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 Scopus citations

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

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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