Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment.
Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment.
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DOI：
10.1371/journal.pone.0169797
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Altiok S
中科院分区：
文献类型：
--
作者：
Holton AB;Sinatra FL;Kreahling J;Conway AJ;Landis DA;Altiok S
肿瘤微环境由细胞和基质成分组成，如肿瘤细胞、间充质细胞、免疫细胞、癌症相关成纤维细胞和支持细胞外基质。肿瘤微环境为肿瘤细胞的生长和进展提供关键支持，并影响肿瘤对治疗干预的反应。为了更好地理解肿瘤生物学和开发有效的癌症治疗剂，重要的是开发临床前平台，其可以忠实地再现肿瘤微环境以及肿瘤与其周围基质元素之间的复杂相互作用。用常规二维癌细胞系模型在体外进行的药物研究不能最佳地代表临床药物反应，因为它们缺乏真正的肿瘤异质性，并且通常在缺乏显著影响细胞代谢活性和增殖的基质肿瘤组分的静态培养条件下进行。最近的微流控方法旨在通过使用在人工三维支持凝胶或微室中衍生的细胞系来克服这些障碍。然而，缺乏真正的肿瘤微环境和完整的间质流，导致肿瘤对药物治疗的反应的评估不太理想。在这里，我们报告了一个连续灌注微流控装置，结合显微镜和图像分析，用于评估药物对完整新鲜肿瘤组织的影响。我们已经证明，可以成功地分析从患者来源的肺腺癌异种移植模型获得的细针抽吸活检物对该活检捕获微流体装置内的离体药物治疗的反应，其中使用蛋白激酶C抑制剂星形孢菌素来评估肿瘤细胞死亡作为原理证明。这种方法有可能在其完整的微环境中研究肿瘤组织，以更好地了解肿瘤对药物治疗的反应，并最终以具有成本效益和及时的方式为个体患者选择最有效的药物和药物组合。
The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements. Drug studies performed in vitro with conventional two-dimensional cancer cell line models do not optimally represent clinical drug response as they lack true tumor heterogeneity and are often performed in static culture conditions lacking stromal tumor components that significantly influence the metabolic activity and proliferation of cells. Recent microfluidic approaches aim to overcome such obstacles with the use of cell lines derived in artificial three-dimensional supportive gels or micro-chambers. However, absence of a true tumor microenvironment and full interstitial flow, leads to less than optimal evaluation of tumor response to drug treatment. Here we report a continuous perfusion microfluidic device coupled with microscopy and image analysis for the assessment of drug effects on intact fresh tumor tissue. We have demonstrated that fine needle aspirate biopsies obtained from patient-derived xenograft models of adenocarcinoma of the lung can successfully be analyzed for their response to ex vivo drug treatment within this biopsy trapping microfluidic device, wherein a protein kinase C inhibitor, staurosporine, was used to assess tumor cell death as a proof of principle. This approach has the potential to study tumor tissue within its intact microenvironment to better understand tumor response to drug treatments and eventually to choose the most effective drug and drug combination for individual patients in a cost effective and timely manner.