In:
The Journal of Pathology, Wiley, Vol. 243, No. 1 ( 2017-09), p. 51-64
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 med according to their FACS profile (Lin − /Sca‐1 + /CD49f med ). Here, we investigated the prevalence and castration resistance of LSC med in various mouse models of prostate tumourigenesis (Pb‐PRL, Pten pc−/− , and Hi‐Myc mice). LSC med 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 pc−/− prostates. LSC med tolerate androgen deprivation and persist or are enriched 2–3 weeks after castration. The tumour‐initiating properties of LSC med from Pten pc−/− mice were demonstrated by regeneration of tumours in vivo . Transcriptomic analysis revealed that LSC med 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 med tolerate androgen deprivation. This also illuminates why Pten pc−/− tumours are castration‐resistant since LSC med represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSC med on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSC med in various mouse prostate specimens. In castrated Pten pc−/− 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 med 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.
Type of Medium:
Online Resource
ISSN:
0022-3417
,
1096-9896
DOI:
10.1002/path.2017.243.issue-1
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
1475280-3
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