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Lin^–Sca-1⁺CD49f^high Stem/Progenitors Are Tumor-Initiating Cells in the Pten-Null Prostate Cancer Model

Departments of ¹ Molecular and Medical Pharmacology and ² Microbiology, Immunology and Molecular Genetics, ³ Howard Hughes Medical Institute, ⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and ⁵ Institute for Molecular Medicine, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Hong Wu, Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, University of California at Los Angeles, CHS 23-214, 650 C.E. Young Drive South, Los Angeles, CA 90095-1735. Phone: 310-825-5160; Fax: 310-267-0242; E-mail: hwu{at}mednet.ucla.edu.

We have shown previously that Pten deletion leads to the expansion of subset of prostate cancer cells positive for CK5 and p63. Although this subpopulation may be involved in tumor initiation or progression, studies to date have not functionally validated this hypothesis. Using in vitro sphere-forming assay and in vivo prostate reconstitution assay, we show here the presence of a tumor-initiating subpopulation in the Pten prostate cancer mouse model. Specifically, we show that the Lin^–Sca-1⁺CD49f^high (LSC) subpopulation overlaps with CK5⁺;p63⁺ cells and is significantly increased during prostate cancer initiation and progression and after castration. Mutant spheres mimic the structural organization of the epithelial compartment in the Pten-null primary tumor. Sorted LSC cells from either Pten-null spheres or primary tumors are able to regenerate prostate epithelial structure with cancerous morphology, closely mimicking that of primary cancers. Therefore, the LSC subpopulation is capable of initiating a cancerous phenotype that recapitulates the pathology seen in the primary lesions of the Pten mutant prostate model. [Cancer Res 2009;69(22):8555–62]

Key Words: prostate cancer • PTEN • stem cell