CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis.
CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis.
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DOI：
10.1038/onc.2017.118
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发表时间：
2017-08-31
期刊：
影响因子：
8
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Chen XW;Yu TJ;Zhang J;Li Y;Chen HL;Yang GF;Yu W;Liu YZ;Liu XX;Duan CF;Tang HL;Qiu M;Wang CL;Zheng H;Yue J;Guo AM;Yang J
肿瘤相关巨噬细胞（tumor associated macrophages, tam）在肿瘤转移中起重要作用。然而，是什么使tam具有在远处器官中建立转移前微环境的优越能力尚不清楚。在这里，我们已经开始揭示tam中细胞色素P450 (CYP) 4A对肺转移前生态位形成和转移的影响。CYP4A+ TAM浸润与乳腺癌患者的转移、转移前生态位形成及不良预后呈正相关。在4T1乳腺癌和B16F10黑色素瘤的自发转移模型中，CYP4A的药理抑制减少了肺转移前生态位的形成（血管内皮生长因子受体1阳性（VEGFR1+）骨髓细胞募集和前转移蛋白表达的减少）和转移负担，并伴有TAM远离M2表型的极化。4T1细胞与高cyp4a10的巨噬细胞共植入促进肺转移前生态位的形成和转移。tam的耗竭破坏了肺转移前生态位，从而阻止了转移。使用cyp4a10高M2巨噬细胞（M2）的CM治疗增加了肺转移前生态位的形成和转移负荷，而CYP4A抑制则减弱了这些作用。CYP4A抑制诱导的离M2型TAM极化降低了VEGFR1+骨髓细胞迁移和纤维连接蛋白的表达，并伴有STAT3信号的下调。相反，CYP4A过表达或外源性添加20-羟基二糖四烯酸可促进巨噬细胞M2极化和细胞因子的产生，从而增强VEGFR1+髓系细胞的迁移，而siRNA或药理抑制STAT3可逆转这一过程。重要的是，联合阻断M2巨噬细胞衍生因子TGF-β、VEGF和SDF-1可消除CYP4A诱导的VEGFR1+骨髓细胞迁移和成纤维细胞活化。综上所述，tam中的CYP4A对肺转移前生态位的形成和转移至关重要，可能是人类癌症的潜在治疗靶点。
Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A+ TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1+) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1+ myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1+ myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1+ myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.
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影响因子：
3.8
作者：
Jia, Xuemei;Yu, Fang;Wang, Junfeng;Iwanowycz, Stephen;Saaoud, Fatma;Wang, Yuzhen;Hu, Jun;Wang, Qian;Fan, Daping
通讯作者：
Fan, Daping
二甲双胍通过抑制肿瘤相关巨噬细胞的 M2 样极化来预防癌症转移
影响因子：
--
作者：
Ding L;Liang G;Yao Z;Zhang J;Liu R;Chen H;Zhou Y;Wu H;Yang B;He Q
通讯作者：
He Q
影响因子：
50.3
作者：
Rolny, Charlotte;Mazzone, Massimiliano;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
11.2
作者：
Acuff, HB;Carter, KJ;Matrisian, LM
通讯作者：
Matrisian, LM