Liu Bob Y, McDermott Sean P, Khwaja Shariq S, Alexander Caroline M
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, WI 53706-1599, USA.
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4158-63. doi: 10.1073/pnas.0400699101. Epub 2004 Mar 12.
Ectopic activation of the Wnt signaling pathway is highly oncogenic for many human tissues. Here, we show that ectopic Wnt signaling increases the effective stem cell activity in mouse mammary glands in vivo. Furthermore, Wnt 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 Wnt 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.
Wnt信号通路的异位激活对许多人体组织具有高度致癌性。在此，我们表明异位Wnt信号在体内增加了小鼠乳腺中的有效干细胞活性。此外，Wnt效应物在体内和体外均诱导小鼠乳腺上皮祖细胞（通过Hoechst染料排斥法检测，一种替代干细胞标记物，侧群细胞）的积累。干细胞的长寿使其成为良好的肿瘤前体候选者，并且我们提出Wnt诱导的祖细胞扩增可能是肿瘤起始的关键。支持这一观点的是，来自抗瘤小鼠品系（syndecan-1基因携带无效突变）的乳腺中侧群细胞较少。当该品系与过表达β-连环蛋白/T细胞因子Wnt途径效应物的小鼠杂交时，祖细胞的扩增减少，同时肿瘤发展的所有后续事件也减少。我们提出干细胞部分的生长动态是肿瘤易感性的主要决定因素。
