The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer
The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer
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DOI：
10.1158/0008-5472.can-10-0522
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发表时间：
2010-09-15
期刊：
影响因子：
11.2
通讯作者：
Cole, Steven W.
中科院分区：
文献类型：
--
作者：
Sloan, Erica K.;Priceman, Saul J.;Cole, Steven W.
远处组织转移是乳腺癌相关死亡率的主要驱动因素，但对调节这一过程的系统生理动力学知之甚少。为了研究神经内分泌激活在癌症进展中的作用，我们使用体内生物发光成像来跟踪原位乳腺癌小鼠模型的转移发展。应激诱导的神经内分泌激活对原发肿瘤生长的影响可以忽略不计，但诱导转移到远处组织（包括淋巴结和肺）的几率增加30倍。这些作用是由β -肾上腺素能信号介导的，它增加了CD11b(+)F4/80（+）巨噬细胞向原发肿瘤实质的浸润，从而诱导了原转移基因的表达特征，并伴有M2巨噬细胞分化的适应症。β -肾上腺素能信号的药理激活诱导了类似的效果，用β -拮抗剂心得安治疗应激动物逆转应激诱导的巨噬细胞浸润，抑制肿瘤向远处组织扩散。使用CSF-1受体激酶抑制剂GW2580抑制体内巨噬细胞也能抑制应激对远处转移的影响。这些发现确定了交感神经系统的激活是乳腺癌转移的一种新的神经调节因子，并提出了针对原发性乳腺癌中β -肾上腺素能诱导前转移基因表达的抗转移治疗的新策略。癌症Res;70 (18);7042 - 52。AACR (C) 2010。
Metastasis to distant tissues is the chief driver of breast cancer-related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the primary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by beta-adrenergic signaling, which increased the infiltration of CD11b(+)F4/80(+) macrophages into primary tumor parenchyma and thereby induced a prometastatic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of beta-adrenergic signaling induced similar effects, and treatment of stressed animals with the beta-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastatic therapies that target the beta-adrenergic induction of prometastatic gene expression in primary breast cancers. Cancer Res; 70(18); 7042-52. (C)2010 AACR.