Macrophage ERα promoted invasion of endometrial cancer cell by mTOR/KIF5B‐mediated epithelial to mesenchymal transition

• Published in: Immunology and cell biology 2019-07, Vol.97 (6), p.563-576
• Main Authors: Jing, Xuanxuan, Peng, Jin, Dou, Yu, Sun, Jintang, Ma, Chao, Wang, Qingjie, Zhang, Lin, Luo, Xia, Kong, Beihua, Zhang, Yun, Wang, Lijie, Qu, Xun
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; CCL18; CCL18 protein; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokines; Chemokines, CC - metabolism; Endometrial cancer; Endometrial Neoplasms - immunology; Endometrial Neoplasms - pathology; Endometriosis; Endometrium; Epithelial-Mesenchymal Transition - immunology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; estrogen receptor α; Estrogen receptors; Female; Gene Expression Regulation, Neoplastic; Health risk assessment; Hormone replacement therapy; Humans; KIF5B; Kinesin - genetics; Kinesin - metabolism; Lung cancer; macrophage; Macrophages; Macrophages - immunology; Mesenchyme; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Ovarian cancer; Signal Transduction; Therapeutic applications; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1111/imcb.12245

Tumor‐associated macrophages (TAMs) exert tumor‐promoting effects. There have been reports that estrogen receptors (ERs) are expressed on the infiltrating macrophages of endometriosis, ovarian cancer and lung cancer. However, the role of ERs in macrophages is not well characterized. In this study, we identified that ER alpha (ERα) expression on the macrophages of human endometrial cancer was positively correlated with cancer progression. Conditioned medium from selective ERα agonist‐treated M2 macrophages induced the epithelial to mesenchymal transition (EMT) in endometrial cancer cells. However, this effect can be inhibited by ERα antagonist. Here, we showed that macrophages ERα‐engaged abundantly produced chemokine (C‐C motif) ligand 18 (CCL18), and its expression promoted the invasion of endometrial cancer cells by activating the extracellular signal‐regulated kinase 1/2 pathway, whereas suppressing CCL18 abrogated these effects. Furthermore, we identified that CCL18 derived from TAMs upregulated KIF5B expression to promote EMT via activating the PI3K/AKT/mTOR signaling pathway in endometrial cancer. Overall, our findings show how ERα‐engaged infiltrating macrophages initiate chronic inflammation and promote the aggressive progression of endometrial cancer cells. ERα‐positive TAMs act as drivers of endometrial cancer, which may become a potential therapeutic target. We identified that estrogen receptor alpha (ERα) expression on macrophages of human endometrial cancer was positively correlated with cancer progression. Conditioned medium from selective ERα agonist‐treated M2 macrophages could induce epithelial to mesenchymal transition and promote migration and invasion of endometrial cancer cells via the chemokine (C‐C motif) ligand 18. ERα‐positive tumor‐associated macrophages act as a driver of endometrial cancer, which may become a potential therapeutic target.