Chen Hongyu, Liu Dan, Guo Liang, Cheng Xiang, Guo Ning, Shi Ming
Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, PR China.
Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
J Pathol. 2018 Jan;244(1):49-60. doi: 10.1002/path.4988. Epub 2017 Nov 15.
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 β-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 β-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 β-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 © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
大量研究表明，原发性肿瘤通过分泌肿瘤衍生因子在远处器官诱导形成前转移微环境。本研究表明，预先暴露于慢性应激会提高循环肿瘤细胞在肺部的定植效率，这表明慢性应激在播散性肿瘤细胞到达之前对前转移肺有至关重要的影响。用6-羟基多巴胺消除交感神经功能或用普萘洛尔阻断β-肾上腺素能信号显著抑制了应激诱导的肺转移。耗尽循环单核细胞或肺巨噬细胞可强烈消除应激诱导的肿瘤细胞在肺中的播种，而在转移前期用β-肾上腺素能激动剂异丙肾上腺素（ISO）治疗小鼠可促进巨噬细胞向肺的浸润。同时，外周血、脾脏和骨髓中的单核细胞数量在ISO刺激下显著增加。这些数据表明，β-肾上腺素能信号通过在转移前期增加单核细胞输出和巨噬细胞浸润到转移前肺中，促进肿瘤细胞在肺中的转移定植。机制研究表明，ISO刺激上调了肺基质细胞中CCL2的表达和单核细胞/巨噬细胞中CCR2的表达，导致巨噬细胞募集并浸润到转移前肺中。通过诱导由CCL2/CCR2轴驱动的单核细胞/巨噬细胞反应，应激相关的儿茶酚胺可能是调节肿瘤细胞转移前微环境和肺定植的关键因素。我们的数据表明，宿主宏观环境稳态的紊乱会影响未来的转移器官。版权所有©2017英国和爱尔兰病理学会。由约翰·威利父子有限公司出版。
