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

Oncogene volume 30, pages 3887–3899 (2011)Cite this article

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A Corrigendum to this article was published on 20 October 2011

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-A4 (LXA4) 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 LXA4, 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-10lowIL-12high M1 profile, whereas M-CSF+MCP-1 and FPR2 agonists skewed them into M2 (IL-10highIL-12low). In that respect, through modulating the phosphorylation of signal transducer and activator of transcription-3 (STAT3), LXA4 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.

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Acknowledgements

We thank Professor Charles N Serhan for helpful comments about FPR2. We also appreciate all anonymous reviewers for helpful suggestions on quality improvement of the paper. This work was supported by China Scholarship Council Fellowship No. 2009616073 and National Natural Science Foundation of China Grants 30570726 and 30772154.

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  1. Department of Pathophysiology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China

    Y Li, L Cai, P Wu, W Gu, H Hao, K Tang, P Yi, M Liu, S Miao & D Ye

  2. Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Boston, MA, USA

    Y Li

  3. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    H Wang

  4. Biomedical Information Technology Laboratory, Graduate School of Computer Science and Engineering, the University of Aizu, Aizu, Japan

    Y Chen

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Li, Y., Cai, L., Wang, H. et al. Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2. Oncogene 30, 3887–3899 (2011). https://doi.org/10.1038/onc.2011.112

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