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Cancer Stem Cells
Article first published online: 2 FEB 2009
Copyright © 2009 AlphaMed Press
Volume 27, Issue 2, pages 290–299, February 2009
How to Cite
Rountree, C. B., Ding, W., He, L. and Stiles, B. (2009), Expansion of CD133-Expressing Liver Cancer Stem Cells in Liver-Specific Phosphatase and Tensin Homolog Deleted on Chromosome 10-Deleted Mice. STEM CELLS, 27: 290–299. doi: 10.1634/stemcells.2008-0332
Author contributions: C.B.R.: conception and design, financial support, collection and assembly of data, data analysis and integration, manuscript writing, and final approval of the manuscript; W.D.: conception and design, collection and assembly of data, data analysis and integration, and final approval of the manuscript; L.H.: collection and assembly of data, data analysis and integration, and final approval of the manuscript; B.S.: conception and design, financial support, data analysis and integration, manuscript writing, and final approval of the manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSExpress November 13, 2008; available online without subscription through the open access option.
- Issue published online: 2 FEB 2009
- Article first published online: 2 FEB 2009
- Manuscript Accepted: 26 OCT 2008
- Manuscript Received: 1 APR 2008
- NIH Award. Grant Number: 1K08DK080928-01
- AGA/AstraZeneca Fellow/Faculty Transition Award
- USC Research Center for Liver Diseases Pilot Feasibility Grant. Grant Number: DK48522
- Office for the Advancement of Telehealth, Health Resources and Services Administration, Department of Health and Human Services. Grant Number: D1BTH06321-01
- Oval cell;
- Cancer stem cell;
- AC133 antigen;
- Liver regeneration;
- Tissue-specific stem cell
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 PtenloxP/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 PtenloxP/loxP; Alb−Cre+ mice represent a bipotent liver progenitor cell population with cancer stem cell phenotype. STEM CELLS2009;27:290–299