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  • Title: Defining a Population of Stem-like Human Prostate Cancer Cells That Can Generate and Propagate Castration-Resistant Prostate Cancer.
    Author: Chen X, Li Q, Liu X, Liu C, Liu R, Rycaj K, Zhang D, Liu B, Jeter C, Calhoun-Davis T, Lin K, Lu Y, Chao HP, Shen J, Tang DG.
    Journal: Clin Cancer Res; 2016 Sep 01; 22(17):4505-16. PubMed ID: 27060154.
    Abstract:
    PURPOSE: We have shown that the phenotypically undifferentiated (PSA(-/lo)) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA(-/lo) population bearing the ALDH(hi)CD44(+)α2β1(+) phenotype (Triple Marker(+)/TM(+)) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM(+) prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies. RESULTS: By focusing on the LAPC9 model, we show that the TM(+) cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM(+) cells, which possess CSC activities in "castrated" culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM(+) cells preferentially express castration resistance and stem cell-associated molecules that regulate their CSC characteristics; and (iii) the TM(+) cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir. CONCLUSIONS: Our results define the TM(+) prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM(+) cell population as a therapeutic target. Clin Cancer Res; 22(17); 4505-16. ©2016 AACR.
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