YCR Cancer Research Unit, Department of Biology (Area 13), University of York, Heslington, York YO10 5DD, UK.
Horm Cancer. 2011 Feb;2(1):47-61. doi: 10.1007/s12672-010-0058-y.
The prostate is a luminal secretory tissue whose function is regulated by male sex hormones. Castration produces involution of the prostate to a reversible basal state, and as the majority of prostate cancers also have a luminal phenotype, drug-induced castration is a front line therapy. It has therefore been assumed that the tumor arises from transformation of a luminal progenitor cell. Here, we demonstrate that a minority basal "cancer stem cell" (CSC) population persists in primary human prostate cancers, as in normal prostate, serving as a reservoir for tumor recurrence after castration therapy. While the CSCs exhibit a degree of phenotypic fluidity from different patients, the tumor-initiating cells in immunocompromised mice express basal markers (such as p63), but do not express androgen receptor (AR) or markers of luminal differentiation (PSA, PAP) when freshly fractionated from human tissues or following culture in vitro. Estrogen receptors α and β and AR are transcriptionally active in the transit amplifying (TA) cell (the progeny of SC). However, AR protein is consistently undetectable in TA cells. The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator. Selected cells with basal phenotypes are tumor initiating, but the resultant tumors are phenotypically intermediate, with focal expression of AR, AMACR, and p63. In vitro differentiation experiments, employing lentivirally transduced SCs with a luminal (PSA-probasin) promoter regulating a fluorescent indicator gene, confirm that the basal SCs are the source of luminal progeny.
前列腺是一种腔分泌组织，其功能受雄性激素调节。去势会导致前列腺退化到可逆转的基础状态，而由于大多数前列腺癌也具有腔表型，因此药物去势是一线治疗方法。因此，人们一直认为肿瘤起源于腔前体细胞的转化。在这里，我们证明在原发性人前列腺癌中，少数基底“癌症干细胞”（CSC）群体仍然存在，就像在正常前列腺中一样，作为去势治疗后肿瘤复发的储备库。虽然 CSC 从不同患者中表现出一定程度的表型灵活性，但在免疫缺陷小鼠中具有肿瘤起始能力的细胞表达基底标志物（如 p63），但当从人组织中新鲜分离或在体外培养时，不表达雄激素受体（AR）或腔分化标志物（PSA、PAP）。雌激素受体α和β和 AR 在过渡扩增（TA）细胞（SC 的后代）中转录活跃。然而，AR 蛋白在 TA 细胞中始终无法检测到。前列腺特异性 TMPRSS2 基因虽然在腔细胞中受 AR 活性上调，但也在基底群体中转录，这证实了 AR 作为表达调节剂的作用。具有基底表型的选定细胞具有肿瘤起始能力，但产生的肿瘤表型为中间型，具有 AR、AMACR 和 p63 的局灶性表达。体外分化实验，使用带有腔（PSA-前原）启动子的慢病毒转导 SC，并调节荧光报告基因，证实了基底 SC 是腔前体后代的来源。
