title: Leptin promotes migration and invasion of breast cancer cells by stimulating IL-8 production in M2 macrophages.
abstract: This study aims to investigate the mechanisms underlying leptin-mediated crosstalk between tumor-associated macrophages (M2 macrophages) and breast cancer cells. THP1 human leukemic monocytes were induced to differentiate into M2 macrophages by PMA (100 nM) and IL-4 (20 ng/mL). Quantitative RT-PCR and Western blot revealed that leptin (100 nM) significantly increased the expression of leptin receptor (ObR) in the M2 macrophages (P < 0.01) and stimulated interleukin (IL)-8 expression in the M2 macrophages, mouse macrophage cells RAW264.7, and primary mouse peritoneal macrophages in a dose- and time-dependent manner. Leptin-induced IL-8 production was sensitive to the ERK inhibitor PD980590 (10 μmol/L), p38 MAPK inhibitor SB203580 (20 μmol/L), and anti-ObR neutralizing antibody (4 μg/mL). Leptin (100 ng/mL) substantially increased the phosphorylation of p38 and ERK1/2. Thus, leptin may induce IL-8 production in M2 macrophages by interacting with ObR to activate the p38 and ERK signaling pathways. Scratch and transwell chamber assay showed that both recombinant IL-8 and leptin-induced M2 macrophage-derived IL-8 promoted the migration and invasion of human breast cancer cells MCF7 and MDA-MB-231 (All P < 0.01). In a nude mice xenograft model of breast cancer (n = 5 per group), injection of leptin (0.1 μg/g) dramatically increased tumor volume and mass, reduced survival, exacerbated pulmonary metastasis, and elevated IL-8 and Ki67 expression in the tumor tissue (All P < 0.05) compared with PBS injection. Depletion of mouse macrophage by Clophosome®-clodronate liposome and injection of anti-mouse IL-8 neutralizing antibodies in the xenograft tumor significantly attenuated those leptin-mediated stimulations (All P < 0.05). These findings indicate that leptin may promote tumor growth and metastasis by stimulating IL-8 production in tumor-associated macrophage.
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Hong
authors: H
authors: Cao
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Yunxiu
authors: Y
authors: Huang
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Lin
authors: L
authors: Wang
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Hong
authors: H
authors: Wang
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Xueli
authors: X
authors: Pang
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Kuangfa
authors: K
authors: Li
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Weiqi
authors: W
authors: Dang
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Hao
authors: H
authors: Tang
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Lan
authors: L
authors: Wei
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Min
authors: M
authors: Su
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Cuiping
authors: C
authors: Tang
authors: Department of Laboratory Medicine Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China.
authors: Tingmei
authors: T
authors: Chen
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D002454:Cell Differentiation; D002465:Cell Movement; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D000067996:RAW 264.7 Cells; D054411:Receptors, Leptin / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D016209:Interleukin-8; C515448:LEPR protein, human; D020738:Leptin; D054411:Receptors, Leptin; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate
keywords: IL-8; breast cancer; invasion; leptin; migration