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: Y Li, L Cai, H Wang, P Wu, W Gu, Y Chen, H Hao, K Tang, P Yi, M Liu, S Miao, D Ye
• Journal: Oncogene (Oncogene) Vol. 30 Issue 36 Pg. 3887-99 (Sep 08 2011) ISSN: 1476-5594 [Electronic] England
• PMID: 21499310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FPR2 protein, human
• NF-kappa B
• Reactive Oxygen Species
• Receptors, CCR2
• Receptors, Formyl Peptide
• Receptors, Lipoxin

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Macrophages (cytology)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• Neoplasms (immunology, pathology)
• Reactive Oxygen Species
• Receptors, CCR2 (metabolism)
• Receptors, Formyl Peptide (metabolism)
• Receptors, Lipoxin (metabolism)
• Time Factors
• U937 Cells