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.

中文翻译：

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间歇性缺氧会诱发乳腺癌的转移表型。

缺氧在实体瘤中经常发生，并且是不良的预后因素，因为它促进肿瘤细胞的增殖，侵袭，血管生成，治疗抗性和转移。值得注意的是，在生长中的肿瘤中存在两种描述的缺氧形式：由肿瘤血管异常引起的慢性缺氧，和由肿瘤供血血管促进的瞬时灌注引起的间歇性缺氧。在这里，我们证明间歇性低氧而不是慢性低氧赋予乳腺癌细胞更大的转移潜能。使用乳腺癌的免疫能力和同基因鼠模型，我们表明间歇性的缺氧会增强体内肺的转移性播种和增生。此外，将乳腺肿瘤细胞暴露于间歇性缺氧会促进克隆多样性，与转移相关的基因表达上调，诱导肿瘤发生前的分泌特征，增加干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的缺氧，而不是慢性的缺氧，会引起许多遗传，分子，生化和细胞变化，这些变化促进肿瘤细胞的存活，定植和允许的微环境的产生，从而促进转移性生长。