Background: PTEN (phosphatase and tensin homologue 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 twelve 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. Methods: We performed immunohistochemistry and flow cytometry isolation using livers from 3 and 6-monthold Pten(loxp/loxp); Alb-Cre+ mice (Mutants) and controls. CD133+CD45- non-parenchymal (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. Results: In Mutant mice, the NP fraction increases in CD133+CD45- cells in 3 and 6-month Pten deleted animals compared to controls. Clone lines expanded from single CD133+CD45- cells demonstrated consistent liver progenitor cell phenotype, with bi-lineage 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 six month-old Mutants formed tumors invivo, and CD133-CD45- NP cells did not. Consistent with a cancer stem cell phenotype, CD133+ cells demonstrate resistance to chemotherapy agents compared to CD133- cells. Conclusions: CD133+CD45- non-parenchymal cells from chronic injury Pten(loxp/loxp); Alb-Cre+ mice represent a bi-potent liver progenitor cell population with cancer stem cell phenotype.The full text of this article is openly accessible [PDF].
Monday, November 17, 2008
Liver progenitor cell population with CSC phenotype
Expansion of CD133 expressing liver cancer stem cells in liver specific PTEN deleted mice by C Bart Rountree, Wei Ding, Lina He, Bangyan Stiles, Stem Cells 2008(Nov 13). [Epub ahead of print]. PubMed Abstract: