title: Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2.
abstract: Cancer cells recruit monocytes, macrophages and other inflammatory cells by producing abundant chemoattractants and growth factors, such as macrophage colony-stimulating factor (M-CSF/CSF-1) and monocyte chemoattractant protein-1 (MCP-1/CCL2), to promote tumor growth and dissemination. An understanding of the mechanisms that target cancer cells and regulate tumor microenvironment is essential in designing anticancer therapies. Here, we showed that serum amyloid-A (SAA) and cathelicidin (LL-37) stimulated M-CSF and MCP-1 expression with or without lipopolysaccharide (LPS) administration; conversely, lipoxin-A(4) (LXA(4)) and annexin-A1 (ANXA1) inhibited LPS-induced M-CSF and MCP-1 production by human (HepG2) and mouse (H22) hepatocellular carcinoma cells (HCCs). The effects of LXA(4), ANXA1, SAA and LL-37 were dependent on the activation of their mutual cell-surface receptor formyl peptide receptor-2 (FPR2) and subsequent ROS-MAPK-NF-kB signalings. Furthermore, our results indicated that LPS switched macrophages into an IL-10(low)IL-12(high) M1 profile, whereas M-CSF+MCP-1 and FPR2 agonists skewed them into M2 (IL-10(high)IL-12(low)). In that respect, through modulating the phosphorylation of signal transducer and activator of transcription-3 (STAT3), LXA(4) and ANXA1 induced monocyte differentiation into M2a+M2c-like cells and showed antitumorigenetic activities, whereas SAA, LL-37 and M-CSF+MCP-1 led to M2b- or M2d-like polarization, which exacerbated HCC invasion in vitro and in vivo, respectively. Our results suggest that FPR2 has an appreciable pleiotropic regulator role in tumor immunoediting.
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China. yli@zeus.bwh.harvard.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Cai
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Wu
authors.forename: W
authors.initials: W
authors.lastname: Gu
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Hao
authors.forename: K
authors.initials: K
authors.lastname: Tang
authors.forename: P
authors.initials: P
authors.lastname: Yi
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Miao
authors.forename: D
authors.initials: D
authors.lastname: Ye
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2 / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D013997:Time Factors; D020298:U937 Cells
chemical_list: C105101:FPR2 protein, human; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin