Involvement of SDF-1α/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma
Involvement of SDF-1α/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma
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DOI：
10.1002/ijc.23083
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发表时间：
2008-01-01
影响因子：
6.4
通讯作者：
Kikkawa, Fumitaka
中科院分区：
文献类型：
--
作者：
Kajiyama, Hiroaki;Shibata, Kiyosumi;Kikkawa, Fumitaka
上皮性卵巢癌（EOC）通过肿瘤细胞植入腹膜腔内衬的人腹膜间皮细胞（HPMCs）而扩散。本研究的目的是确定是否基质细胞衍生因子-1 α（SDF-1 α）/CXCR 4轴参与卵巢癌细胞与腹膜转移HPMCs的相互作用。在临床上，我们首先使用免疫组织化学方法评估了36例原发性EOCs切片中CXCR 4的表达。我们接下来检查了SDF-1 α是否在EOC进展中发挥作用，包括增殖、细胞运动、与HPMC的附着以及通过CXCR 4的腹膜转移的体内发展。36例乳腺癌中CXCR 4阳性表达16例（44.4%）。与阴性表达相比，CXCR 4阳性表达显著预测较差的总生存期（p = 0.0069）。我们发现CXCR 4在EOC细胞和HPMCs中均有表达。与此相反，由HPMCs产生的SDF-1 α的水平高于各种EOC细胞。在功能上，SDF-1 α诱导ES-2细胞与HPMC或细胞外基质成分之间的附着增强。CXCR 4拮抗剂AMD 3100、磷脂酰肌醇3激酶和p44/42抑制剂可抑制SDF-1 α对粘附潜力的增强作用。此外，用AMD 3100腹膜内处理导致接种ES-2细胞的裸鼠中的播散减少。目前的研究结果表明，SDF-1 α/CXCR 4轴和增强的腹膜内扩散EOC之间可能存在联系，CXCR 4可能是治疗EOC的新靶点。(C)2007 Wiley-Liss，Inc.
Epithelial ovarian carcinoma (EOC) spreads by implantation of tumor cells onto the human peritoneal mesothelial cells (HPMCs) lining the peritoneal cavity. The aim of this study was to determine whether the stromal cell-derived factor-1 alpha (SDF-1 alpha)/CXCR4 axis is involved in the interaction of EOC cells with HPMCs in peritoneal metastasis. Clinically, we first evaluated CXCR4 expression in sections from 36 primary EOCs using immunohistochemistry. We next examined whether SDF-1 alpha played roles in EOC progression, including in proliferation, cell motility, attachment to HPMCs, and the in vivo development of peritoneal metastasis through CXCR4. Of the 36 carcinomas, 16 cases (44.4%) were positive for CXCR4 immunoexpression. Positive CXCR4 expression significantly predicted poorer overall survival compared with negative expression (p = 0.0069). We found CXCR4 expression in both EOC cells and HPMCs. In contrast, the level of production of SDF-1 alpha by HPMCs was higher than that by various EOC cells. Functionally, SDF-1 alpha induced enhanced attachment between ES-2 cells and HPMCs or extracellular matrix components. The enhancement of adhesion potential by SDF-1 alpha was inhibited by AMD3100, a CXCR4 antagonist, and by phosphatidylinositol 3 kinase and p44/42 inhibitors. Furthermore, intraperitoneal treatment with AMD3100 resulted in reduced dissemination in nude mice inoculated with ES-2 cells. The present results suggest that there may be a link between the SDF-1 alpha/CXCR4 axis and enhanced intraperitoneal dissemination of EOC and that CXCR4 may be a novel target for the treatment of EOC. (C) 2007 Wiley-Liss, Inc.