Lin-Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model.
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.
Mulholland
David J
DJ
Departments of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California 90095-1735, USA.
Xin
Li
L
Morim
Ashkan
A
Lawson
Devon
D
Witte
Owen
O
Wu
Hong
H
D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000032:analysis*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D039503:Integrin alpha6 / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008817:Mice, Mutant Strains; D008863:Microspheres; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000096:biosynthesis; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*
D000950:Antigens, Ly; D014408:Biomarkers, Tumor; D039503:Integrin alpha6; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C057535:lincosaminide O-nucleotidyltransferase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse