Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Stem Cell Reports. 2018 Jan 9;10(1):228-242. doi: 10.1016/j.stemcr.2017.11.016. Epub 2017 Dec 21.
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.
前列腺中存在缓慢循环的管腔细胞这一观点已经提出，但这些细胞的身份和功能特性仍不清楚。我们利用一种双基因小鼠模型来标记、分离和鉴定静止的干细胞样细胞，将管腔细胞层中的标记保留细胞 (LRC) 群体鉴定为管腔祖细胞。分子和生物学特征表明，这些管腔 LRC 在小鼠近端前列腺中显著富集，表现出相对休眠状态，在体外和体内实验中均表现出双能性，并表达与侵袭性前列腺癌相似的干细胞/祖细胞基因特征。重要的是，与大量管腔细胞相比，这些 LRC 表达的雄激素受体 (AR) 水平较低，并且在体内对雄激素的依赖性较低，也具有抗去势作用。最后，表型标志物分析揭示了管腔祖细胞群体内的异质性。我们的研究确立了管腔 LRC 作为祖细胞，可能是去势抵抗性前列腺癌的细胞起源。
