期刊
CANCER CELL
卷 31, 期 3, 页码 355-367出版社
CELL PRESS
DOI: 10.1016/j.ccell.2017.01.007
关键词
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资金
- Deutsche Krebshilfe
- Cooperation Program in Cancer Research of the German Cancer Research Center
- Israel's Ministry of Science, Technology and Space
- Deutsche Forschungsgemeinschaft [SFB-TR23, FOR 2033]
- Dietmar Hopp Foundation
- Helmholtz Society
- German Research Council (DFG) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]
- German Federal Ministry of Education and Research [01KH0404, 01ER0814]
Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis. Thus, sustained vascular Notch signaling facilitates metastasis by generating a senescent, pro-inflammatory endothelium. Consequently, treatment with Notch1 or VCAM1-blocking antibodies prevented Notch-driven metastasis, and genetic ablation of EC Notch signaling inhibited peritoneal neutrophil infiltration in an ovarian carcinoma mouse model.
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