Journal
JOURNAL OF PATHOLOGY
Volume 244, Issue 1, Pages 49-60Publisher
WILEY
DOI: 10.1002/path.4988
Keywords
chronic stress; beta-adrenergic receptor; macrophage; pre-metastatic niche; metastatic colonization; CCL2; CCR2
Funding
- National High-Tech Research and Development Plan (863 Program) [2014AA020604]
- National Natural Science Foundation of China [31370825, 81272232, 81402562, 81572845, 81773086, 81773258, 31500702]
- Beijing Natural Science Foundation [7162144, 7132163, 7122124]
- China Postdoctoral Science Foundation [2015T81095]
- Jiangsu Natural Science Foundation [BK20171161]
- Key University Science Research Project of Jiangsu Province [17KJA320009]
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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.
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