CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling.
CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling.
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DOI：
10.1186/s12943-016-0542-2
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发表时间：
2016-09-09
期刊：
影响因子：
37.3
通讯作者：
Piché A
中科院分区：
文献类型：
--
作者：
Lane D;Matte I;Laplante C;Garde-Granger P;Carignan A;Bessette P;Rancourt C;Piché A
卵巢癌（OC）腹水存在于促炎肿瘤环境中，其特征是存在多种细胞因子、趋化因子和生长因子。腹水中这些炎症相关因子的存在与更具侵袭性的肿瘤表型相关。CCL18是CCL趋化因子中的一员，其表达与某些癌症的不良预后有关。然而，其在OC进展中的作用尚未确定。因此，本研究的目的是阐明腹水CCL18在卵巢癌进展中的作用。采用ELISA和组织芯片分别检测腹水中CCL18和癌组织中phospho-Pyk2的表达。用博伊登腔评估细胞迁移。利用siRNA和外源基因表达检测卵巢癌细胞中CCL18和腹水信号。在这里，我们发现CCL18水平在晚期浆液性OC腹水中明显高于良性女性的腹膜积液。腹水和CCL18剂量依赖性地增强了OC细胞系CaOV3和OVCAR3的迁移。腹水中CCL18水平与腹水促进细胞迁移的能力呈正相关。CCL18阻断抗体显著减弱腹水诱导的细胞迁移。腹水和CCL18刺激CaOV3和OVCAR3细胞中富脯氨酸酪氨酸激酶2 （Pyk2）的磷酸化。最重要的是，在浆液性OC肿瘤中磷酸化Pyk2的表达与较短的无进展生存期相关。此外，Pyk2的强制表达促进了肿瘤细胞的迁移，而sirna介导的Pyk2下调则减弱了细胞的迁移。下调Pyk2可显著抑制腹水和ccl18诱导的细胞迁移。综上所述，我们的研究结果确定了CCL18作为腹水的一个组成部分在肿瘤细胞迁移中的重要作用，并确定了Pyk2是腹水诱导的OC细胞迁移的预后因素和关键的下游信号通路。本文的在线版本（doi:10.1186/s12943-016-0542-2）包含补充材料，可供授权用户使用。
Ovarian cancer (OC) ascites consist in a proinflammatory tumor environment that is characterized by the presence of various cytokines, chemokines and growth factors. The presence of these inflammatory-related factors in ascites is associated with a more aggressive tumor phenotype. CCL18 is a member of CCL chemokines and its expression has been associated with poor prognosis in some cancers. However, its role in OC progression has not been established. Therefore, the aim of the current study was to elucidate the role of ascites CCL18 in OC progression. ELISA and tissue microarrays were used to assess CCL18 in ascites and phospho-Pyk2 expression in cancer tissues respectively. Cell migration was assessed using Boyden chambers. CCL18 and ascites signaling was examined in ovarian cancer cells utilizing siRNA and exogenous gene expression. Here, we show that CCL18 levels are markedly increased in advanced serous OC ascites relative to peritoneal effusions from women with benign conditions. Ascites and CCL18 dose-dependently enhanced the migration of OC cell lines CaOV3 and OVCAR3. CCL18 levels in ascites positively correlated with the ability of ascites to promote cell migration. CCL18 blocking antibodies significantly attenuated ascites-induced cell migration. Ascites and CCL18 stimulated the phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) in CaOV3 and OVCAR3 cells. Most importantly, the expression of phosphorylated Pyk2 in serous OC tumors was associated with shorter progression-free survival. Furthermore, enforced expression of Pyk2 promoted tumor cell migration while siRNA-mediated downregulation of Pyk2 attenuated cell migration. Downregulation of Pyk2 markedly inhibited ascites and CCL18-induced cell migration. Taken together, our findings establish an important role for CCL18, as a component of ascites, in the migration of tumor cells and identify Pyk2 as prognostic factor and a critical downstream signaling pathway for ascites-induced OC cell migration. The online version of this article (doi:10.1186/s12943-016-0542-2) contains supplementary material, which is available to authorized users.
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影响因子：
37.3
作者：
Keleg, Shereen;Buchler, Peter;Ludwig, Roman;Buchler, Markus W;Friess, Helmut
通讯作者：
Friess, Helmut
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.8
作者：
Lane D;Matte I;Rancourt C;Piché A
通讯作者：
Piché A
影响因子：
37.3
作者：
Goncharenko-Khaider N;Matte I;Lane D;Rancourt C;Piché A
通讯作者：
Piché A
DOI：
10.1073/pnas.1834348100
发表时间：
2003-09-16
影响因子：
11.1
作者：
Okigaki, M;Davis, C;Schlessinger, J
通讯作者：
Schlessinger, J