马克 普朗克心肺研究院 肿瘤细胞通过死亡受体6诱导内皮细胞坏死促进转移

Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis

 

 

摘要

转移是人类癌症相关死亡的主要原因。

这是一个复杂的多步骤过程,在此过程中,单个肿瘤细胞主要通过循环系统扩散到远处的器官。

 

一旦进入血液循环,肿瘤细胞仍然脆弱,它们的转移潜力很大程度上取决于通过内皮屏障快速有效地逃离血流。有证据表明,肿瘤细胞外溢类似于白细胞转内皮细胞迁移。

 

然而,目前尚不清楚肿瘤细胞在外溢过程中如何与内皮细胞相互作用,以及这些过程在分子水平上是如何调控的。

 

在这里我们展示了人类和小鼠肿瘤细胞诱导内皮细胞程序性坏死(坏死),促进肿瘤细胞渗出和转移。

 

使用受体相互作用的丝氨酸/苏氨酸蛋白激酶1 (RIPK1)-抑制剂死亡抑制素1或内皮细胞特异性敲除RIPK3可减少肿瘤细胞诱导的内皮坏死、肿瘤细胞外溢和转移。

 

相比之下,caspase抑制或内皮细胞特异性丢失caspase-8促进了这些过程。此外,我们在体外和体内研究表明,肿瘤细胞诱导的内皮坏死导致的渗出和转移需要由肿瘤细胞及其受体,即死亡受体6 (DR6)在内皮细胞上表达的淀粉样前体蛋白作为这些作用的主要介质。

 

我们的数据确定了肿瘤细胞渗出和转移的新机制,并提示内皮DR6介导的坏死信号通路作为抗转移治疗的靶点。

 

Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis

Boris Strilic, Lida Yang, Julián Albarrán-Juárez, Laurens Wachsmuth, Kang Han, Ulrike C. Müller, Manolis Pasparakis & Stefan Offermanns

Nature volume 536, pages 215–218 (11 August 2016) | Download Citation

 

Abstract

Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs1,2,3. Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier4,5,6,7,8,9. Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration7,8,9. However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell-induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies.

Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis | Nature  https://www.nature.com/articles/nature19076

http://nutriforce.cn/index.htm