Date of Award

6-30-2016

Document Type

Open Access Dissertation

Department

Biomedical Science

Sub-Department

School of Medicine

First Advisor

Daping Fan

Abstract

Macrophages are pleiotropic cells capable of performing a broad spectrum of functions. Their phenotypes are classified along a continuum between the extremes of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. The seemingly opposing functions of M1 and M2 macrophages must be tightly regulated for an effective inflammatory response to foreign molecules or damaged tissue. Excessive activation of either M1 or M2 macrophages contributes to the pathology of many diseases. Infiltration of macrophages into breast tumors correlates with increased metastasis and decreased patient survival. Tumors recruit macrophages to the primary site as well as pre-metastatic niches, and educate them to adopt an M2-like phenotype, thereby creating a growth-promoting immunosuppressive microenvironment. Emodin is a Chinese herb-derived single compound and has shown potential to inhibit macrophage activation and to prevent tumor growth. In this study, the effects of emodin on macrophage response to M1 or M2 stimuli were investigated. Further, emodin was used to treat mice bearing breast tumors and its effect on tumor cell-macrophage interactions was examined. Emodin was found to bi-directionally tune the activation of macrophages induced by LPS/IFNγ or IL4 through inhibiting NFkB/IRF5/STAT1 or IRF4/STAT6 signaling pathways respectively. Furthermore, emodin inhibited the removal of H3K27m3 and the placement of H3K27ac histone modifications on genes associated with macrophage activation. In mice bearing breast cancer, emodin treatment attenuated tumor growth by reducing macrophage infiltration into the primary tumors and subsequent M2-like polarization. Reduced accumulation of M2-like macrophages in the tumors leads to increased T cell activation and decreased angiogenesis. Emodin was shown to suppress infiltration and M2-like polarization of TAMs by targeting the TAM-tumor interaction. Emodin inhibited macrophage M2-like polarization in response to tumor cell secreted molecules, inhibited tumor cell recruitment of macrophages through reducing CCL2 and CSF1 expression, and block tumor cell-macrophage adhesion. In conclusion, our data suggest that emodin is uniquely able to suppress excessive response of macrophages to both M1 and M2 stimuli, and that emodin has potential as a new anti-breast cancer therapy.

Rights

© 2016, Stephen Iwanowycz

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