Emodin reduces Breast Cancer Lung Metastasis by suppressing Macrophage-induced Breast Cancer Cell Epithelial-mesenchymal transition and Cancer Stem Cell formation
Emodin reduces Breast Cancer Lung Metastasis by suppressing Macrophage-induced Breast Cancer Cell Epithelial-mesenchymal transition and Cancer Stem Cell formation
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DOI：
10.7150/thno.45395
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Fan, Daping
中科院分区：
文献类型：
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作者：
Liu, Qing;Hodge, Johnie;Fan, Daping
我们以前的研究表明，天然化合物大黄素阻断癌细胞和巨噬细胞之间的促肿瘤前馈相互作用，从而改善肿瘤微环境的免疫抑制状态。由于肿瘤相关的巨噬细胞（TAMs）也影响上皮间质转化（EMT）和癌症干细胞（CSC）的形成，在这里，我们的目的是测试，如果大黄素作为新辅助治疗通过衰减TAM诱导的EMT和CSC形成的乳腺癌cells.Methods：生物信息学分析，以检查巨噬细胞丰度和EMT/CSC标志物在人类乳腺肿瘤之间的相关性。进行细胞培养和共培养研究以测试大黄素是否抑制TGF-β 1或巨噬细胞诱导的乳腺癌细胞的EMT和CSC形成，以及是否抑制乳腺癌细胞的迁移和侵袭。使用小鼠模型，我们测试了在手术切除乳腺肿瘤前短期给予大黄素是否可以阻止乳腺癌术后肺部转移复发。大黄素对乳腺癌细胞TGF-β 1信号通路的影响通过Western印迹和免疫荧光imaging.Results检测：巨噬细胞丰度与人乳腺肿瘤中的EMT和CSC标志物呈正相关。大黄素抑制乳腺癌细胞和巨噬细胞中TGF-β 1的产生，并减弱TGF-β 1或巨噬细胞诱导的乳腺癌细胞的EMT和CSC形成。手术前短期给予大黄素通过减少促肿瘤巨噬细胞和抑制原发性肿瘤中EMT和CSC的形成来阻止乳腺癌术后肺转移复发。机制研究表明，大黄素抑制乳腺癌细胞中经典和非经典的TGF-β 1信号通路，并抑制EMT和CSC关键转录因子。结论：天然化合物大黄素通过阻断TGF-β 1介导的TAMs与乳腺癌细胞之间的相互作用，抑制乳腺癌细胞EMT和CSC的形成。我们的研究提供的证据表明，大黄素具有临床开发的潜力，作为一种新的有效和安全的药物，以阻止乳腺癌的转移复发。
Our previous studies demonstrated that the natural compound emodin blocks the tumor-promoting feedforward interactions between cancer cells and macrophages, and thus ameliorates the immunosuppressive state of the tumor microenvironment. Since tumor-associated macrophages (TAMs) also affect epithelial mesenchymal-transition (EMT) and cancer stem cell (CSC) formation, here we aimed to test if emodin as a neoadjuvant therapy halts breast cancer metastasis by attenuating TAM-induced EMT and CSC formation of breast cancer cells.Methods: Bioinformatical analysis was performed to examine the correlation between macrophage abundance and EMT/CSC markers in human breast tumors. Cell culture and co-culture studies were performed to test if emodin suppresses TGF-beta 1 or macrophage-induced EMT and CSC formation of breast cancer cells, and if it inhibits breast cancer cell migration and invasion. Using mouse models, we tested if short-term administration of emodin before surgical removal of breast tumors halts breast cancer post-surgery metastatic recurrence in the lungs. The effects of emodin on TGF-beta 1 signaling pathways in breast cancer cells were examined by western blots and immunofluorescent imaging.Results: Macrophage abundance positively correlates with EMT and CSC markers in human breast tumors. Emodin suppressed TGF-beta 1 production in breast cancer cells and macrophages and attenuated TGF-beta 1 or macrophage-induced EMT and CSC formation of breast cancer cells. Short-term administration of emodin before surgery halted breast cancer post-surgery metastatic recurrence in the lungs by reducing tumor-promoting macrophages and suppressing EMT and CSC formation in the primary tumors. Mechanistic studies revealed that emodin inhibited both canonical and noncanonical TGF-beta 1 signaling pathways in breast cancer cells and suppressed transcription factors key to EMT and CSC.Conclusion: Natural compound emodin suppresses EMT and CSC formation of breast cancer cells by blocking TGF-beta 1-mediated crosstalk between TAMs and breast cancer cells. Our study provides evidence suggesting that emodin harbors the potential for clinical development as a new effective and safe agent to halt metastatic recurrence of breast cancer.