心理应激通过影响“预转移微环境”促进乳腺癌肺转移的机制研究

Elucidation of the determinants, which critically influence the metastatic colonization of circulating cells at distant organs, is very important for developing novel approaches to treat cancer metastasis. Our data in the recent studies showed that chronic psychological stress evidently enhanced lung colonization efficiency by circulating breast cancer cells. Ablation of sympathetic nerve function by 6-OHDA or blockage of the β-adrenergic signaling by propranolol remarkably suppressed psychological stress-induced lung metastasis. These data demonstrated that chronic psychological stress promotes lung metastatic colonization of circulating tumor cells mainly through activating adrenergic signaling. Subsequently, we found that activation of adrenergic signaling remarkably increased the number of monocytes and neutrophils in peripheral blood, and enhanced the infiltration of macrophages to the lung, before arrival of disseminated tumor cells at the lung. Importantly, depletion of circulating neutrophils or lung macrophages strongly abolished adrenergic signaling-induced lung seeding by circulating tumor cells. Our current data suggested that psychological stress induced the disturbance of neuroendocrine-immune network homeostasis to decorate a hospitable microenvironment (pre-metastatic niche) for the coming disseminated cancer cells, and promoted the subsequent metastatic colonization. Our studies will shed some new light on the development of new adjuvant therapies for preventing and treating lung metastasis of breast cancer.

阐明影响循环肿瘤细胞在远端器官定植的关键因素，对于建立防治肿瘤转移的新策略具有重要意义。本课题的前期研究发现，慢性心理应激可显著促进循环乳腺癌细胞在肺组织中的定植及转移灶形成。应用6-羟多巴胺破坏交感神经末梢或普萘洛尔阻断肾上腺素能信号可逆转上述效应，提示慢性心理应激通过激活肾上腺素能信号，促进循环肿瘤细胞肺转移。进一步研究发现，在循环肿瘤细胞尚未到达肺组织之前，肾上腺素能信号活化可导致小鼠外周血中单核细胞和中性粒细胞的数量显著增加，并可促进巨噬细胞在肺组织中浸润，而去除中性粒细胞或肺组织中的巨噬细胞则可显著抑制肾上腺素能信号促进循环肿瘤细胞肺转移性定植的效应。因此，我们提出假设，慢性心理应激通过扰动机体“神经-内分泌-免疫”网络的稳态，诱导预转移肺微环境（niche）形成，促进乳腺癌细胞的肺转移性定植。本课题将深入探索其中的分子机制，为乳腺癌肺转移防治新策略的建立提供实验及理论依据。

阐明影响循环肿瘤细胞在远端器官定植的关键因素，对于建立防治肿瘤转移的新策略具有重要意义。本课题研究发现，1.慢性心理应激通过激活β-肾上腺素能信号促进乳腺癌肺转移；2.β-肾上腺素能信号激活促进循环肿瘤细胞转移性定植；3.巨噬细胞在β-肾上腺素能信号激活诱导的肺预转移微环境形成中发挥关键作用；4.β-肾上腺素能信号激活诱导巨噬细胞在肺组织中聚集；5.慢性心理应激刺激肺组织中巨噬细胞表达CCL2；6.肾上腺素能信号诱导单核/巨噬细胞表达CCR2。综上，慢性心理应激诱导的β肾上腺素能信号可动员骨髓中单核细胞进入外周循环。同时，通过激活CCL2/CCR2轴，诱导巨噬细胞向肺组织趋化、浸润，调变预转移肺组织微环境，从而促进循环肿瘤细胞在肺组织中的浸润及定植。本课题揭示了慢性心理应激调控肺脏预转移微环境的分子机制，为乳腺癌肺转移防治新策略的建立提供了实验及理论依据。