Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs.
Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs.
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DOI：
10.1007/s10549-014-3164-7
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发表时间：
2014-11
影响因子：
3.8
通讯作者：
Fan, Daping
中科院分区：
文献类型：
--
作者：
Jia, Xuemei;Yu, Fang;Wang, Junfeng;Iwanowycz, Stephen;Saaoud, Fatma;Wang, Yuzhen;Hu, Jun;Wang, Qian;Fan, Daping
由于缺乏有效的转移治疗，乳腺癌是女性癌症患者的主要死亡原因。巨噬细胞是原发和转移肿瘤中含量最丰富的免疫细胞，参与肿瘤的发生、发展和转移。大黄素已被发现通过促进细胞周期停滞、细胞凋亡和抑制血管生成而发挥抗肿瘤作用，但其在肿瘤转移过程中对肿瘤相关巨噬细胞的影响尚未见报道。原位接种4T1或EO771乳腺癌细胞的小鼠在原发肿瘤达到200mm3后给予大黄素治疗。分析原发肿瘤生长、肺转移和肺内巨噬细胞浸润情况。体外实验观察大黄素对巨噬细胞迁移和M2极化的影响及其机制。大黄素显著抑制两种原位小鼠模型的乳腺癌肺转移，而对原发肿瘤无明显影响。大黄素处理组小鼠肺内F4/80+巨噬细胞和YM1+M2巨噬细胞浸润减少。体外实验表明，大黄素可减少巨噬细胞向肿瘤细胞条件培养液的迁移，并抑制中药诱导的巨噬细胞M2极化。机制上，大黄素抑制IL-4或中药处理的巨噬细胞中STAT6的磷酸化和C/EBPβ的表达，这是巨噬细胞M2极化中的两个关键信号事件。综上所述，我们的研究首次证明大黄素可能通过减少STAT6的磷酸化和C/EBPβ的表达来抑制巨噬细胞募集和肺内M2极化，从而抑制乳腺癌的肺转移。
Breast cancer is the leading cause of death in female cancer patients due to the lack of effective treatment for metastasis. Macrophages are the most abundant immune cells in the primary and metastatic tumors, and contribute to tumor initiation, progression and metastasis. Emodin has been found to exert anti-tumor effects through promoting cell cycle arrest and apoptosis, and inhibiting angiogenesis, but its effects on tumor-associated macrophages during cancer metastasis have not been investigated. Mice inoculated with 4T1 or EO771 breast cancer cells orthotopically were treated with Emodin after the primary tumors reached 200 mm3 in size. Primary tumor growth, lung metastasis, and macrophage infiltration in the lungs were analyzed. In vitro experiments were performed to examine the effects of Emodin on macrophage migration and M2 polarization, and the underlying mechanisms. Emodin significantly suppressed breast cancer lung metastasis in both orthotopic mouse models without apparent effects on primary tumors. Reduced infiltration of F4/80+ macrophages and Ym1+ M2 macrophages in lungs was observed in Emodin-treated mice. In vitro experiments demonstrated that Emodin decreased the migration of macrophages towards tumor cell conditioned medium (TCM) and inhibited macrophage M2 polarization induced by TCM. Mechanistically, Emodin suppressed STAT6 phosphorylation and C/EBPβ expression, two crucial signaling events in macrophage M2 polarization, in macrophages treated with IL-4 or TCM. Taken together, our study, for the first time, demonstrated that Emodin suppressed pulmonary metastasis of breast cancer probably through inhibiting macrophage recruitment and M2 polarization in the lungs by reducing STAT6 phosphorylation and C/EBPβ expression.
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影响因子：
4
作者：
Doyle, Danielle M.;Miller, Kathy D.
通讯作者：
Miller, Kathy D.
影响因子：
3.8
作者：
Dai F;Liu L;Che G;Yu N;Pu Q;Zhang S;Ma J;Ma L;You Z
通讯作者：
You Z
DOI：
10.1177/1535370214530247
发表时间：
2014-08
期刊：
Experimental biology and medicine (Maywood, N.J.)
影响因子：
--
作者：
Jia X;Iwanowycz S;Wang J;Saaoud F;Yu F;Wang Y;Hu J;Chatterjee S;Wang Q;Fan D
通讯作者：
Fan D
影响因子：
24.1
作者：
He, Min;Xu, Zhenqun;Zheng, Limin
通讯作者：
Zheng, Limin
影响因子：
50.3
作者：
Chen Q;Zhang XH;Massagué J
通讯作者：
Massagué J