Journal Article

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

Singh, Udai P., Wang, Dawei, Fan, Daping, Hodge, Johnie, Wang, Junfeng, Wang, Yuzhen, Li, Yong, Murphy, E. Angela, Wang, Lianming, Nagarkatti, Prakash, Xu, Peisheng, Ai, Walden, Liu, Qing, Yao, Yongzhong, Chen, Hexin

2020

Overview

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. 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. 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. 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.

• Publisher: Ivyspring International Publisher Pty Ltd,Ivyspring International Publisher
• Subject: Animals / Antibodies / Breast cancer / Breast Neoplasms - immunology / Breast Neoplasms - pathology / Breast Neoplasms - therapy / Cancer therapies / Cell adhesion & migration / Cell Communication - drug effects / Cell Line, Tumor / Cell Movement - drug effects / Chemotherapy, Adjuvant - methods / Coculture Techniques / Computational Biology / Drug Screening Assays, Antitumor / Emodin - pharmacology / Emodin - therapeutic use / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - immunology / Female / Flow cytometry / Gene expression / Humans / Laboratory animals / Lung cancer / Lung Neoplasms - immunology / Lung Neoplasms - prevention & control / Lung Neoplasms - secondary / Mammary Neoplasms, Experimental - drug therapy / Mammary Neoplasms, Experimental - immunology / Mammary Neoplasms, Experimental - pathology / Mastectomy / Metastasis / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - pathology / Primary Cell Culture / Research Paper / Signal Transduction - drug effects / Signal Transduction - immunology / Surgery / Thermal cycling / Transforming Growth Factor beta1 - metabolism / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumor-Associated Macrophages - drug effects / Tumor-Associated Macrophages - immunology / Tumors