Defining castration-resistant prostate cancer stem cells

Purpose: We have shown that the phenotypically undifferentiated (PSA-/lo) prostate cancer (PCa) cell population harbors long-term self-renewing cancer stem cells (CSCs) that resist castration and a subset of the cells within PSA-/lo population bearing the ALDHhiCD44+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 biological properties of TM+ PCa cell population, particularly in the context of initiating and propagating CRPC. Experimental Design: The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent (AD) and androgen-independent (AI) PCa 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 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 1) the phenotypic markers are causally involved in CRPC development; 2) the TM+ cells preferentially express castration resistance and stem cell-associated molecules that regulate their CSC characteristics; and 3) the TM+ cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir. Conclusions: Our results define the TM+ PCa cells as a population of pre-existent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM+ cell population as a therapeutic target.

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