The tumor microenvironment is important in promoting treatment resistance of tumor cells via multiple mechanisms. However, studying this interaction often proves difficult. In vivo animal models are costly, time-consuming, and often fail to adequately predict human response to treatment. Conversely, testing drug response on human tumor cells in vitro in 2D cell culture excludes the important contribution of stromal cells and biophysical forces seen in the in vivo tumor microenvironment. Here, we present tissue-engineered models of both human brain and breast tumor microenvironments incorporating key stromal cell populations for assessing multiple mechanisms of therapeutic response using flow cytometry. We show our physiologically-relevant systems used to interrogate a variety of parameters associated with chemotherapeutic efficacy, including cell death, proliferation, drug uptake, and invasion of cancer and stromal cell populations. The use of flow cytometry allows for single cell, quantitative, and fast assessments of multiple outcomes affecting anti-tumor therapy failure. Our system can be modified to add and remove cellular components with ease, thereby enabling the study of individual cellular contributions in the tumor microenvironment. Together, our models and analysis methods illustrate the importance of developing fast, cost-effective, and reproducible methods to model complex human systems in a physiologically-relevant manner that may prove useful for drug screening efforts in the future.

中文翻译：

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评估组织工程肿瘤微环境模型中的多参数药物反应

肿瘤微环境通过多种机制促进肿瘤细胞的治疗耐药性。然而，研究这种相互作用通常很困难。体内动物模型成本高、耗时长，并且通常无法充分预测人类对治疗的反应。相反，在体外 2D 细胞培养中测试对人类肿瘤细胞的药物反应排除了在体内肿瘤微环境中观察到的基质细胞和生物物理力的重要贡献。在这里，我们提出了人脑和乳腺肿瘤微环境的组织工程模型，这些模型结合了关键的基质细胞群，用于使用流式细胞术评估多种治疗反应机制。我们展示了用于询问与化疗功效相关的各种参数的生理相关系统，包括细胞死亡、增殖、药物吸收以及癌症和基质细胞群的侵袭。流式细胞术的使用允许对影响抗肿瘤治疗失败的多个结果进行单细胞、定量和快速评估。我们的系统可以修改为轻松添加和删除细胞成分，从而能够研究肿瘤微环境中的单个细胞贡献。总之，我们的模型和分析方法说明了开发快速、经济高效且可重复的方法以生理相关方式模拟复杂人体系统的重要性，这可能对未来的药物筛选工作有用。以及对影响抗肿瘤治疗失败的多种结果的快速评估。我们的系统可以修改为轻松添加和删除细胞成分，从而能够研究肿瘤微环境中的单个细胞贡献。总之，我们的模型和分析方法说明了开发快速、经济高效且可重复的方法以生理相关方式模拟复杂人体系统的重要性，这可能对未来的药物筛选工作有用。以及对影响抗肿瘤治疗失败的多种结果的快速评估。我们的系统可以修改为轻松添加和删除细胞成分，从而能够研究肿瘤微环境中的单个细胞贡献。总之，我们的模型和分析方法说明了开发快速、经济高效且可重复的方法以生理相关方式模拟复杂人体系统的重要性，这可能对未来的药物筛选工作有用。