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Emodin reduces Breast Cancer Lung Metastasis by suppressing Macrophage-induced Breast Cancer Cell Epithelial-mesenchymal transition and Cancer Stem Cell formation.


ABSTRACT: 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-?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-?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-?1 production in breast cancer cells and macrophages and attenuated TGF-?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-?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-?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.

SUBMITTER: Liu Q 

PROVIDER: S-EPMC7381725 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Emodin reduces Breast Cancer Lung Metastasis by suppressing Macrophage-induced Breast Cancer Cell Epithelial-mesenchymal transition and Cancer Stem Cell formation.

Liu Qing Q   Hodge Johnie J   Wang Junfeng J   Wang Yuzhen Y   Wang Lianming L   Singh Udai U   Li Yong Y   Yao Yongzhong Y   Wang Dawei D   Ai Walden W   Nagarkatti Prakash P   Chen Hexin H   Xu Peisheng P   Murphy E Angela EA   Fan Daping D  

Theranostics 20200709 18


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 form  ...[more]

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