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PMID: 19008348 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

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

Stem cells (Dayton, Ohio) ·Vol. 27 ·No. 2 ·2009-02-00 ·Pages 290-9

Rountree CB, Ding W, He L, Stiles B

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 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.

MeSH Terms
AC133 Antigen Animals Antigens, CD/metabolism Blotting, Western Cell Survival/genetics,physiology Cells, Cultured Chromosomes, Mammalian/genetics Flow Cytometry Glycoproteins/metabolism Immunohistochemistry Leukocyte Common Antigens/metabolism Liver Neoplasms/metabolism,pathology Mice Mice, Mutant Strains Mice, Nude Neoplastic Stem Cells/metabolism,pathology PTEN Phosphohydrolase/genetics Peptides/metabolism Polymerase Chain Reaction
Chemicals
AC133 Antigen Antigens, CD Glycoproteins Peptides Prom1 protein, mouse Leukocyte Common Antigens PTEN Phosphohydrolase Pten protein, mouse
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Rountree C Bart
Department of Pediatrics, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033-0850, USA. CRountree@hmc.psu.edu
Ding Wei
He Lina
Stiles Bangyan
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Article Info
Journal
Stem cells (Dayton, Ohio)
Abbr.
Stem Cells
ISSN
1549-4918
DOI
10.1634/stemcells.2008-0332
Email
crountree@hmc.psu.edu
Published
2009-02-00
Pages
290-9
Language
English
Region
United States
NLM ID
9304532
PMCID
PMC2847372
Subset
IM
Grants
NIDDK NIH HHS · 1K08DK080928-01 · United States
NIDDK NIH HHS · R01 DK084241 · United States
NIDDK NIH HHS · K08 DK080928 · United States
NIDDK NIH HHS · K08 DK080928-02 · United States
NCI NIH HHS · R01 CA154986 · United States
NIDDK NIH HHS · P30 DK048522 · United States
NIDDK NIH HHS · R21 DK075928 · United States
NIDDK NIH HHS · DK48522 · United States
NIDDK NIH HHS · K08 DK080928-01 · United States
PHS HHS · D1BTH06321-01 · United States
External Links
PubMed source DOI: 10.1634/stemcells.2008-0332 PMC Full Text View journal details
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