A rare castration‐resistant progenitor cell population is highly enriched in Pten‐null prostate tumours

Abstract

Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSC according to their FACS profile (Lin /Sca-1 /CD49f ). Here, we investigated the prevalence and castration resistance of LSC in various mouse models of prostate tumourigenesis (Pb-PRL, Pten , and Hi-Myc mice). LSC prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Pten prostates. LSC tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSC from Pten mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSC represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSC tolerate androgen deprivation. This also illuminates why Pten tumours are castration-resistant since LSC represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSC on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSC in various mouse prostate specimens. In castrated Pten prostates, there was significant proliferation of CK4 cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSC as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration

“…Third, stem-like luminal cells may function as tumor-propagating cells ( Stoyanova et al., 2013 ), in line with mouse genetic studies ( Abou-Kheir et al., 2010 , Korsten et al., 2009 ) and with previous report showing that aggressive breast basal-like cancers actually originate from luminal progenitors rather than from basal SCs ( Molyneux et al., 2010 ). Fourth, while this manuscript was under revision, a study identified a rare castration-resistant luminal progenitor cell population with a Lin − /SCA-1 + /CD49f med phenotype highly enriched in Pten -null prostate tumors ( Sackmann Sala et al., 2017 ). Finally, the luminal progenitor gene expression profile can be linked to advanced and aggressive PCa subtypes ( Liu et al., 2016 , Sackmann Sala et al., 2017 , Zhang et al., 2017 ; this study).…”

“…Fourth, while this manuscript was under revision, a study identified a rare castration-resistant luminal progenitor cell population with a Lin − /SCA-1 + /CD49f med phenotype highly enriched in Pten -null prostate tumors ( Sackmann Sala et al., 2017 ). Finally, the luminal progenitor gene expression profile can be linked to advanced and aggressive PCa subtypes ( Liu et al., 2016 , Sackmann Sala et al., 2017 , Zhang et al., 2017 ; this study). This notion is further strengthened by the molecular resemblance of our luminal LRCs to recently reported human CD38 low prostatic luminal progenitors ( Liu et al., 2016 ), which has been shown to be associated with inflammation and PCa progression with poor outcome.…”

Current methods in translational cancer research

“…Silencing RNF2 suppressed metastasis. The Pten PC −/− mice develop prostate cancer but have little to no metastasis, whereas the genetically modified Pten PC −/−Smad4 PC −/− develops metastatic prostate cancer [117,118]. This provides a model for studying how PRC1/RNF2 alters prostate cancer cells to influence metastasis.…”

STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice

“…Second, these prostates showed amplification of another primitive cell population that had never been described before as it is very rare in the healthy prostate. This newly-identified epithelial cell pool, called LSC med according to its cell sorting profile (Lin−/Sca-1+/CD49f med ), combines luminal (Cytokeratin [CK] 8 positive) and stem (Stem-cell antigen-1 positive) phenotypic features and exhibits stem/progenitor properties in functional assays [31,32]. Notably, while the basal/stem cell compartment has been long described to be castrate-resistant in rats [33], we recently reported that the LSC med cell compartment survived castration even better than basal/stem cells in mice [32].…”

“…Of interest, careful analysis of immunostaining data suggested that the emergence of these two primitive cell populations in Pb-PRL tumors may be zonally correlated to elevated STAT5 activation [31]. However, as neither basal/stem nor LSC med cell population exhibit detectable levels of PRLR expression [32], the role of STAT5 signaling in their amplification remains elusive and may involve paracrine mechanisms. In order to elucidate the actual contribution of STAT5 signaling in the various hallmarks of PRL-induced prostate tumorigenesis, we took advantage of previously developed floxed Stat5a/b mice [34] to abolish STAT5 expression in the epithelial cells of Pb-PRL mice.…”