title: 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 antitumor 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 MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward 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. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR.
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina.
authors.forename: Stephen
authors.initials: S
authors.lastname: Iwanowycz
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina.
authors.forename: Johnie
authors.initials: J
authors.lastname: Hodge
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina. Department of Nutrition and Food Hygiene, Fourth Military Medical University, Xi'an, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina. daping.fan@uscmed.sc.edu.
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
mesh_terms: D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004642:Emodin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D004642:Emodin