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首页> 外文期刊>The Analyst: The Analytical Journal of the Royal Society of Chemistry: A Monthly International Publication Dealing with All Branches of Analytical Chemistry >A spatiotemporally defined in vitro microenvironment for controllable signal delivery and drug screening
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A spatiotemporally defined in vitro microenvironment for controllable signal delivery and drug screening

机译：时空定义的体外微环境，可控制信号传递和药物筛选

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摘要

Cancer metastasis and drug resistance are important malignant tumor phenotypes that cause roughly 90% mortality in human cancers. Current therapeutic strategies, however, face substantial challenges partially due to a lack of applicable pre-clinical models and drug-screening platforms. Notably, microscale and three-dimensional (3D) tissue culture platforms capable of mimicking in vivo microenvironments to replicate physiological conditions have become vital tools in a wide range of cellular and clinical studies. Here, we present a microfluidic device capable of mimicking a configurable tumor microenvironment to study in vivo-like cancer cell migration as well as screening of inhibitors on both parental tumors and migratory cells. In addition, a novel evaporation-based paper pump was demonstrated to achieve adaptable and sustainable concentration gradients for up to 6 days in this model. This straightforward modeling approach allows for fast patterning of a wide variety of cell types in 3D and may be further integrated into biological assays. We also demonstrated cell migration from tumor spheroids induced by an epidermal growth factor (EGF) gradient and exhibited lowered expression of an epithelial marker (EpCAM) compared with parental cells, indicative of partial epithelial-mesenchymal transition (EMT) in this process. Importantly, pseudopodia protrusions from the migratory cells – critical during cancer metastasis – were demonstrated. Insights gained from this work offer new opportunities to achieve active control of in vitro tumor microenvironments on-demand, and may be amenable towards tailored clinical applications.
机译：癌症转移和耐药性是重要的恶性肿瘤表型，可导致约90％的人类癌症死亡。然而，由于缺乏适用的临床前模型和药物筛选平台，当前的治疗策略面临着严峻的挑战。值得注意的是，能够模拟体内微环境以复制生理条件的微型和三维（3D）组织培养平台已成为广泛的细胞和临床研究的重要工具。在这里，我们提出了一种微流体装置，该装置能够模拟可配置的肿瘤微环境，以研究体内样癌细胞的迁移以及在亲代肿瘤和迁移细胞上筛选抑制剂。此外，在该模型中，新型的基于蒸发的纸泵被证明可在长达6天的时间内实现适应性和可持续性的浓度梯度。这种简单的建模方法可以在3D模式下快速图案化多种细胞类型，并且可以进一步整合到生物学分析中。我们还证明了由表皮生长因子（EGF）梯度诱导的肿瘤球体中的细胞迁移，并且与亲代细胞相比，上皮标志物（EpCAM）的表达降低，这表明该过程中存在部分上皮-间质转化（EMT）。重要的是，证实了迁移细胞产生的伪足突起-在癌症转移期间至关重要。从这项工作中获得的见识为实现按需主动控制体外肿瘤微环境提供了新的机会，并且可能适合于量身定制的临床应用。

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