The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells.
The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells.
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DOI：
10.1158/0008-5472.can-08-3084
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Isaacs JT
中科院分区：
文献类型：
--
作者：
Vander Griend DJ;Karthaus WL;Dalrymple S;Meeker A;DeMarzo AM;Isaacs JT
解决前列腺癌起源的特定细胞对于确定治疗干预的合理靶点至关重要，并且需要分离和表征正常人前列腺干细胞和前列腺癌起始细胞（CIC）。评价了来自新鲜正常人前列腺组织的单个上皮细胞和来自它们的前列腺上皮细胞（PrEC）培养物中表达干细胞标志物并表现出干细胞样生长特征的亚群的存在。当在体内接种含有表达干细胞标志物CD 133+的细胞的上皮细胞悬浮液时，复层的人前列腺腺的再生需要诱导的前列腺基质细胞。PrEC培养物含有一小部分CD 133+细胞亚群，荧光激活细胞分选纯化的CD 133 + PrEC可自我更新并再生表达转运扩增细胞（ΔNp63）、中间细胞（前列腺干细胞抗原）和神经内分泌细胞（CD 56）标志物的细胞群。使用一系列CD133单克隆抗体，CD133+ PrEC的附着和生长需要全长糖基化CD133蛋白的表面表达。在一系列雄激素受体阳性（AR+）人前列腺癌细胞系中，CD 133+细胞以低频率存在，自我更新，表达AR，产生CD 133阴性的表型异质子代，并具有无限增殖能力，与CD 133+细胞是CIC一致。与正常成人前列腺干细胞不同，前列腺CIC是AR+，不需要功能性CD 133。这表明（a）表达AR的前列腺CIC来源于获得“干细胞样活性”的恶性转化的中间细胞，而不是来源于恶性转化的正常干细胞，和（B）AR信号传导途径是前列腺CIC的治疗靶点。
Resolving the specific cell of origin for prostate cancer is critical to define rational targets for therapeutic intervention and requires the isolation and characterization of both normal human prostate stem cells and prostate cancer-initiating cells (CIC). Single epithelial cells from fresh normal human prostate tissue and prostate epithelial cell (PrEC) cultures derived from them were evaluated for the presence of subpopulations expressing stem cell markers and exhibiting stem-like growth characteristics. When epithelial cell suspensions containing cells expressing the stem cell marker CD133+ are inoculated in vivo, regeneration of stratified human prostate glands requires inductive prostate stromal cells. PrEC cultures contain a small subpopulation of CD133+ cells, and fluorescence-activated cell sorting–purified CD133+ PrECs self-renewand regenerate cell populations expressing markers of transit-amplifying cells (ΔNp63), intermediate cells (prostate stem cell antigen), and neuroendocrine cells (CD56). Using a series of CD133 monoclonal antibodies, attachment and growth of CD133+ PrECs requires surface expression of full-length glycosylated CD133 protein. Within a series of androgen receptor–positive (AR+) human prostate cancer cell lines, CD133+ cells are present at a low frequency, self-renew, express AR, generate phenotypically heterogeneous progeny negative for CD133, and possess an unlimited proliferative capacity, consistent with CD133+ cells being CICs. Unlike normal adult prostate stem cells, prostate CICs are AR+ and do not require functional CD133. This suggests that (a) AR-expressing prostate CICs are derived from a malignantly transformed intermediate cell that acquires “stem-like activity” and not from a malignantly transformed normal stem cell and (b) AR signaling pathways are a therapeutic target for prostate CICs.