Abstract
Undifferentiated, low-PSA prostate cancer cells are the cell-of-origin of CRPC.
Major finding: Undifferentiated, low-PSA prostate cancer cells are the cell-of-origin of CRPC.
Clinical relevance: Low tumor PSA levels are associated with lower recurrence-free and overall survival.
Impact: Androgen deprivation therapy may not affect a significant population of tumor-initiating cells.
Blocking androgen production or androgen receptor (AR) signaling with androgen-deprivation therapy is the main treatment for advanced and recurrent prostate cancer, but castration-resistant prostate cancer (CRPC) ultimately develops. Noting that prostate cancers heterogeneously express prostate-specific antigen (PSA), the AR-regulated target commonly used as a biomarker of response to androgen-deprivation therapy and prostate cancer progression, Qin and colleagues evaluated the role of undifferentiated cells expressing little or no PSA (PSA-/lo) in CPRC. In contrast to serum PSA levels, which tend to be elevated in advanced prostate cancer, advanced and recurrent human prostate tumors had lower PSA mRNA levels and a higher proportion of PSA-/lo cells. Low tumor PSA levels also correlated with reduced biochemical recurrence-free and overall survival. Using a PSA-promoter driven lentiviral GFP-reporter system, the authors separated PSA+ and PSA-/lo prostate cancer cells and showed that PSA-/lo, but not PSA+, cells were resistant to androgen deprivation in vitro and expressed high levels of antistress and survival genes. PSA-/lo cells also expressed stem cell genes, were quiescent, and were capable of undergoing asymmetric cell division to regenerate PSA+ cells, suggesting that PSA-/lo cells might represent a CRPC stem cell population. Indeed, serial transplantation assays revealed that PSA-/lo prostate cancer cells were consistently tumorigenic in hormonally intact mice, whereas the tumor-propagating capacity of PSA+ cells decreased. Furthermore, PSA-/lo prostate cancer cells grew larger tumors more quickly than PSA+ cells in surgically and chemically castrated mice, and a purified PSA-/lo population overexpressing aldehyde dehydrogenase 1, integrin α2, and CD44 could regenerate tumors with as few as 10 cells. Together, these findings indicate that targeting the castration-resistant PSA-/lo cancer stem cell population in conjunction with androgen-deprivation therapy may improve clinical outcome.
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