
authors.lastname: Zeng
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.|4 School of Biotechnology, Southern Medical University , Guangzhou, China .
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.|5 Department of Internal Medicine, Korea Institute of Radiological & Medical Sciences , Seoul, Korea.
authors.forename: Su Cheol
authors.initials: SC
authors.lastname: Park
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.|6 Department of Internal Medicine, Yeungnam University College of Medicine , Daegu, Korea.
authors.forename: Jong Ryeol
authors.initials: JR
authors.lastname: Eun
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.
authors.forename: Ngoc Tue
authors.initials: NT
authors.lastname: Nguyen
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tschudy-Seney
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.|7 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: Jung
authors.affiliation: 8 Department of Pathology and Medicine, Beth Israel Medical Center , Albert Einstein College of Medicine, New York, New York.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Theise
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zern
authors.affiliation: 1 Department of Internal Medicine, University of California Davis Medical Center , Sacramento, California.|2 Institute for Regenerative Cures, University of California Davis Medical Center , Sacramento, California.|9 Department of Dermatology, University of California Davis Medical Center , Sacramento, California.
authors.forename: Yuyou
authors.initials: Y
authors.lastname: Duan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018952:Antigens, CD34 / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D016207:Cytokines; D015850:Interleukin-6