Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells
Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells
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DOI：
10.1158/0008-5472.can-06-0054
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Wicha, Max S.
中科院分区：
文献类型：
--
作者：
Liu, Suling;Dontu, Gabriela;Wicha, Max S.
乳腺上皮成分被认为来自具有自我更新和多系分化能力的干细胞。此外，这些细胞和/或它们的直接后代可能是转化的目标。我们使用体外培养和异种移植小鼠模型来研究hedgehog信号和Bmi-1在调节正常和恶性人乳腺干细胞自我更新中的作用。我们发现hedgehog信号成分PTCH1、Gli1和Gli2在作为乳腺球培养的正常人乳腺干细胞/祖细胞中高度表达，并且当细胞被诱导分化时，这些基因被下调。hedgehog信号的激活会增加乳腺球起始细胞的数量和乳腺球的大小，而抑制该途径则会减少这些作用。这些影响是由多梳基因Bmi-1介导的。在人源化非肥胖糖尿病-严重联合免疫缺陷小鼠模型中，乳腺球起始细胞中Gli2的过度表达导致导管增生，而乳腺球起始细胞中Bmi-1表达的调节改变了乳腺发育。此外，我们发现hedgehog信号通路在CD44(+)CD24(-)/(low)Lin（-）的人类乳腺癌干细胞中被激活。这些研究支持了一种癌症干细胞模型，其中hedgehog通路和Bmi-1在调节正常和致瘤性人乳腺干细胞的自我更新中发挥重要作用。
The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast "cancer stem cells" characterized as CD44(+)CD24(-)/(low)Lin(-). These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating self-renewal of normal and tumorigenic human mammary stem cells.