Endothelial Notch1 Activity Facilitates Metastasis
Endothelial Notch1 Activity Facilitates Metastasis
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DOI：
10.1016/j.ccell.2017.01.007
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发表时间：
2017-03-13
期刊：
影响因子：
50.3
通讯作者：
Fischer, Andreas
中科院分区：
文献类型：
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作者：
Wieland, Elfriede;Rodriguez-Vita, Juan;Fischer, Andreas
内皮细胞（EC）提供血管分泌因子协调肿瘤进展。在这里，我们发现，激活的Notch1受体（N1ICD）经常观察到人类癌和黑色素瘤的EC，并在小鼠转移前的小生境的EC。黑色素瘤中EC N1ICD表达与较短的无进展生存期相关持续的N1ICD活性诱导EC衰老，表达趋化因子和粘附分子VCAM 1。这促进了中性粒细胞浸润、肿瘤细胞（TC）粘附于内皮、内渗、肺定植和术后转移。因此，持续的血管Notch信号传导通过产生衰老的促炎内皮来促进转移。因此，用Notch 1或VCAM 1阻断抗体治疗可预防Notch驱动的转移，并且EC Notch信号传导的基因消融可抑制卵巢癌小鼠模型中的腹膜中性粒细胞浸润。
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.