生物
细胞生物学
发芽
斑马鱼
癌症研究
血管生成
索克斯10
转移
病理
乳腺癌
休眠
利基
免疫学
癌症
神经嵴
医学
胚胎
基因
发芽
植物
生物化学
遗传学
生态学
作者
Cyrus M. Ghajar,Héctor Peinado,Hidetoshi Mori,Irina Matei,Kimberley Evason,Hélène Brazier,Dena Almeida,Antonius Koller,Katherine A. Hajjar,Didier Y. R. Stainier,Emily I. Chen,David Lyden,Mina J. Bissell
摘要
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.
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