Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression
Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression
复制标题
DOI：
10.1038/s41593-019-0430-3
复制
发表时间：
2019-08-01
影响因子：
25
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
--
作者：
Kamiya, Atsunori;Hayama, Yohsuke;Ochiya, Takahiro
肿瘤的自主神经支配对肿瘤生长的影响尚不清楚。在这里，我们开发了一系列的遗传技术，以操纵自主神经支配的肿瘤和纤维类型的特定方式在小鼠与人类乳腺癌异种移植物和大鼠与化学诱导的乳腺肿瘤。乳腺癌的生长和进展在刺激肿瘤中的交感神经后加速，但在刺激副交感神经后减少。肿瘤特异性交感神经去支配抑制肿瘤生长，并在更大程度上下调免疫检查点分子（程序性死亡-1（PD-1）、程序性死亡配体-1（PD-L1）和FOXP 3）的表达。遗传诱导的肿瘤副交感神经支配的模拟降低PD-1和PD-L1表达。在人类中，对来自29名患者的乳腺癌标本的回顾性分析显示，肿瘤中交感神经密度增加和副交感神经密度降低与临床结局不良相关，并与免疫检查点分子的较高表达相关。这些发现表明，自主神经支配的肿瘤调节乳腺癌的进展。
The effects of autonomic innervation of tumors on tumor growth remain unclear. Here we developed a series of genetic techniques to manipulate autonomic innervation in a tumor-and fiber-type-specific manner in mice with human breast cancer xenografts and in rats with chemically induced breast tumors. Breast cancer growth and progression were accelerated following stimulation of sympathetic nerves in tumors, but were reduced following stimulation of parasympathetic nerves. Tumor-specific sympathetic denervation suppressed tumor growth and downregulated the expression of immune checkpoint molecules (programed death-1 (PD-1), programed death ligand-1 (PD-L1), and FOXP3) to a greater extent than with pharmacological a-or beta-adrenergic receptor blockers. Genetically induced simulation of parasympathetic innervation of tumors decreased PD-1 and PD-L1 expression. In humans, a retrospective analysis of breast cancer specimens from 29 patients revealed that increased sympathetic and decreased parasympathetic nerve density in tumors were associated with poor clinical outcomes and correlated with higher expression of immune checkpoint molecules. These findings suggest that autonomic innervation of tumors regulates breast cancer progression.