Characterization of prostatic stem cells and prostate cancer-initiating cells
Principal Investigator: L Xin
Abstract: Prostate cancer is the second-leading cause of the cancer-related death in men in the United States. We have enriched prostate stem cell activity using the Sca-1 surface antigen and demonstrated that cells with enriched stem cell activity serve as a target for tumor initiation. Our long-term goals are to fully characterize the identity of stem cells and cancer-initiating cells in prostate. This study will provide general insights for the studies on stem cell biology and cancer biology. Our specific aims are: (1) Fully characterize the prostatic stem cells. (A) We will investigate whether stem cells reside in a specific prostatic epithelial cell lineage using the dissociated prostate cell regeneration system. We will (i) isolate individual lineages and test their regenerative capacity, and (ii) permanently mark individual lineages and determine the lineage status of their progeny. These can be achieved by creating a prostate basal cell-specific green fluorescence protein-marked transgenic mouse model or through the Cre-loxp marking system regulated by prostate lineage-specific promoters. (B) We will continue to screen the expression of surface antigens in prostate, fractionate prostate cells using surface antigens and identify the fraction(s) with enriched stem cell activity using the regeneration system. (2) Identify the prostate cancer-initiating cells. (A) We will evaluate the susceptibility of basal cells and luminal cells to oncogenic transformation. We will induce Pten deletion in individual lineages by infecting prostate epithelial cells from the PTENIoxp/loxp transgenic mouse model with lentivirus that express the Cre recombinase regulated by lineage-specific promoters. Infected cells will be tested in the regeneration system to determine which cell lineage(s) have been transformed. (B) We will determine the susceptibility of each cell population fractionated in Aim1 B to malignant transformation induced by single or a combination of oncogenic stimuli. Cell fractions from the wild type and P53-/- mice that represent stem cells, short-term progenitor cells and terminally differentiated cells will be infected with lentivirus that mediate distinct oncogenic signals, such as myc, inactivation of the pRB family proteins, perturbations in the PTEN-AKT signaling pathway and others. The infected cells will be microinjected into immunodeficient host mouse prostate or tested in the regeneration system to determine their capacity to initiate cancer.
Funding Period: 2007-09-01 - 2009-08-31
more information: NIH RePORT
- Enhanced paracrine FGF10 expression promotes formation of multifocal prostate adenocarcinoma and an increase in epithelial androgen receptorSanaz Memarzadeh
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Cancer Cell 12:572-85. 2007..We also show that transient exposure to a paracrine growth factor may be sufficient for the initiation of oncogenic transformation...
- Epithelial stem cells of the prostate and their role in cancer progressionR U Lukacs
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, USA
Cold Spring Harb Symp Quant Biol 73:491-502. 2008....
- Lin-Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer modelDavid J Mulholland
Departments of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California 90095 1735, USA
Cancer Res 69:8555-62. 2009..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...
- Basal epithelial stem cells are efficient targets for prostate cancer initiationDevon A Lawson
Department of Microbiology, The Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095, USA
Proc Natl Acad Sci U S A 107:2610-5. 2010..This finding provides evidence in support of basal epithelial stem cells as one target cell for prostate cancer initiation and demonstrates the propensity of primitive cells for tumorigenesis...
- Low-density Taqman miRNA array reveals miRNAs differentially expressed in prostatic stem cells and luminal cellsLi Zhang
Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA
Prostate 70:297-304. 2010..miRNAs are a class of naturally occurring small RNAs that generally repress gene expression. They have been shown to actively control diverse biological processes including stem cell differentiation and lineage commitment...
- Dicer ablation impairs prostate stem cell activity and causes prostate atrophyLi Zhang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Stem Cells 28:1260-9. 2010..Our results demonstrate a critical role of microRNAs for the proliferative capacity of prostate stem cells and the maintenance of prostate homeostasis...