Intermittent hypoxia induces a metastatic phenotype in breast cancer
Intermittent hypoxia induces a metastatic phenotype in breast cancer
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DOI：
10.1038/s41388-018-0259-3
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发表时间：
2018-08-02
期刊：
影响因子：
8
通讯作者：
Moller, Andreas
中科院分区：
文献类型：
--
作者：
Chen, Anna;Sceneay, Jaclyn;Moller, Andreas
缺氧在实体瘤中频繁出现，并且是不良预后因素，因为它促进肿瘤细胞增殖、侵袭、血管生成、治疗抗性和转移。值得注意的是，生长中的肿瘤中存在两种描述形式的缺氧：由异常肿瘤血管系统引起的慢性缺氧和由肿瘤供应血管促进的瞬时灌注引起的间歇性缺氧。在这里，我们证明了间歇性缺氧，而不是慢性缺氧，赋予乳腺癌细胞更大的转移潜力。使用免疫活性和同基因小鼠乳腺癌模型，我们表明，间歇性缺氧增强转移种植和生长在体内肺。此外，乳腺肿瘤细胞暴露于间歇性缺氧促进克隆多样性，上调转移相关基因的表达，诱导促肿瘤发生分泌型，增加干细胞样细胞标志物的表达，并以相对较高的频率产生肿瘤起始细胞。这项工作表明，间歇性缺氧，而不是慢性缺氧，诱导了许多遗传，分子，生化和细胞的变化，促进肿瘤细胞的生存，定植，并创造一个宽容的微环境，从而提高转移性生长。
Hypoxia arises frequently in solid tumors and is a poor prognostic factor as it promotes tumor cell proliferation, invasion, angiogenesis, therapy resistance, and metastasis. Notably, there are two described forms of hypoxia present in a growing tumor: chronic hypoxia, caused by abnormal tumor vasculature, and intermittent hypoxia, caused by transient perfusion facilitated by tumor-supplying blood vessels. Here, we demonstrate that intermittent hypoxia, but not chronic hypoxia, endows breast cancer cells with greater metastatic potential. Using an immunocompetent and syngeneic murine model of breast cancer, we show that intermittent hypoxia enhances metastatic seeding and outgrowth in lungs in vivo. Furthermore, exposing mammary tumor cells to intermittent hypoxia promoted clonal diversity, upregulated metastasis-associated gene expression, induced a pro-tumorigenic secretory profile, increased stem-like cell marker expression, and gave rise to tumor-initiating cells at a relatively higher frequency. This work demonstrates that intermittent hypoxia, but not chronic hypoxia, induces a number of genetic, molecular, biochemical, and cellular changes that facilitate tumor cell survival, colonization, and the creation of a permissive microenvironment and thus enhances metastatic growth.