Cooperative roles of SDF-1α and EGF gradients on tumor cell migration revealed by a robust 3D microfluidic model.
Cooperative roles of SDF-1α and EGF gradients on tumor cell migration revealed by a robust 3D microfluidic model.
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DOI：
10.1371/journal.pone.0068422
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Kim BJ;Hannanta-anan P;Chau M;Kim YS;Swartz MA;Wu M
趋化因子介导的定向肿瘤细胞在三维（3D）基质内的迁移或化学侵袭是癌症转移的重要早期步骤。尽管它的临床重要性，这是在很大程度上是未知的细胞因子和生长因子梯度内的肿瘤微环境调节化疗侵袭。我们研究了肿瘤细胞的化学侵袭在良好定义和稳定的化学梯度使用一个强大的三维微流体模型。我们使用了CXCL 12（也称为SDF-1α）和表皮生长因子（EGF），这两种众所周知的细胞外信号分子共存于肿瘤微环境（例如淋巴结或血管内渗部位），以及嵌入I型胶原的恶性乳腺肿瘤细胞系MDA-MB-231。当单独接受SDF-1α梯度时，MDA-MB-231细胞沿梯度向上迁移，测得的化疗敏感性（定义为沿着梯度方向的平均细胞速度）遵循配体-受体（SDF-1α -CXCR 4）结合动力学。另一方面，当受到单独的EGF梯度，肿瘤细胞增加了他们的整体运动，但没有统计学上显着的趋化性（定向）迁移，在以前的报告中使用二维趋化性测定相反。有趣的是，我们发现，在EGF浓度均匀的情况下，SDF-1α梯度的化学侵袭行为被消除甚至逆转;然而，SDF-1α和EGF的存在共同调节肿瘤细胞的运动性。这些发现证明了我们的微流体模型在为细胞重新创建复杂微环境方面的能力，以及多种细胞因子和生长因子梯度在调节3D环境中细胞迁移方面的合作作用的重要性。
Chemokine-mediated directed tumor cell migration within a three dimensional (3D) matrix, or chemoinvasion, is an important early step in cancer metastasis. Despite its clinical importance, it is largely unknown how cytokine and growth factor gradients within the tumor microenvironment regulate chemoinvasion. We studied tumor cell chemoinvasion in well-defined and stable chemical gradients using a robust 3D microfluidic model. We used CXCL12 (also known as SDF-1α) and epidermal growth factor (EGF), two well-known extracellular signaling molecules that co-exist in the tumor microenvironment (e.g. lymph nodes or intravasation sites), and a malignant breast tumor cell line, MDA-MB-231, embedded in type I collagen. When subjected to SDF-1α gradients alone, MDA-MB-231 cells migrated up the gradient, and the measured chemosensitivity (defined as the average cell velocity along the direction of the gradient) followed the ligand – receptor (SDF-1α – CXCR4) binding kinetics. On the other hand, when subjected to EGF gradients alone, tumor cells increased their overall motility, but without statistically significant chemotactic (directed) migration, in contrast to previous reports using 2D chemotaxis assays. Interestingly, we found that the chemoinvasive behavior to SDF-1α gradients was abrogated or even reversed in the presence of uniform concentrations of EGF; however, the presence of SDF-1α and EGF together modulated tumor cell motility cooperatively. These findings demonstrate the capabilities of our microfluidic model in re-creating complex microenvironments for cells, and the importance of cooperative roles of multiple cytokine and growth factor gradients in regulating cell migration in 3D environments.
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影响因子：
3.8
作者：
Kim, Beum Jun;Wu, Mingming
通讯作者：
Wu, Mingming
影响因子：
2.5
作者：
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作者：
Hachet-Haas, Muriel;Balabanian, Karl;Galzi, Jean-luc
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粘着斑蛋白在三维细胞运动中的独特作用。
影响因子：
21.3
作者：
Fraley, Stephanie I.;Feng, Yunfeng;Krishnamurthy, Ranjini;Kim, Dong-Hwee;Celedon, Alfredo;Longmore, Gregory D.;Wirtz, Denis
通讯作者：
Wirtz, Denis
影响因子：
64.8
作者：
Laemmermann, Tim;Bader, Bernhard L.;Sixt, Michael
通讯作者：
Sixt, Michael