Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells

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.

Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting

“…However, there are reports suggesting that a significant proportion of prostate cancer may be resistant to androgen ablation for which the exact mechanism is still under investigation 5152. It is well appreciated that AR heterogeneity becomes more pronounced in castration-resistant prostate cancers than in the primary tumors and activation of alternative AR signaling in prostate cancer cells may promote cell proliferation under androgen-deprived environment 5354…”

Defining a Population of Stem-like Human Prostate Cancer Cells That Can Generate and Propagate Castration-Resistant Prostate Cancer

“…CSCs in many human solid tumors have been implicated in tumor initiation, progression, metastasis and therapy resistance (3, 4). Like other human cancers, prostate cancer (PCa) is a heterogeneous malignancy containing phenotypically differentiated cancer cells and immature cancer cells with stem cell properties, i.e., prostate CSCs (PCSCs) (4-19). …”

“…Whether this cell population can serve as the cell-of-origin for CRPC is presently unknown. Recent evidence indicates that some PCSC populations in hormone naive PCa xenograft models and patient tumors express low levels of AR and could potentially function as the cell-of-origin of CRPC (6, 13, 16, 19), and vice versa, several cell populations, such as the CD166 + (23) and N-Cadherin + (24) cells, become enriched in CRPC models. Using a lentiviral reporter tracking system, we have recently demonstrated that long-term self-renewing and tumor-propagating PCSCs are enriched in the undifferentiated PCa cell population that lacks prostate specific antigen (PSA) expression (i.e., PSA −/lo ) (16).…”

Single nucleotide variations in cultured cancer cells: Effect of mismatch repair

“…DU145 cells showed heterogeneity in expression of cancer [8] and epigenetic [9] markers. They also exhibited chromosomal instability and karyotype heterogeneity, which were demonstrated by spectral karyotype analysis [10].…”