CD34+ Liver Cancer Stem Cells Were Formed by Fusion of Hepatobiliary Stem/Progenitor Cells with Hematopoietic Precursor-Derived Myeloid Intermediates

Changjun Zeng, Yanling Zhang, Su Cheol Park, Jong Ryeol Eun, Ngoc Tue Nguyen, Benjamin Tschudy-Seney, Yong Jin Jung, Neil D. Theise, Mark A Zern, YuYou Duan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2467-2478
Number of pages12
JournalStem Cells and Development
Volume24
Issue number21
DOIs
StatePublished - Nov 1 2015

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Neoplastic Stem Cells
Liver Neoplasms
Stem Cells
Liver
Heterografts
Interleukin-12 Subunit p35
Cytokines
Phenotype
CXC Chemokines
Interleukin-18
Cytogenetic Analysis
Interleukins
Interleukin-8
Chemokines
Interleukin-4
Interferons
Lipopolysaccharides
Hepatocytes
Albumins
Interleukin-6

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

CD34+ Liver Cancer Stem Cells Were Formed by Fusion of Hepatobiliary Stem/Progenitor Cells with Hematopoietic Precursor-Derived Myeloid Intermediates. / Zeng, Changjun; Zhang, Yanling; Park, Su Cheol; Eun, Jong Ryeol; Nguyen, Ngoc Tue; Tschudy-Seney, Benjamin; Jung, Yong Jin; Theise, Neil D.; Zern, Mark A; Duan, YuYou.

In: Stem Cells and Development, Vol. 24, No. 21, 01.11.2015, p. 2467-2478.

Research output: Contribution to journalArticle

Zeng, Changjun ; Zhang, Yanling ; Park, Su Cheol ; Eun, Jong Ryeol ; Nguyen, Ngoc Tue ; Tschudy-Seney, Benjamin ; Jung, Yong Jin ; Theise, Neil D. ; Zern, Mark A ; Duan, YuYou. / CD34+ Liver Cancer Stem Cells Were Formed by Fusion of Hepatobiliary Stem/Progenitor Cells with Hematopoietic Precursor-Derived Myeloid Intermediates. In: Stem Cells and Development. 2015 ; Vol. 24, No. 21. pp. 2467-2478.
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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.",
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AU - Park, Su Cheol

AU - Eun, Jong Ryeol

AU - Nguyen, Ngoc Tue

AU - Tschudy-Seney, Benjamin

AU - Jung, Yong Jin

AU - Theise, Neil D.

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AU - Duan, YuYou

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