| Summary: | Prostate cancer (PCa) is heterogeneous containing phenotypically diverse cells. It is unclear whether these phenotypically different PCa cells are functionally distinct and possess divergent tumorigenic potential. Androgen signaling plays important roles in differentiation and survival of malignant PCa cells, and prostate specific antigen (PSA) as one of the androgen signaling target genes is used as a biomarker of AR signaling to assess tumor progression and evaluate therapeutic efficiency in clinic. Here we present evidence for discordant AR and PSA expression resulting in AR⁺/PSA⁺, AR⁺/PSA⁻, AR⁻/PSA⁻, and AR⁻/PSA⁺ PCa cells in human tumors. We also show that prostate tumor PSA mRNA levels inversely correlate with poor clinical outcomes and patient survival. By employing a lentiviral reporter system, we have fractionated bulk PCa cells into PSA⁺ and PSA⁻[superscript '/lo'] cell populations, with the former being AR⁺/PSA⁺ and the latter containing both AR⁺/PSA⁻ and AR⁻/PSA⁻ cells. The PSA⁺ and PSA⁻[superscript '/lo'] PCa cells demonstrate distinct molecular, cellular, and tumor-propagating properties. PSA⁻[superscript '/lo'] PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division to generate PSA⁺ cells. Of great clinical interest, PSA⁻[superscript '/lo'] PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and they harbor highly tumorigenic castration resistant PCa cells. In contrast, PSA⁺ PCa cells possess more limited tumor-propagating capacity, undergo symmetric division, and are sensitive to castration. Systemic androgen levels dynamically regulate the relative abundance of PSA⁺/PSA⁻[superscript '/lo'] PCa cells in the tumors, which in turn impact the kinetics of tumor growth. Further studies reveal that the PSA⁻[superscript '/lo'] PCa cell population harbors several overlapping but nonidentical tumorigenic subsets including ALDH⁺, CD44⁺, and [alpha]2[beta]1⁺ cells and ALDH⁺CD44⁺[alpha]2[beta]1⁺ can further enrich castration resistant PCa cells. These observations together suggest that heterogeneous PCa cells are organized as a tumorigenic hierarchy. Our results have important implications in understanding how different subpopulations of PCa cells manifest differential responses to current androgen deprivation therapy (ADT). === text
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