WNT/β-catenin mediates radiation resistance of mouse mammary progenitor cells
WNT/β-catenin mediates radiation resistance of mouse mammary progenitor cells
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DOI：
10.1073/pnas.0606599104
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发表时间：
2007-01-09
影响因子：
11.1
通讯作者：
Rosen, Jeffrey M.
中科院分区：
文献类型：
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作者：
Woodward, Wendy A.;Chen, Mercy S.;Rosen, Jeffrey M.
最近的研究已经从人乳腺癌中鉴定出具有干/祖细胞特性的高度致瘤性细胞亚群，并且已经表明乳腺癌治疗后残留的干/祖细胞可能引起疾病复发。我们假设祖细胞对辐射具有抗性，辐射是传统乳腺癌治疗的一个组成部分，并且这种抗性至少部分由Wnt信号传导介导，这与干细胞存活有关。为了验证这一假设，我们研究了放射抗性治疗的原代BALB/c小鼠乳腺上皮细胞与临床相关剂量的辐射，并发现富集在正常的祖细胞（干细胞抗原1阳性和侧群祖细胞）。辐射选择性富集乳腺上皮细胞中的祖细胞，这些细胞是从具有激活的Wnt/β-连环蛋白信号传导的转基因小鼠中分离的，而不是背景匹配的对照，并且与干细胞抗原1阴性细胞相比，辐射干细胞抗原1阳性细胞具有活性β-连环蛋白和生存素表达的选择性增加。在克隆形成测定中，干细胞抗原1阳性祖细胞中的集落形成不受临床相关剂量的辐射的影响。辐射还诱导富集侧群祖细胞在人乳腺癌细胞系MCF-7。这些数据表明，与分化的细胞相比，祖细胞具有不同的细胞存活特性，这可能有助于靶向抗祖细胞疗法的发展。
Recent studies have identified a subpopulation of highly tumorigenic cells with stem/progenitor cell properties from human breast cancers, and it has been suggested that stem/progenitor cells, which remain after breast cancer therapy, may give rise to recurrent disease. We hypothesized that progenitor cells are resistant to radiation, a component of conventional breast cancer therapy, and that that resistance is mediated at least in part by Wnt signaling, which has been implicated in stem cell survival. To test this hypothesis, we investigated radioresistance by treating primary BALB/c mouse mammary epithelial cells with clinically relevant doses of radiation and found enrichment in normal progenitor cells (stem cell antigen 1-positive and side population progenitors). Radiation selectively enriched for progenitors in mammary epithelial cells isolated from transgenic mice with activated Wnt/beta-catenin signaling but not for background-matched controls, and irradiated stem cell antigen 1-positive cells had a selective increase in active beta-catenin and survivin expression compared with stem cell antigen 1-negative cells. in clonogenic assays, colony formation in the stem cell antigen 1-positive progenitors was unaffected by clinically relevant doses of radiation. Radiation also induced enrichment of side population progenitors in the human breast cancer cell line MCF-7. These data demonstrate that, compared with differentiated cells, progenitor cells have different cell Survival properties that may facilitate the development of targeted antiprogenitor cell therapies.