Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation
Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation
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DOI：
10.1111/j.1349-7006.2010.01652.x
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发表时间：
2010-10-01
期刊：
影响因子：
5.7
通讯作者：
Takeya, Motohiro
中科院分区：
文献类型：
--
作者：
Takaishi, Kiyomi;Komohara, Yoshihiro;Takeya, Motohiro
晚期上皮性卵巢癌（AdEOC）中的腹水巨噬细胞通过改变肿瘤微环境参与癌症转移和进展。然而，巨噬细胞和肿瘤细胞之间的细胞间相互作用的确切机制仍不清楚。本研究的重点是激活信号转导和转录激活因子3（Stat 3），这是一个关键的信号转导分子，在一个点的收敛，为许多致癌信号通路，以及控制M2-穿孔的巨噬细胞。AdEOC腹水中检测到高浓度的白细胞介素（IL）-6、IL-10、生长相关癌基因-α和血管内皮生长因子，其刺激人卵巢癌细胞系SKOV 3的增殖。通过中和抗体同时阻断IL-6和IL-10抑制腹水诱导的肿瘤细胞增殖。与巨噬细胞共培养可诱导SKOV 3细胞中Stat 3的活化，尤其是与巨噬细胞集落刺激因子致敏的M2巨噬细胞共培养，但与粒细胞-巨噬细胞集落刺激因子致敏的未成熟巨噬细胞共培养的程度较低。与巨噬细胞共培养也显著诱导SKOV 3细胞中Cyclin-D1的表达。通过小干扰RNA阻断巨噬细胞中的Stat 3，抑制巨噬细胞产生IL-6和IL-10，并抑制共培养的SKOV 3细胞中Stat 3活化和cyclin-D1诱导。通过同时中和IL-6和IL-10消除SKOV 3细胞中的Stat 3活化。这些结果表明，IL-6和IL-10激活Stat 3在AdEOC腹水中肿瘤细胞和巨噬细胞之间的细胞间相互作用中起重要作用。（Cancer Sci 2010）。
Ascites macrophages in advanced epithelial ovarian cancer (AdEOC) are involved in cancer metastasis and progression by modifying the tumor microenvironment. However, the precise mechanisms of cell-to-cell interaction between macrophages and tumor cells are still unclear. This study focused on the activation of signal transducer and activator of transcription 3 (Stat3) which is a critical signal transduction molecule at a point of convergence for numerous oncogenic signaling pathways as well as controlling the M2-poralization of macrophages. AdEOC ascites, in which high concentration of interleukin (IL)-6, IL-10, growth-related oncogene-alpha and vascular endothelial growth factor were detected, stimulated the proliferation of SKOV3 cells, a human ovarian cancer cell line. The simultaneous blocking of IL-6 and IL-10 by neutralizing antibodies suppressed ascites-induced tumor cell proliferation. Stat3 activation in SKOV3 cells was induced by co-culture with macrophages especially with macrophage colony stimulating factor-primed M2 macrophages but lesser extent with granulocyte-macrophage colony stimulating factor-primed immature macrophages. Cyclin-D1 expression in SKOV3 cells was also significantly induced by co-culture with macrophages. Blocking of Stat3 in macrophages by small interfering RNA inhibited the production of IL-6 and IL-10 by macrophages, and suppressed Stat3 activation and cyclin-D1 induction in co-cultured SKOV3 cells. Stat3 activation in SKOV3 cells was abrogated by simultaneous neutralization of IL-6 and IL-10. These results indicate that Stat3 activation by IL-6 and IL-10 plays an important role in cell-to-cell interaction between tumor cells and macrophages in the ascites of AdEOC. (Cancer Sci 2010).