Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre-metastatic niche through activating β-adrenergic signaling
Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre-metastatic niche through activating β-adrenergic signaling
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慢性心理压力通过激活 β 肾上腺素能信号传导装饰转移前生态位，促进循环乳腺癌细胞的肺转移定植
DOI：
10.1002/path.4988
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发表时间：
2018-01-01
影响因子：
7.3
通讯作者：
Shi, Ming
中科院分区：
文献类型：
--
作者：
Chen, Hongyu;Liu, Dan;Shi, Ming
大量研究表明，原发肿瘤通过分泌肿瘤衍生因子，在远处器官形成转移前的生态位。本研究表明，慢性应激预暴露可提高循环中肿瘤细胞对肺的定植效率，提示慢性应激在播散性肿瘤细胞到来之前对转移前肺有重要影响。6-OHDA消融交感神经功能或心得安阻断β-肾上腺素能信号可显著抑制应激诱导的肺转移。循环单核细胞或肺巨噬细胞的耗竭强烈地消除了肿瘤细胞应激诱导的肺种植，而在转移前阶段用β-肾上腺素能激动剂异丙肾上腺素(ISO)处理小鼠，促进了巨噬细胞向肺的渗透。同时，在ISO刺激下，外周血、脾和骨髓中的单核细胞数显著增加。这些数据表明，β-肾上腺素能信号通过增加转移前阶段单核细胞的产量和巨噬细胞向转移前肺的渗透来促进肿瘤细胞对肺转移的定植。机制研究表明，ISO刺激上调肺间质细胞CCL2和单核/巨噬细胞CCR2的表达，导致巨噬细胞向转移前肺组织募集和渗透。通过诱导CCL2/CCR2轴驱动的单核/巨噬细胞的反应，应激儿茶酚胺可能是调节肿瘤细胞转移前生态位和肺定植的关键因素。我们的数据表明，宿主宏观环境动态平衡的紊乱对未来的转移器官有影响。版权所有(C)2017年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Numerous studies have indicated that primary tumors induce the formation of a pre-metastatic niche in distant organs by secreting tumor-derived factors. The present study shows that pre-exposure to chronic stress enhanced lung colonization efficiency by circulating tumor cells, suggesting that chronic stress critically influences pre-metastatic lungs before the arrival of disseminated tumor cells. Ablation of the sympathetic nerve function by 6-OHDA or blockage of the beta-adrenergic signaling by propranolol remarkably suppressed stress-induced lung metastasis. Depletion of circulating monocytes or lung macrophages strongly abolished stress-induced lung seeding by tumor cells, whereas treatment of mice with the beta-adrenergic agonist isoproterenol (ISO) during the pre-metastatic phase promoted the infiltration of macrophages to the lung. Meanwhile, the numbers of monocytes in peripheral blood, spleen, and bone marrow were remarkably increased in response to ISO stimulation. These data indicate that the beta-adrenergic signaling promotes lung metastatic colonization by tumor cells through increased output of monocytes in the pre-metastatic phase and infiltration of macrophages into the pre-metastatic lung. Mechanistic studies revealed that ISO stimulation upregulated the expression of CCL2 in pulmonary stromal cells and CCR2 in monocytes/macrophages, leading to the recruitment and infiltration of macrophages into the pre-metastatic lung. By inducing a response of monocytes/macrophages driven by the CCL2/CCR2 axis, stress-related catecholamine may act as a crucial factor in regulating the pre-metastatic niche for and lung colonization by tumor cells. Our data demonstrate that disturbance of host macro-environmental homeostasis has an influence on future metastatic organs. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.