Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre‐metastatic niche through activating β‐adrenergic signaling

Abstract

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 -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 -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 -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.

Tumor Neurobiology and the War of Nerves in Cancer

“…Epidemiologic studies have long reported that psychological and social conditions, such as low social support, can affect the progression of some cancers (65), including the development of metastasis (66). There is also some evidence that molecular profiles of tumors may be affected by psychosocial conditions (67,68), and the emerging fields of psycho-oncology and social genomics have been nicely reviewed (69).…”

“…Various studies have shown that nerve density is increased in primary human tumors and that there is an association with metastatic or aggressive disease (66). Therefore, the value of quantifying nerve infiltration by pathologic examination of clinical specimens to predict patient outcome or treatment response should now be investigated in large retrospective and prospective cohorts of patients with cancer.…”

β2AR-HIF-1α-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells

“…Isoproterenol of sympathetic nerve activation factor has no direct effect on migration and invasion of prostate cancer cells Psychological distress was highest in men with biochemical recurrence and elevated clinical symptoms [21]. As chronic stress has been linked to cancer progression [7][8][9], whether increasing stress hormone in sympathetic outflow, typically caused by chronic stress, could directly alter migration and invasion of prostate cancer cells is of particular interest. Therefore, we first determined whether 10 μM isoproterenol(ISO), a non-selective bAR agonist as a pharmacological surrogate of sympathetic nerve activation [8], increased migration and invasion of human prostate cancer cells.…”

“…Accumulating evidence showed that persistent secretion of stress-related hormones and neurotransmitters plays pivotal roles in the initiation and promotion of tumors [7]. Isoproterenol (ISO), a non-selective b-adrenergic receptor (bAR) agonist as a pharmacological surrogate of sympathetic nerve activation, promoted invasion and metastasis of tumors both in vitro and in vivo [8][9][10]. Current studies demonstrated that central and sympathetic nervous systems activated by chronic stress contributed to the tumor metastasis through b2-adrenergic receptor (b2AR) [11].…”

Effects of propranolol and paclitaxel on angiogenesis in breast cancer cell lines

“…Yapılan yeni çalışmalar göstermiştir ki kronik stres ve artmış beta-adrenerjik sinyaller akciğerlerde bir "metastatik" niş oluşturmakta, böylece akciğer kanser hücrelerinin kolonizasyonuna yol açmaktadır. Bu niş oluşumu propranolol tarafından inhibe edilmiştir 23 . Nagaraja ve meslektaşları diğer yakın zamanlı çalışmalarında beta adrenerjik reseptör sinyali ile tümör stroması arasındaki ilişkiyi araştırmıştır 24 .…”