Contrasting Hypoxic Effects on Breast Cancer Stem Cell Hierarchy Is Dependent on ER-α Status
Contrasting Hypoxic Effects on Breast Cancer Stem Cell Hierarchy Is Dependent on ER-α Status
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DOI：
10.1158/0008-5472.can-12-2505
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发表时间：
2013-02-15
期刊：
影响因子：
11.2
通讯作者：
Landberg, Goran
中科院分区：
文献类型：
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作者：
Harrison, Hannah;Rogerson, Lynsey;Landberg, Goran
肿瘤缺氧通常与乳腺癌患者的生存率降低有关，目前的治疗策略旨在靶向缺氧反应。其中一种方法是通过阻断缺氧诱导的血管生成。抗血管生成疗法显示出一定的治疗潜力，增加了无病生存期，但这些最初有希望的结果是短暂的，随后是肿瘤进展。我们假设这可能是由于肿瘤缺氧增加导致的癌症干细胞（CSC）活性改变。我们研究了缺氧对CSC活性的影响，使用体外mammosphere和holoclone测定以及体内有限稀释实验，在13个患者来源的样品和4个细胞系。ER-α阳性的癌症在低氧暴露后有HIF-1 α依赖性CSC增加，这可通过抑制雌激素和Notch信号传导来阻断。在ER-α阴性癌症中观察到CSC的对比减少。我们接下来开发了细胞系和患者来源的样品的异种移植物模型以评估缺氧CSC反应。收集不同大小的异种移植物并分析HIF 1-α表达和CSC。观察到相同的ER-α依赖性对比缺氧CSC反应，验证了初始观察结果。这些数据表明，ER-α阳性和阴性乳腺癌亚型对缺氧的反应不同，因此，抗血管生成治疗不适合这两个亚组。Cancer Res; 73（4）; 1420-33. (C)2012年AACR。
Tumor hypoxia is often linked to decreased survival in patients with breast cancer and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia-induced angiogenesis. Antiangiogenic therapies show some therapeutic potential with increased disease-free survival, but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting from increased tumor hypoxia. We studied the effects of hypoxia on CSC activity, using in vitro mammosphere and holoclone assays as well as in vivo limiting dilution experiments, in 13 patient-derived samples and four cell lines. There was a HIF-1 alpha-dependent CSC increase in ER-alpha-positive cancers following hypoxic exposure, which was blocked by inhibition of estrogen and Notch signaling. A contrasting decrease in CSC was seen in ER-alpha-negative cancers. We next developed a xenograft model of cell lines and patient-derived samples to assess the hypoxic CSC response. Varying sizes of xenografts were collected and analyzed for HIF1-alpha expression and CSC. The same ER-alpha-dependent contrasting hypoxic-CSC response was seen validating the initial observation. These data suggest that ER-alpha-positive and negative breast cancer subtypes respond differently to hypoxia and, as a consequence, antiangiogenic therapies will not be suitable for both subgroups. Cancer Res; 73(4); 1420-33. (C) 2012 AACR.