1. Department of Urology, University of Pittsburgh School of Medicine, Shadyside Medical Center, 5200 Centre Avenue, Pittsburgh, PA 15232, USA.
J Cancer. 2013 Jun 21;4(5):383-90. doi: 10.7150/jca.6545. Print 2013.
Our previous research has shown that plasma fibronectin promotes lung metastasis by facilitating tumor cell invasion in clotted plasma. To evaluate the role of clotted plasma for tumor cell survival, we treated B16F1 cells embedded in a 3-dimensional matrix of fibrin with tumor necrosis factor α (TNFα), a cytokine with anti-tumor activity. Under these conditions, TNFα caused significant cytotoxicity, which was prevented when we added plasma fibronectin to the fibrin clot. Fibronectin-mediated TNFα resistance was dependent on PI3-kinase, which also mediated the pro-adhesive and pro-invasive effects of plasma fibronectin on tumor cells. To further investigate the role of plasma fibronectin in tumor cell signaling, we performed a gene array that showed specific upregulation of Tie2 in B16F1 cells embedded in fibrin-fibronectin compared to fibrin. Importantly, inhibition of Tie2 resulted in decreased tumor cell invasion, reduced colony formation and increased tumor cell death in response to TNFα. Together, our findings indicate that plasma fibronectin induces tumor cell invasion and protects tumor cells from the cytotoxic effects of inflammatory mediators through up-regulation of Tie2.
我们之前的研究表明，纤维连接蛋白可通过促进凝固血浆中的肿瘤细胞侵袭，从而促进肺转移。为了评估凝固血浆对肿瘤细胞存活的作用，我们用肿瘤坏死因子α（TNFα）处理嵌入纤维蛋白三维基质中的 B16F1 细胞，TNFα 是一种具有抗肿瘤活性的细胞因子。在这些条件下，TNFα 引起了明显的细胞毒性，而当我们向纤维蛋白凝块中添加纤维连接蛋白时，这种毒性就被阻止了。纤维连接蛋白介导的 TNFα 耐药性依赖于 PI3-激酶，该激酶还介导纤维连接蛋白对肿瘤细胞的促黏附和促侵袭作用。为了进一步研究纤维连接蛋白在肿瘤细胞信号转导中的作用，我们进行了基因芯片分析，结果显示与纤维蛋白相比，嵌入纤维蛋白-纤维连接蛋白中的 B16F1 细胞中 Tie2 的特异性上调。重要的是，抑制 Tie2 导致肿瘤细胞侵袭减少、集落形成减少和对 TNFα 的细胞死亡增加。总之，我们的研究结果表明，纤维连接蛋白通过上调 Tie2 诱导肿瘤细胞侵袭，并保护肿瘤细胞免受炎症介质的细胞毒性作用。
