Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages

Abstract

Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing anti-tumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2 related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration towards and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis.

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

“…In mice bearing EO771 or 4T1 breast tumors, emodin suppressed tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced tumor angiogenesis (Iwanowycz et al, 2016). At molecular level, emodin inhibited IRF4, STAT6, and C/EBPb signaling and significantly increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages (Iwanowycz et al, 2016). In BALB/c nude mice xenograft with human hepatocellular cancer SMMC-7721 cells, emodin suppressed tumor growth and induced apoptosis with increases in ERK and p38 phosphorylation and suppression of p-JNK expression (Lin et al, 2016).…”

“…The in vitro molecular mechanism showed that emodin activated ER stress and TRIB3/nuclear factor-kB signaling (Su et al, 2017). In mice bearing EO771 or 4T1 breast tumors, emodin suppressed tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced tumor angiogenesis (Iwanowycz et al, 2016). At molecular level, emodin inhibited IRF4, STAT6, and C/EBPb signaling and significantly increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages (Iwanowycz et al, 2016).…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Emodin has immunomodulatory effects in cancer and immunity. It inhibits cell growth and metastasis through blocking the tumor-promoting feed forward loop between macrophages and breast cancer cells [394].…”

A New Immunosuppressive Molecule Emodin Induces both CD4+FoxP3+ and CD8+CD122+ Regulatory T Cells and Suppresses Murine Allograft Rejection

“…Emodin has long been used to treat chronic kidney diseases with few side effects (11). Recently, many studies have also documented laxative effects of emodin as well as its inhibitory effects on tumors (12), viruses (13), bacteria (14), and inflammation (15) without any major side effect. Furthermore, emodin is also available in China at a low cost.…”