Department of Neurobiology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Int J Gynecol Cancer. 2011 May;21(4):616-24. doi: 10.1097/IGC.0b013e3182150e98.
Tumor-associated macrophage infiltration and up-regulation of tissue factor-factor VII (TF-FVIIa) complex have been observed in the peritoneum and stroma of epithelial ovarian cancer (EOC). However, it is not clear how tumor-associated macrophage and TF-FVIIa complex promotes EOC invasion. In the present study, we aimed to determine the mechanism by which interaction of TF-FVIIa and monocytes (MOs) promotes EOC metastasis.
Matrigel invasion assay was used to analyze the potential of EOC metastasis. Enzyme-linked immunosorbent assay and real-time polymerase chain reaction were used to detect expressions of cytokines and chemokines. Fluorescence-activated cell sorting was used to count the percentage of CD14, CD68, and CD163 of MOs.
We found that the TF-FVIIa complex caused dynamic changes in MOs cytokine and chemokine expression. CD14 and CD163 were also upregulated on MOs by TF-FVIIa. Epithelial ovarian cancer cells were cocultured with TF-FVIIa-stimulated MOs, demonstrating increased invasion potential. Interleukin 8 (IL-8) was proposed as the major chemoattractant mediating EOC invasion based on MOs messenger RNA and protein expression profiles. Anti-IL-8 monoclonal neutralizing antibody attenuated EOC cell invasion in a concentration-dependent manner, and tumor necrosis factor α from TF-FVIIa-stimulated MOs was observed to amplify IL-8 production. The following transcription factors in MOs were activated by TF-FVIIa and inhibited by the tissue factor pathway inhibitor: oncogenes HIF-1α, HIF-1β, Oct I, Oct II, and Egr-1; inflammatory mediators c-Fos and c-Rel; and STAT family members STAT5A and STAT5B.
Our study suggested that the interaction between the TF-FVIIa complex might play a role in mediating EOC invasion and metastasis depending on MOs mechanism.
在卵巢上皮癌（EOC）的腹膜和基质中观察到肿瘤相关巨噬细胞浸润和组织因子-因子 VII（TF-FVIIa）复合物上调。然而，肿瘤相关巨噬细胞和 TF-FVIIa 复合物如何促进 EOC 侵袭尚不清楚。本研究旨在确定 TF-FVIIa 与单核细胞（MOs）相互作用促进 EOC 转移的机制。
采用 Matrigel 侵袭实验分析 EOC 转移的潜力。酶联免疫吸附试验和实时聚合酶链反应检测细胞因子和趋化因子的表达。荧光激活细胞分选术计数 MOs 中 CD14、CD68 和 CD163 的百分比。
我们发现 TF-FVIIa 复合物引起 MOs 细胞因子和趋化因子表达的动态变化。TF-FVIIa 还上调了 MOs 的 CD14 和 CD163。上皮性卵巢癌细胞与 TF-FVIIa 刺激的 MOs 共培养，显示出增加的侵袭潜力。根据 MOs 信使 RNA 和蛋白表达谱，白细胞介素 8（IL-8）被提出为主要趋化因子介导 EOC 侵袭。抗 IL-8 单克隆中和抗体以浓度依赖的方式减弱 EOC 细胞侵袭，并且观察到 TF-FVIIa 刺激的 MOs 中的肿瘤坏死因子α放大了 IL-8 的产生。TF-FVIIa 激活了 MOs 中的以下转录因子，并抑制了组织因子途径抑制剂：癌基因 HIF-1α、HIF-1β、Oct I、Oct II 和 Egr-1；炎症介质 c-Fos 和 c-Rel；和 STAT 家族成员 STAT5A 和 STAT5B。
我们的研究表明，TF-FVIIa 复合物的相互作用可能通过 MOs 机制在介导 EOC 侵袭和转移中发挥作用。
