Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages
Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages
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儿茶酚胺通过肿瘤相关巨噬细胞促进肺癌的新血管形成
DOI：
10.1016/j.bbi.2019.06.004
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发表时间：
2019-06
期刊：
影响因子：
--
通讯作者：
Wu Gang
中科院分区：
文献类型：
--
作者：
Xia Yun;Wei Ye;Li Zhen Yu;Cai Xian Yi;Zhang Li Ling;Dong Xiao Rong;Zhang Sheng;Zhang Rui Guang;Meng Rui;Zhu Fang;Wu Gang
目的肿瘤微环境中儿茶酚胺的升高与肿瘤的发生发展密切相关。然而，儿茶酚胺调节肺癌生长的机制仍然知之甚少。本研究旨在探讨儿茶酚胺诱导的巨噬细胞极化在血管生成和肿瘤发生中的作用和机制。实验设计建立体外培养和活体动物模型，研究儿茶酚胺和巨噬细胞在肺癌中的关系。结果在交感神经系统的控制下，儿茶酚胺可分泌到肿瘤细胞内，维持肿瘤微环境。体内，6OHDA化学耗竭天然儿茶酚胺储备，可减少肿瘤组织中儿茶酚胺的释放，抑制交替激活的M2巨噬细胞的功能，抑制肿瘤新生血管形成，抑制肿瘤生长。体外，儿茶酚胺治疗可触发巨噬细胞M2极化，增强血管内皮生长因子的表达，促进肿瘤血管生成肾上腺素能受体拮抗剂心得安可逆转儿茶酚胺的上述效应。除了调节肿瘤相关巨噬细胞()的募集，降低儿茶酚胺水平还可以通过减少髓系来源的抑制细胞(MDSCs)的募集和促进树突状细胞(DC)的激活来改变免疫抑制的微环境，从而可能导致积极的抗肿瘤免疫反应。结论我们的研究证实了肾上腺素能应激和儿茶酚胺驱动的肾上腺素能信号转导TAMS调节肿瘤微环境的免疫状态，为抗癌治疗提供了潜在的靶点。
PurposeElevated catecholamines in the tumor microenvironment often correlate with tumor development. However, the mechanisms by which catecholamines modulate lung cancer growth are still poorly understood. This study is aimed at examining the functions and mechanisms of catecholamine-induced macrophage polarization in angiogenesis and tumor development.Experimental designWe establishedin vitroandin vivomodels to investigate the relationship between catecholamines and macrophages in lung cancer. Flow cytometry, cytokine detection, tube formation assay, immunofluorescence, and western blot analysis were performed, and animal models were also used to explore the underlying mechanism of catecholamine-induced macrophage polarization and host immunological response.ResultsCatecholamines were shown to be secreted into tumor under the control of the sympathetic nerve system to maintain the pro-tumoral microenvironment.In vivo, the chemical depletion of the natural catecholamine stock with 6OHDA could reduce the release of catecholamines within tumor tissues, restrain the function of alternatively activated M2 macrophage, attenuate tumor neovascularization, and inhibit tumor growth.In vitro, catecholamine treatment triggered the M2 polarization of macrophages, enhanced the expression of VEGF, promoted tumor angiogenesis, and these catecholamine-stimulated effects could be reversed by the adrenergic receptor antagonist propranolol. In addition to regulating tumor-associated macrophages (TAM) recruitment, decreasing catecholamine levels could also shift the immunosuppressive microenvironment by decreasing myeloid-derived suppressor cells’ (MDSCs) recruitment and facilitating dendritic cells’ (DCs) activation, potentially resulting in a positive antitumor immune response.ConclusionOur study demonstrates the potential of adrenergic stress and catecholamine-driven adrenergic signaling of TAMs to regulate the immune status of a tumor microenvironment and provides promising targets for anticancer therapies.
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影响因子：
17.1
作者：
Nilsson MB;Sun H;Diao L;Tong P;Liu D;Li L;Fan Y;Poteete A;Lim SO;Howells K;Haddad V;Gomez D;Tran H;Pena GA;Sequist LV;Yang JC;Wang J;Kim ES;Herbst R;Lee JJ;Hong WK;Wistuba I;Hung MC;Sood AK;Heymach JV
通讯作者：
Heymach JV
影响因子：
5.6
作者：
Scanzano A;Cosentino M
通讯作者：
Cosentino M
影响因子：
1.5
作者：
K. Bryniarski;M. Szczepanik;M. Ptak;W. Ptak
通讯作者：
K. Bryniarski;M. Szczepanik;M. Ptak;W. Ptak
影响因子：
5.3
作者：
Grailer JJ;Haggadone MD;Sarma JV;Zetoune FS;Ward PA
通讯作者：
Ward PA
影响因子：
45.3
作者：
Barron, Thomas I.;Connolly, Roisin M.;Visvanathan, Kala
通讯作者：
Visvanathan, Kala