Antitumor and Antimetastatic Activity of Synthetic Hydroxystilbenes Through Inhibition of Lymphangiogenesis and M2 Macrophage Differentiation of Tumor-associated Macrophages.
Antitumor and Antimetastatic Activity of Synthetic Hydroxystilbenes Through Inhibition of Lymphangiogenesis and M2 Macrophage Differentiation of Tumor-associated Macrophages.
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DOI：
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发表时间：
2016
影响因子：
2
通讯作者：
Y. Kimura;M. Sumiyoshi;K. Baba
中科院分区：
文献类型：
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作者：
Y. Kimura;M. Sumiyoshi;K. Baba
肿瘤微环境周围肿瘤相关巨噬细胞（TAM）的增加与癌症患者的不良预后密切相关，M2 TAM通过刺激肿瘤中的血管生成或淋巴管生成促进肿瘤生长和肿瘤转移。我们在此研究了9种合成羟基芪类化合物对M2巨噬细胞活化和分化的影响，以及3种选择的二羟基芪类化合物对血管内皮细胞生长因子（VEGF）-C诱导的人淋巴管内皮细胞（HLEC）管形成的影响（体外）。我们还研究了三种合成的二羟基芪类化合物在荷LM 8小鼠体内的抗肿瘤和抗转移作用。三种选定的合成芪类化合物（浓度为5、10、25和50 μM）抑制M2巨噬细胞中白细胞介素-10和单核细胞趋化蛋白-1的产生，但促进转化生长因子-β1的产生。三种二羟基芪类化合物（浓度为10-50 μM）抑制M2巨噬细胞分化过程中信号转导子和转录激活子3的磷酸化，但不影响其表达。此外，2，3-和4，4 '-二羟基二苯乙烯抑制VEGF-C诱导的HLEC中的淋巴管生成。2，3-和4，4 '-二羟基芪（10和25 mg/kg，每日两次）均抑制小鼠肿瘤生长和肺转移。这些结果提示，2，3-和4，4 '-二羟基二苯乙烯的抗肿瘤和抗转移作用部分是通过抑制淋巴管生成和调节M2巨噬细胞的活化和分化而实现的。
An increase in tumor-associated macrophages (TAMs) around the tumor microenvironment has been closely associated with a poor prognosis in patients with cancer, and M2 TAMs promote tumor growth and tumor metastasis by stimulating angiogenesis or lymphangiogenesis in tumors. We herein examined the effects of nine synthetic hydroxystilbenes on M2 macrophage activation and differentiation, and three selected dihydroxystilbenes on vascular endothelial cell growth factor (VEGF)-C-induced tube formation in human lymphatic endothelial cells (HLECs) (in vitro). We also investigated the antitumor and antimetastatic effects of three synthetic dihydroxystilbenes in LM8-bearing mice in vivo. The three selected synthetic stilbenes (at concentrations of 5, 10, 25, and 50 μM) inhibited the production of interleukin-10 and monocyte chemoattractant protein-1 in M2 macrophages, but promoted that of transforming growth factor-β1. The three dihydroxystilbenes (at concentrations of 10-50 μM) inhibited the phosphorylation of signal transducer and activator of transcript 3 without affecting its expression in the differentiation of M2 macrophages. Furthermore, the 2,3- and 4,4'-dihydroxystilbene inhibited VEGF-C-induced lymphangiogenesis in HLECs. Both 2,3- and 4,4'-dihydroxystilbene (at 10 and 25 mg/kg, twice daily) inhibited tumor growth and metastasis to the lung in mice. These results suggested that the antitumor and antimetastatic effects of 2,3- and 4,4'-dihydroxystilbene were partly due to anti-lymphangiogenesis, and the regulation of M2 macrophage activation and differentiation.