Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells.

Hongzhong Li,Jing Huang,Guosheng Ren,Salem Chouaib,Tingxiu Xiang,Bing Yang,Yong Lin,Jingyuan Wan,Hongyuan Li

doi:10.18632/oncotarget.4936

Abstract

Tumor-associated macrophages (TAMs) play an important role in cancer cell survival, however, the mechanism of which remains elusive. In this study, we found that COX-2 was abundantly expressed in breast TAMs, which was correlated to poor prognosis in breast cancer patients. Ectopic over-expression of COX-2 in TAMs enhanced breast cancer cell survival both in vitro and in vivo. COX-2 in TAMs was determined to be essential for the induction and maintenance of M2-phenotype macrophage polarity. COX-2(+) TAMs promoted breast cancer cell proliferation and survival by increasing Bcl-2 and P-gp and decreasing Bax in cancer cells. Furthermore, COX-2 in TAMs induced the expression of COX-2 in breast cancer cells, which in turn promoted M2 macrophage polarization. Inhibiting PI3K/Akt pathway in cancer cells suppressed COX-2(+) TAMs-induced cancer cell survival. These findings suggest that COX-2, functions as a key cancer promoting factor by triggering a positive-feedback loop between macrophages and cancer cells, which could be exploited for breast cancer prevention and therapy.

Highlights

The tumor microenvironment comprises a variety of stromal cells that play an essential role in tumor initiation and progression [1]
Primary Tumor associated macrophages (TAMs) isolated from breast cancer tissue produced a large amount of IL-10 and arginase-1, and a small amount of IL-12/23, and exhibited a cluster of differentiation (CD)163high/CD206high phenotype (Supplementary Figure S1)
The results showed that inhibiting the prostaglandin E2 (PGE2) signal pathway only partly attenuated cell proliferation and drug resistance in breast cancer cells induced by TAMs (Figure 3B–3C), suggesting that other mediators are involved in COX-2-mediated communication between TAMs and breast cancer cells

Summary

Introduction

The tumor microenvironment comprises a variety of stromal cells that play an essential role in tumor initiation and progression [1]. Tumor associated macrophages (TAMs), the most abundant inflammatory stromal cells in malignant tumors including breast cancer, have been implicated in orchestration of many stages of tumor progression such as tumor growth, angiogenesis, metastasis, and resistance to treatment, through releasing various factors including chemokines, inflammatory and growth factors [2, 3]. When exposed to Th2 cytokines such as IL-4 and IL-13, they are polarized to immunosuppressive M2 macrophages and involved in parasite containment, tissue remodeling and tumor progression. Compared with M1 macrophages, M2 macrophages do not produce proinflammatory mediators such as tumor necrosis factor-α (TNF-α), IL-1β and IL-12/23, but express high levels of immunosuppressive cytokines such as IL-10 and TGF-β, high arginase-1 activity and specific surface markers such as CD163 and CD206 (mannose receptor). As a www.impactjournals.com/oncotarget particular pathophysiological consequence in the setting of cancer, the M1-M2 switch is the key step that accelerates tumor aggressiveness [2, 6, 7]

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