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-β1 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-β1 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-β1 production in breast cancer cells and macrophages and attenuated TGF-β1 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-β1 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-β1-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.

• Authors: Qing Liu, Johnie Hodge, Junfeng Wang, Yuzhen Wang, Lianming Wang, Udai Singh, Yong Li, Yongzhong Yao, Dawei Wang, Walden Ai, Prakash Nagarkatti, Hexin Chen, Peisheng Xu, E Angela Murphy, Daping Fan
• Journal: Theranostics (Theranostics) Vol. 10 Issue 18 Pg. 8365-8381 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 32724475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• TGFB1 protein, human
• Transforming Growth Factor beta1
• Emodin

Topics

• Animals
• Breast Neoplasms (immunology, pathology, therapy)
• Cell Communication (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Chemotherapy, Adjuvant (methods)
• Coculture Techniques
• Computational Biology
• Drug Screening Assays, Antitumor
• Emodin (pharmacology, therapeutic use)
• Epithelial-Mesenchymal Transition (drug effects, immunology)
• Female
• Humans
• Lung Neoplasms (immunology, prevention & control, secondary)
• Mammary Neoplasms, Experimental (drug therapy, immunology, pathology)
• Mastectomy
• Neoplastic Stem Cells (drug effects, pathology)
• Primary Cell Culture
• Signal Transduction (drug effects, immunology)
• Transforming Growth Factor beta1 (metabolism)
• Tumor Microenvironment (drug effects, immunology)
• Tumor-Associated Macrophages (drug effects, immunology)