Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensle homolog deleted on chromosome 10-deleted mice

C. Bart Rountree, Wei Ding, Lina He, Bangyan Stiles

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase that regulates mitogenic signaling pathways, and deficiency of PTEN results in cell proliferation, survival, and malignancy. Murine liver-specific Pten deletion models develop liver malignancy by 12 months of age. Using this model, we describe a population of CD133+ liver cancer stem cells isolated during the chronic injury phase of disease progression and before primary carcinoma formation. We performed immunohistoehemis-try and flow cytometry isolation using livers from 3- and 6-month-old piemloxp/loxp; Alb-Cre+ mice (mutants) and controls. CD133+CD45- nonparenchymal (NP) cells were analyzed for gene expression profile and protein levels. Single CD133+CD45- oval cells were isolated for clonal expansion and tumor analysis. Cultured and freshly isolated liver CD133+CD45- and CD133-CD45- NP cells were injected into immune-deficient and immune-competent mice. In mutant mice, the NP fraction increased in CD133+CD45- cells in 3- and 6-month-old Pten-deleted animals compared with controls. Clone lines expanded from single CD133+CD45- cells demonstrated consistent liver progenitor cell phenotype, with bilineage gene expression of hepatocyte and cholangiocyte markers. CD133+ cells from expanded clone lines formed robust tumors in immune-deficient and immune-competent mice. Furthermore, freshly isolated CD133+CD45- NP liver cells from 6-month-old mutants formed tumors in vivo, and CD133-CD45- NP cells did not. Consistent with a cancer stem cell phenotype, CD133+ cells demonstrate resistance to chemotherapy agents compared with CD 133- cells. CD133+CD45- nonparenchymal cells from chronic injury Ptenloxp/loxp; Alb- Cre+ mice represent a bipotent liver progenitor cell population with cancer stem cell phenotype.

Original languageEnglish (US)
Pages (from-to)290-299
Number of pages10
JournalSTEM CELLS
Volume27
Issue number2
DOIs
StatePublished - Feb 1 2009

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Chromosomes, Human, Pair 10
Neoplastic Stem Cells
Liver Neoplasms
Phosphoric Monoester Hydrolases
Liver
Neoplasms
Phenotype
Stem Cells
Clone Cells
PTEN Phosphohydrolase
Wounds and Injuries
Transcriptome
Population
Disease Progression
Hepatocytes
Cell Survival
Flow Cytometry
Cell Proliferation
Carcinoma
Lipids

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

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title = "Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensle homolog deleted on chromosome 10-deleted mice",
abstract = "PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase that regulates mitogenic signaling pathways, and deficiency of PTEN results in cell proliferation, survival, and malignancy. Murine liver-specific Pten deletion models develop liver malignancy by 12 months of age. Using this model, we describe a population of CD133+ liver cancer stem cells isolated during the chronic injury phase of disease progression and before primary carcinoma formation. We performed immunohistoehemis-try and flow cytometry isolation using livers from 3- and 6-month-old piemloxp/loxp; Alb-Cre+ mice (mutants) and controls. CD133+CD45- nonparenchymal (NP) cells were analyzed for gene expression profile and protein levels. Single CD133+CD45- oval cells were isolated for clonal expansion and tumor analysis. Cultured and freshly isolated liver CD133+CD45- and CD133-CD45- NP cells were injected into immune-deficient and immune-competent mice. In mutant mice, the NP fraction increased in CD133+CD45- cells in 3- and 6-month-old Pten-deleted animals compared with controls. Clone lines expanded from single CD133+CD45- cells demonstrated consistent liver progenitor cell phenotype, with bilineage gene expression of hepatocyte and cholangiocyte markers. CD133+ cells from expanded clone lines formed robust tumors in immune-deficient and immune-competent mice. Furthermore, freshly isolated CD133+CD45- NP liver cells from 6-month-old mutants formed tumors in vivo, and CD133-CD45- NP cells did not. Consistent with a cancer stem cell phenotype, CD133+ cells demonstrate resistance to chemotherapy agents compared with CD 133- cells. CD133+CD45- nonparenchymal cells from chronic injury Ptenloxp/loxp; Alb- Cre+ mice represent a bipotent liver progenitor cell population with cancer stem cell phenotype.",
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Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensle homolog deleted on chromosome 10-deleted mice. / Rountree, C. Bart; Ding, Wei; He, Lina; Stiles, Bangyan.

In: STEM CELLS, Vol. 27, No. 2, 01.02.2009, p. 290-299.

Research output: Contribution to journalArticle

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