Metastatic cancer is regarded as one of the largest contributors to disease-related deaths worldwide. Poor patient prognosis and treatment outcome is tied to the lack of efficacious anti-cancer therapies, which is due in part to the lack of physiologically relevant in vitro screening systems that can mimic the native tumor microenvironment. Conventional drug-screening platforms, which are often used in the pharmaceutical industry, are either two-dimensional (2D) assays or three-dimensional (3D) hydrogel-based matrices that lack precise control over cell distribution, matrix architecture, and organization. Despite the significance of in vivo models, they have limitations as it is difficult to control and analyze the influence of specific variables within their tumor microenvironment. Thus, there is still a crucial need to develop tumor models that enable precise control of microenvironmental cues (e.g. matrix composition, soluble factors, cellular organization) to assess the efficacy of anti-cancer drugs. Herein, we report the development and validation of a 3D microfluidic invasion platform for anti-cancer drug studies. Our platform allowed for compartmentalization of tumor and stromal fibroblasts in a defined architecture, thereby enabling pharmacokinetic drug transport to a cell-dense tumor region. We analyzed the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, on the behavior of SUM159 breast cancer cells. Many HDAC inhibitors, including SAHA, have been a subject of controversy with highly conflicting results for the treatment of solid tumors in vitro as well as in clinical trials. We found that SAHA significantly inhibited cellular migration/proliferation, and decreased microtubule polarization.

中文翻译：

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异戊酰苯胺异羟肟酸（SAHA）对肿瘤基质微流模型中乳腺癌细胞的影响

转移性癌症被认为是世界范围内与疾病相关的死亡的最大原因之一。不良的患者预后和治疗结果与缺乏有效的抗癌治疗有关，这部分是由于缺乏可以模拟天然肿瘤微环境的生理相关的体外筛选系统。在制药行业中经常使用的常规药物筛选平台是基于二维（2D）分析或基于三维（3D）水凝胶的基质，这些基质缺乏对细胞分布，基质结构和组织的精确控制。尽管有体内意义由于难以控制和分析肿瘤微环境中特定变量的影响，因此它们具有局限性。因此，仍然迫切需要开发能够精确控制微环境线索的肿瘤模型（例如基质成分，可溶性因子，细胞组织）以评估抗癌药的功效。在此，我们报告了用于抗癌药物研究的3D微流体入侵平台的开发和验证。我们的平台允许在定义的体系结构中将肿瘤和基质成纤维细胞区分开，从而使药代动力学药物转运到细胞密集的肿瘤区域。我们分析了组蛋白脱乙酰基酶（HDAC）抑制剂suberoylyllide异羟肟酸（SAHA）对SUM159乳腺癌细胞行为的影响。许多HDAC抑制剂，包括SAHA，一直是争议很大的话题，在体外治疗实体瘤方面以及在临床试验中。我们发现SAHA显着抑制细胞迁移/增殖，并降低微管极化。