Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells
Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells
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DOI：
10.1016/j.celrep.2020.108105
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发表时间：
2020-09-08
期刊：
影响因子：
8.8
通讯作者：
Aceto, Nicola
中科院分区：
文献类型：
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作者：
Donato, Cinzia;Kunz, Leo;Aceto, Nicola
循环肿瘤细胞（CTC）以单个或簇状细胞的形式从实体癌中脱落，后者表现出非凡的启动转移能力。然而，人们对引发原发性癌性病变中 CTC 簇脱落的生物学现象知之甚少。在这里，当沿着癌症进展动态标记乳腺癌细胞时，我们观察到大多数 CTC 簇都处于缺氧状态，而单个 CTC 大部分处于正常含氧状态。引人注目的是，我们发现血管内皮生长因子（VEGF）靶向导致原发肿瘤缩小，但它增加了肿瘤内缺氧，导致更高的 CTC 簇脱落率和转移形成。相反，促血管生成治疗会增加原发肿瘤的大小，但它会显着抑制 CTC 簇的形成和转移。因此，肿瘤内缺氧导致具有高转移能力的簇状 CTC 的形成，促血管生成疗法通过阻止 CTC 簇的生成来抑制转移形成。
Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through prevention of CTC cluster generation.