Microfluidic platform for tumor cell invasion

项目摘要 癌症转移占所有癌症死亡的90%以上。癌症转移级联过程中的一个限制步骤是 使肿瘤细胞向血管壁迁移，与血管壁相互作用，并挤过血管壁 通过血液循环扩散到继发性肿瘤部位。生物物理力，包括间隙和 壁间流动，已被证明在调节黏附分子、空间细胞因子方面发挥关键作用 分布和组织结构；所有这些都有助于3D BioMatrix内的肿瘤细胞侵袭。尽管 生物物理力在肿瘤细胞跨内皮细胞迁移中的临床意义和作用较差 明白了。这在一定程度上是由于缺乏能够跟踪肿瘤细胞迁移的体外工具。 实时事件，并有良好控制的生物流动。目前的动物细胞侵袭试验，博伊登 由于很难重建复杂的肿瘤微环境，因此腔室是有限的。此外，结果显示， 在两个时间终点以人口为基础。活体成像极大地促进了我们对 关于在生理上真实的环境下肿瘤微环境和瞬变电磁场之间的相互作用。然而， 很难分析单独的环境线索对瞬变电磁过程的贡献。世界银行的目标是 建议的研究是开发一种具有良好控制肿瘤的生理上真实的微流体模型。 用于研究肿瘤细胞的透射电子显微镜过程的微环境；以及识别 促进电子显微镜的发展。为了实现这些目标，我们将开发一个有机类型的实时微流体模型 可控微环境下肿瘤细胞的透射电子显微镜成像。我们将使用 球体和细胞流事件，以指导透射电子显微镜成像部位。使用微流体模型，我们将 良好控制下单个肿瘤细胞特性与透射电子显微镜活性关系的探讨 间质和壁间血流。PI实验室和其他人之前的研究表明，间质 在3D BioMatrix中，流动对肿瘤细胞的迁移起着至关重要的调节作用。在这里，我们假设肿瘤细胞 瞬变电磁能力与细胞的微环境密切相关，包括流体流动。建议数 该项目具有创新性，因为它代表了第一代有机型微流控平台， 包括间质和壁内流动，将当前的微流体肿瘤模型向 生理上真实的方向。在这里学到的经验教训最终将导致对 开发癌症的新诊断或/和治疗策略。该平台可以很容易地扩展 用于TEM很重要的其他生物系统，包括免疫细胞贩运。

Project Summary Cancer metastasis accounts for over 90% of all cancer deaths. A limiting step in cancer metastatic cascade is for tumor cells to migrate towards, interact with and squeeze through the blood vessel wall before disseminating to secondary tumor sites via the blood circulation. Biophysical forces, including interstitial and intramural flows, have shown to play critical roles in regulating adhesion molecules, spatial cytokine distributions and tissue architecture; all of which contribute to tumor cell invasion within 3D biomatrix. Despite the clinical importance, roles of biophysical forces in tumor cell transendothelial migration (TEM) are poorly understood. This is in part due to the lack of in vitro tools that are able to follow tumor cell transmigration events in real time, and with well controlled biological flows. Current animal cell invasion assay, the Boyden Chamber, is limited because it is difficult to recreate complex tumor microenvironment. In addition, the results are population based at two time end points. Intravital imaging has advanced significantly our understanding about the interplays between tumor microenvironment and TEM in a physiologically realistic setting. However, it is difficult to dissect the contribution of individual environmental cues to TEM processes. The goals of the proposed research are to develop a physiologically realistic microfluidic model with well controlled tumor microenvironment for studies of tumor cell TEM processes; and to identify tumor microenvironment that promotes TEM. To achieve these goals, we will develop an organotypic microfluidic model for real time imaging of tumor cell TEM events under well controlled micro-environment. We will use the location of spheroid and cell streaming event to guide TEM imaging sites. Using the microfluidic model, we will explore the relations between single tumor cell properties and TEM activities under well controlled interstitial and intramural flows. Previous work from the PI’s lab and others have indicated that interstitial flows critically regulate tumor cell migration within 3D biomatrix. Here, we hypothesize that tumor cells’ TEM capabilities are closed correlated with cells’ microenvironment including fluid flows. The proposed project is innovative because it represents the first generation of organotypic microfluidic platform that includes both interstitial and intramural flows, moving the current microfluidic tumor model towards a physiologically realistic direction. Lessons learned here will eventually lead to knowledge important for developing novel diagnostic or/and treatment strategies for cancer. This platform can be readily extended for use in other biological systems where TEMs are important including immune cell trafficking.