Jones Jon, Marian Dana, Weich Eva, Engl Tobias, Wedel Steffen, Relja Borna, Jonas Dietger, Blaheta Roman A
Klinik für Urologie und Kinderurologie, Zentrum der Chirurgie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Exp Cell Res. 2007 Nov 15;313(19):4051-65. doi: 10.1016/j.yexcr.2007.07.001. Epub 2007 Jul 10.
The mechanisms leading to renal cell carcinoma (RCC) metastasis are incompletely understood. Although evidence shows that the chemokine receptor CXCR4 and its ligand CXCL12 may regulate tumor dissemination, their role in RCC is not clearly defined. We examined CXCR4 expression and functionality on RCC cell lines, and explored CXCL12-triggered tumor adhesion to human endothelium (HUVEC) or extracellular matrix proteins. Functional CXCR4 was expressed on A498 tumor cells, enabling them to migrate towards a CXCL12 gradient. CXCR4 engagement by CXCL12 induced elevated cell adhesion to HUVEC, to immobilized fibronectin, laminin or collagen. Anti-CXCR4 antibodies or CXCR4 knock down by siRNA applied prior to CXCL12 stimulation impaired CXCL12-triggered tumor adhesion. However, blocking CXCR4 subsequent to CXCL12 stimulation did not. This pointed to an indirect control of tumor cell adhesion by CXCR4. In fact, CXCR4 engagement by CXCL12 also induced alterations of receptors of the integrin family, notably alpha3, alpha5, beta1 and beta3 subunits, and blocking beta1 integrins with a function-blocking antibody prevented CXCL12-induced A498 adhesion. Focal adhesion kinase (total and activated) and integrin-linked kinase significantly increased in CXCL12-treated A498 cells, accompanied by a distinct up-regulation of ERK1/2, JNK and p38 phosphorylation. Therefore, CXCR4 may be crucial in controlling adhesion of A498 cells via cross talking with integrin receptors. These data show that CXCR4 receptors contribute to RCC dissemination and may provide a novel link between CXCR4 chemokine receptor expression and integrin triggered RCC adhesion to the vascular wall and subendothelial matrix components.
导致肾细胞癌（RCC）转移的机制尚未完全明确。尽管有证据表明趋化因子受体CXCR4及其配体CXCL12可能调节肿瘤扩散，但其在RCC中的作用尚不清楚。我们检测了RCC细胞系上CXCR4的表达和功能，并探究了CXCL12引发的肿瘤与人内皮细胞（HUVEC）或细胞外基质蛋白的黏附。功能性CXCR4在A498肿瘤细胞上表达，使其能够朝着CXCL12梯度迁移。CXCL12与CXCR4结合会导致细胞与HUVEC、固定化纤连蛋白、层粘连蛋白或胶原蛋白的黏附增加。在CXCL12刺激之前应用抗CXCR4抗体或通过siRNA敲低CXCR4会损害CXCL12引发的肿瘤黏附。然而，在CXCL12刺激之后阻断CXCR4则不会。这表明CXCR4对肿瘤细胞黏附起间接调控作用。事实上，CXCL12与CXCR4结合还会诱导整合素家族受体发生改变，尤其是α3、α5、β1和β3亚基，用功能阻断抗体阻断β1整合素可阻止CXCL12诱导的A498细胞黏附。在经CXCL12处理的A498细胞中，黏着斑激酶（总蛋白和活化形式）以及整合素连接激酶显著增加，同时ERK1/2、JNK和p38磷酸化明显上调。因此，CXCR4可能通过与整合素受体相互作用在控制A498细胞黏附方面起关键作用。这些数据表明CXCR4受体有助于RCC扩散，并可能在CXCR4趋化因子受体表达与整合素引发的RCC与血管壁及内皮下基质成分的黏附之间提供新的联系。
