TY - JOUR
T1 - CD34+ Liver Cancer Stem Cells Were Formed by Fusion of Hepatobiliary Stem/Progenitor Cells with Hematopoietic Precursor-Derived Myeloid Intermediates
AU - Zeng, Changjun
AU - Zhang, Yanling
AU - Park, Su Cheol
AU - Eun, Jong Ryeol
AU - Nguyen, Ngoc Tue
AU - Tschudy-Seney, Benjamin
AU - Jung, Yong Jin
AU - Theise, Neil D.
AU - Zern, Mark A.
AU - Duan, Yuyou
N1 - Publisher Copyright:
© 2015 Mary Ann Liebert, Inc.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84945418363&partnerID=8YFLogxK
U2 - 10.1089/scd.2015.0202
DO - 10.1089/scd.2015.0202
M3 - Article
C2 - 26192559
AN - SCOPUS:84945418363
SN - 1547-3287
VL - 24
SP - 2467
EP - 2478
JO - Stem Cells and Development
JF - Stem Cells and Development
IS - 21
ER -