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Theranostics 2020; 10(18):8365-8381. doi:10.7150/thno.45395 This issue Cite

Research Paper

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

Qing Liu¹, Johnie Hodge¹, Junfeng Wang¹, Yuzhen Wang¹, Lianming Wang², Udai P. Singh³, Yong Li¹, Yongzhong Yao⁴, Dawei Wang⁵, Walden Ai⁶, Prakash Nagarkatti³, Hexin Chen⁷, Peisheng Xu⁸, E. Angela Murphy³, Daping Fan^1✉

1. Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209.
2. Department of Statistics, University of South Carolina, Columbia, SC 29208.
3. Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209.
4. Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China, 210008.
5. Guangdong Provincial Hospital of Chinese Medicine, the 2nd Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.
6. Department of Biology and Environmental Health Science, Benedict College, Columbia, SC 29204.
7. Department of Biological Sciences, University of South Carolina, Columbia, SC 29208.
8. Department of Drug Discovery and Biomedical Sciences, University of South Carolina, College of Pharmacy, Columbia, SC 29208.

✉ Corresponding author: Daping Fan, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209. Phone: 803-216-3806; Fax: 803-216-3846; E-mail: daping.fansc.edu.

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.

Keywords: Breast cancer, Emodin, Macrophage, Epithelial-mesenchymal transition, Cancer stem cell

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