Journal
STEM CELLS
Volume 27, Issue 2, Pages 290-299Publisher
WILEY
DOI: 10.1634/stemcells.2008-0332
Keywords
Oval cell; PTEN; Cancer stem cell; AC133 antigen; Liver regeneration; Tissue-specific stem cell
Categories
Funding
- NIH [1K08DK080928-01]
- AGA/AstraZeneca Fellow/Faculty Transition Award
- USC Research Center [DK48522]
- Office for the Advancement of Telehealth, Health Resources and Children's Hospital Los Angeles [D1BTH06321-01]
- Department of the Navy
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK048522, R01DK084241, K08DK080928, R21DK075928] Funding Source: NIH RePORTER
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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 immunohistochemistry and flow cytometry isolation using livers from 3- and 6-month-old Pten(loxp/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 CD133+ cells. CD133+CD45- nonparenchymal cells from chronic injury Pten(loxp/loxp); Alb-Cre+ mice represent a bipotent liver progenitor cell population with cancer stem cell phenotype. STEM CELLS 2009; 27: 290-299
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