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.

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，引起原发性癌性病变导致四氯化碳簇脱落的生物学现象知之甚少。在这里，当动态标记沿着癌症进展的乳腺癌细胞时，我们观察到大多数CTC簇都处于缺氧状态，而单个CTC大部分是常氧血症。令人惊讶的是，我们发现靶向血管内皮生长因子（VEGF）导致原发性肿瘤缩小，但它增加了肿瘤内的缺氧，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性肿瘤的大小，但会显着抑制CTC簇的形成和转移。从而，