Low-dose paclitaxel suppresses the induction of M2 macrophages in gastric cancer
Low-dose paclitaxel suppresses the induction of M2 macrophages in gastric cancer
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DOI：
10.3892/or.2017.5586
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发表时间：
2017-06-01
期刊：
影响因子：
4.2
通讯作者：
Ohta, Tetsuo
中科院分区：
文献类型：
--
作者：
Yamaguchi, Takahisa;Fushida, Sachio;Ohta, Tetsuo
M2表型的肿瘤相关巨噬细胞促进肿瘤增殖，并与各种恶性肿瘤患者（包括伴有腹膜播散的胃癌）的不良预后相关。本研究评估了紫杉醇（PTX）是否通过作为Toll样受体4（TLR 4）激动剂抑制M2巨噬细胞。将来源于THP-1单核细胞系的巨噬细胞和来源于外周血单核细胞（PBMC）的巨噬细胞与胃癌细胞一起在含有PTX的培养基中培养，PTX的浓度不影响细胞增殖。通过蛋白质印迹法评价PTX对M2巨噬细胞标志物CD 204和M1巨噬细胞标志物NOS 2的巨噬细胞表达的影响。通过评估NF-κ B的p65亚基的表达来确定PTX刺激NF-κ B核内易位的能力。在THP-1巨噬细胞中，低剂量PTX（1和5 nM）抑制CD 204的表达，增强NOS 2的表达，并显著抑制STAT 3的磷酸化，这是M2表型所必需的。低剂量PTX还抑制来源于PBMC的原代巨噬细胞中的CD 204表达。PTX处理THP-1巨噬细胞1小时诱导NF-κ B p65显著核内易位。低剂量PTX通过TLR 4信号传导抑制M2表型并诱导Ml表型，表明低剂量PTX可以改变巨噬细胞表型，而临床剂量可以杀死癌细胞。这些结果表明，PTX的抗癌作用是由于其细胞毒性和免疫调节活性。
Tumor-associated macrophages of the M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with various malignancies, including gastric cancer with peritoneal dissemination. The present study assessed whether paclitaxel (PTX) suppresses M2 macrophages, by acting as a Toll-like receptor 4 (TLR4) agonist. Macrophages derived from the THP-1 monocytic cell line and peripheral blood mononuclear cell (PBMC)-derived macrophages were cultured with gastric cancer cells in medium containing PTX, at a concentration that did not affect cell proliferation. The effects of PTX on macrophage expression of CD204, a marker of M2 macrophages and NOS2, a marker of M1 macrophages, was evaluated by western blotting. The ability of PTX to stimulate intranuclear translocation of NF-kappa B was determined by evaluating the expression of the p65 subunit of NF-kappa B. In THP-1 macrophages, low-dose PTX (1 and 5 nM) inhibited the expression of CD204, enhanced the expression of NOS2, and significantly suppressed the phosphorylation of STAT3, which is essential for the M2 phenotype. Low-dose PTX also inhibited CD204 expression in primary macrophages derived from PBMCs. PTX treatment of THP-1 macrophages for 1 h induced marked intranuclear translocation of NF-kappa B p65. Low-dose PTX inhibited the M2 phenotype and induced the Ml phenotype via TLR4 signaling, suggesting that low-dose PTX can alter the macrophage phenotype, whereas clinical doses can kill cancer cells. These results suggest that the anticancer effects of PTX are due both to its cytotoxic and immunomodulatory activities.