The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells
The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells
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DOI：
10.1073/pnas.0400699101
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发表时间：
2004-03-23
影响因子：
11.1
通讯作者：
Alexander, CM
中科院分区：
文献类型：
--
作者：
Liu, BY;McDermott, SP;Alexander, CM
Writ 信号通路的异位激活对许多人体组织具有高度致癌性。在这里，我们发现异位令状信号传导增加了小鼠体内乳腺的有效干细胞活性。此外，Writ 效应器在体内和体外诱导小鼠乳腺上皮祖细胞的积累（通过 Hoechst 染料排斥、替代干细胞标记、侧群细胞进行测定）。干细胞的长寿使其成为良好的候选肿瘤前体细胞，我们认为 Wnt 诱导的祖细胞扩增可能是肿瘤发生的关键。为了支持这一观点，抗肿瘤小鼠品系（携带 syndecan-1 无效突变）的乳腺含有较少的侧群细胞。当该品系与过度表达β-连环蛋白/T细胞因子Writ通路效应子的小鼠杂交时，祖细胞的扩增以及肿瘤发展的所有后续事件都会减少。我们认为干细胞部分的生长动态是肿瘤易感性的主要决定因素。
Ectopic activation of the Writ signaling pathway is highly oncogenic for many human tissues. Here, we show that ectopic Writ signaling increases the effective stem cell activity in mouse mammary glands in vivo. Furthermore, Writ effectors induce the accumulation of mouse mammary epithelial progenitors (assayed by Hoechst dye exclusion, a surrogate stem cell marker, side population cells) both in vivo and in vitro. The longevity of stem cells makes them good candidate tumor precursors, and we propose that Wnt-induced progenitor amplification is likely to be key to tumor initiation. In support of this notion, mammary glands from a tumor-resistant strain of mice (carrying a null mutation in syndecan-1) contain fewer side population cells. When this strain is crossed to mice that overexpress effectors of the beta-catenin/T cell factor Writ pathway, the amplification of progenitors is reduced, together with all subsequent events of tumor development. We propose that the growth dynamic of the stem cell fraction is a major determinant of tumor susceptibility.