Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

• Published in: Oncogene Vol. 30; no. 36; pp. 3887 - 3899
• Main Authors: Li, Y, Cai, L, Wang, H, Wu, P, Gu, W, Chen, Y, Hao, H, Tang, K, Yi, P, Liu, M, Miao, S, Ye, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-09-2011; Nature Publishing Group
• Subjects: 631/67/580/1884/2323; 692/420/755; 692/698/690/292; 692/699/67/1504/1610; Amyloid; Animals; Apoptosis; Biological and medical sciences; Cancer; cathelicidins; Cell activation; Cell Biology; Cell differentiation; Cell Line; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell receptors; Cell structures and functions; Cell surface; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells; Chemotactic factors; Colony-stimulating factor; Differentiation; Female; formyl peptides; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Growth factors; Hep G2 Cells; Hepatocellular carcinoma; Human Genetics; Humans; Inflammation; Internal Medicine; Lipopolysaccharides; Lipoxin A4; Macrophage colony-stimulating factor; Macrophages - cytology; MAP kinase; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Microenvironments; Miscellaneous; Molecular and cellular biology; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Neoplasms - immunology; Neoplasms - pathology; Neurons; NF-kappa B - metabolism; NF-κB protein; Oncology; original-article; Peptides; Phosphorylation; Polarization; Reactive Oxygen Species; Receptors, CCR2 - metabolism; Receptors, Formyl Peptide - metabolism; Receptors, Lipoxin - metabolism; Stat3 protein; Time Factors; Transcription; Tumor microenvironment; Tumorigenesis; Tumors; U937 Cells; Japan; monocyte chemoattractant protein-1; macrophages; tumorigenesis; formyl peptide receptor-2; macrophage colony-stimulating factor; Polarization; Monocyte; Peptides; Carcinogenesis; Protein; Pleiotropy; Regulation(control); Macrophage colony stimulating factor; Macrophage; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.112

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-
k
B 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.