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

ABSTRACT: The existence of slow-cycling luminal cells in the prostate has been suggested, but their identity and functional properties remain unknown. Using a bigenic mouse model to earmark, isolate, and characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC) population in the luminal cell layer as luminal progenitors. Molecular and biological characterizations show that these luminal LRCs are significantly enriched in the mouse proximal prostate, exhibit relative dormancy, display bipotency in both in vitro and in vivo assays, and express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these LRCs, compared with bulk luminal cells, maintain a lower level of androgen receptor (AR) expression and are less androgen dependent and also castration resistant in vivo. Finally, analysis of phenotypic markers reveals heterogeneity within the luminal progenitor cell pool. Our study establishes luminal LRCs as progenitors that may serve as a cellular origin for castration-resistant prostate cancer.

SUBMITTER: Zhang D

PROVIDER: S-EPMC5768933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:Identification of defined cell populations with stem/progenitor properties is key for our understanding of prostate development and tumorigenesis. Prior studies have provided strong evidence of the existence of prostate luminal progenitors, but their identity and functional properties remains unknown. Using an unbiased novel bigenic mouse model to specifically earmark, prospectively isolate, and functionally characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC) population in the mouse prostate luminal cell layer as candidate luminal progenitors. Through comprehensive molecular and biological characterizations, we show that these luminal LRCs exhibit relative dormancy with significant enrichment in the mouse proximal prostate, display bipotent potential in both in vitro organoid formation and the in vivo prostate regeneration assay, express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these luminal LRCs maintain a lower level of Ar expression, are androgen-independent, and resist castration in vivo. Furthermore, analysis of phenotypic markers by immunefluorescent staining reveals heterogeneity within luminal progenitor cell pool. Collectively, our studies establish luminal LRCs as progenitors that may serve as a cellular origin for castration resistant prostate cancer.

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Label-retaining cells in the adult murine salivary glands possess characteristics of adult progenitor cells.

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Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics.

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Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells.

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