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

// Hongzhong Li 1 , Bing Yang 1 , Jing Huang 1 , Yong Lin 1 , Tingxiu Xiang 1 , Jingyuan Wan 2 , Hongyuan Li 1 , Salem Chouaib 3 , Guosheng Ren 1 1 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China 2 Department of Pharmacology, Chongqing Medical University, Chongqing, China 3 Unite INSERM U753, Institut de Cancerologie Gustave Roussy, Paris, France Correspondence to: Guosheng Ren, e-mail: rengs726@126.com Keywords: tumor microenvironment, macrophages, breast cancer, cyclooxygenase-2, prostaglandin E 2 Received: May 13, 2015 Accepted: July 28, 2015 Published: August 10, 2015 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.