The PSA−/lo Prostate Cancer Cell Population Harbors Self-Renewing Long-Term Tumor-Propagating Cells that Resist Castration

Abstract

SUMMARY Prostate cancer (PCa) is heterogeneous and contains both differentiated and undifferentiated tumor cells, but the relative functional contribution of these two cell populations remains unclear. Here we report distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (PSA+) and low (PSA−/lo) levels of the differentiation marker PSA. PSA−/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 generating PSA+ cells. Importantly, PSA−/lo PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, undergo symmetric division and are sensitive to castration. Together, our study suggests PSA−/lo cells may represent a critical source of castration-resistant PCa cells.

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

“…5). Similar results are reported by Tang and coworkers 48 , showing that PSA þ prostate cancer cells (luminal-like cells) undergo exclusive and more rapid, symmetrical cell divisions to generate more PSA þ cells, whereas a faction of PSA À /lo cells (ALDH þ CD44 þ a2b1 þ phenotype, basal-like cells) undergo asymmetric cell divisions. These findings together are essentially in agreement with a recent lineagetracing study proposing that basal cells need to differentiate into transformation-competent luminal cells and then initiate prostate cancer 7 .…”

New insights into prostate cancer stem cells

“…In support of this conjecture, we could further fractionate a subpopulation of ALDH + CD44 + α2β1 + cells from the PSA −/lo cell population, and show that these cells could regenerate serially transplantable tumors in fully castrated mice. 8 Another recent study found a small subset of CK18 − /CK19 − cells in docetaxel-resistant cell lines (Du145-DR and 22Rv1-DR) and primary as well as metastatic PCa patient samples that express low levels of differentiation marker (HLA). 11 Using a lentiviral reporter system, this group has shown that CK18 − /CK19 − cells in both Du145-DR and 22Rv1-DR models can survive docetaxel exposure and acquire chemoresistance via upregulation of Notch and Hedgehog signaling, whereas targeting these two pathways can abolish the chemoresistance both in vitro and in vivo.…”

“…On the other hand, advanced PCa mainly consist of poorly differentiated or undifferentiated areas, but differentiated regions can also be seen. [8][9][10] The heterogeneous expression patterns of PSA and AR in PCa cells imply the existence of distinct cell subpopulations, i. Tumor cell heterogeneity can be explained by two models: the clonal evolution (stochastic) model and the cancer stem cell (hierarchical) model. The two models may not necessarily be mutually exclusive.…”

Targeted therapy against cancer stem cells

“…In PCa, the prostate-specific antigen (PSA)-negative or low-expressing (PSA -/lo ) cell population harbors self-renewing cells that fulfill all criteria defining prostate CSCs (PCSCs) (32). PSA + cells in untreated PCa are highly proliferative, contributing to tumor mass, whereas PSA -/lo PCa cells are notably tumorigenic and metastatic (32).…”

“…PSA + cells in untreated PCa are highly proliferative, contributing to tumor mass, whereas PSA -/lo PCa cells are notably tumorigenic and metastatic (32). Significantly, PSA + cancer cells are plastic since constitutive overexpression of Nanog or persistent castration in vitro and in vivo induces their de-differentiation into PSA -/lo cells (32,33). Taken together, these data suggest that various subsets of PCSCs as well as cells-of-origin of PCa may all be encompassed in the PSA -/lo pool.…”