Abstract
M2-like polarized tumor-associated macrophages (TAMs) play a pivotal role in promoting cancer cell growth, invasion, metastasis and angiogenesis. The identification of M2-like TAMs during tumor progression is an attractive approach for cancer therapy. In this study, we investigated the relevance of macrophage polarization and the antitumor effect of gefitinib in Lewis Lung cancer (LLC) in vitro and in vivo. Gefitinib at a concentration below 2.5 μmol/L did not cause significant growth inhibition on LLC and RAW 264.7 cell lines and bone marrow-derived macrophage (BMDMs). However, a small concentration of gefitinib (0.62 μmol/L) significantly inhibited IL-13-induced M2-like polarization of macrophages, evidenced by the decreased expression of the M2 surface markers CD206 and CD163, down-regulation of specific M2-marker genes (Mrc1, Ym1, Fizz1, Arg1, IL-10 and CCL2) as well as inhibition of M2-like macrophage-mediated invasion and migration of LLC cells. In RAW 264.7 cells, gefitinib inhibits IL-13-induced phosphorylation of STAT6, which was a crucial signaling pathway in macrophage M2-like polarization. In LLC mice metastasis model, oral administration of gefitinib (75 mg·kg−1·d−1, for 21 d) significantly reduced the number of lung metastasis nodules, down-regulated the expression of M2 marker genes and the percentages CD206+ and CD68+ macrophages in tumor tissues. These results demonstrated that gefitinib effectively inhibits M2-like polarization both in vitro and in vivo, revealing a novel potential mechanism for the chemopreventative effect of gefitinib.
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We also acknowledge Zhejiang University for providing a scholarship for PhD studies to Mr Muhammad TARIQ.
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Tariq, M., Zhang, Jq., Liang, Gk. et al. Gefitinib inhibits M2-like polarization of tumor-associated macrophages in Lewis lung cancer by targeting the STAT6 signaling pathway. Acta Pharmacol Sin 38, 1501–1511 (2017). https://doi.org/10.1038/aps.2017.124
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DOI: https://doi.org/10.1038/aps.2017.124
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