Abstract
Human cancers are heterogeneous containing stem-like cancer cells operationally defined as cancer stem cells (CSCs) that possess great tumor-initiating and long-term tumor-propagating properties. In this study, we systematically dissect the phenotypic, functional and tumorigenic heterogeneity in human prostate cancer (PCa) using xenograft models and >70 patient tumor samples. In the first part, we further investigate the PSA-/lo PCa cell population, which we have recently shown to harbor self-renewing long-term tumor-propagating cells and present several novel findings. We show that discordant AR and PSA expression in both untreated and castration-resistant PCa (CRPC) results in AR+PSA+, AR+PSA-, AR-PSA-, and AR-PSA+ subtypes of PCa cells that manifest differential sensitivities to therapeutics. We further demonstrate that castration leads to a great enrichment of PSA-/lo PCa cells in both xenograft tumors and CRPC samples and systemic androgen levels dynamically regulate the relative abundance of PSA+ versus PSA-/lo PCa cells that impacts the kinetics of tumor growth. We also present evidence that the PSA-/lo PCa cells possess distinct epigenetic profiles. As the PSA-/lo PCa cell population is heterogeneous, in the second part, we employ two PSA- (Du145 and PC3) and two PSA+ (LAPC9 and LAPC4) PCa models as well as patient tumor cells to further dissect the clonogenic and tumorigenic subsets. We report that different PCa models possess distinct tumorigenic subpopulations that both commonly and uniquely express important signaling pathways that could represent therapeutic targets. Our results have important implications in understanding PCa cell heterogeneity, response to clinical therapeutics, and cellular mechanisms underlying CRPC.
Highlights
Cellular heterogeneity represents an omnipresent feature in human tumors, which contain cells with diverse morphology, cytogenetic markers, growth kinetics, immunological characteristics, metastatic ability, and sensitivity to therapeutics [1]
We further demonstrate that castration leads to a great enrichment of PSA−/lo prostate cancer (PCa) cells in both xenograft tumors and castration-resistant PCa (CRPC) samples and systemic androgen levels dynamically regulate the relative abundance of PSA+ versus PSA−/lo PCa cells that impacts the kinetics of tumor growth
We have demonstrated that PCa cell Side Population (SP) and holoclones, as well as CD44+ and CD44+α2β1+ subpopulations in some PCa models are enriched in prostate cancer stem cells (CSCs) (PCSCs) with high tumorigenic and metastatic potential [6,7,8,9,10,11,12]
Summary
Cellular heterogeneity represents an omnipresent feature in human tumors, which contain cells with diverse morphology, cytogenetic markers, growth kinetics, immunological characteristics, metastatic ability, and sensitivity to therapeutics [1]. Driven by genetic instability of tumor cells, and phenotypic maturation and diversification, driven by cancer stem cells (CSCs), operate hand-in-hand to generate tumor cell www.impactjournals.com/oncotarget heterogeneity [2]. One of the key biological properties of CSCs is the ‘stemness’, which confers on a subpopulation of cancer cells two fundamental traits of normal stem cells, i.e., self-renewal and differentiation ability. Like normal stem cells, whose self-renewal and multi-lineage differentiation (i.e., pluripotency) are regulated by an intricate network of transcription factors, CSC stemness is bestowed by critical signaling pathways (e.g., Notch, HH, and Wnt) and transcription factors and epigenetic regulators such as Nanog, Bmi-1, and Polycomb proteins [3,4,5]. It has become clear that intra-clonally, genetic mutations, epigenetic changes and tumor microenvironment converge on regulating the CSC stemness to generate the phenotypic diversity and functional heterogeneity of tumor cells [2]
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