Development of a Colorectal Cancer 3D Micro-tumor Construct Platform From Cell Lines and Patient Tumor Biospecimens for Standard-of-Care and Experimental Drug Screening
Development of a Colorectal Cancer 3D Micro-tumor Construct Platform From Cell Lines and Patient Tumor Biospecimens for Standard-of-Care and Experimental Drug Screening
复制标题
DOI：
10.1007/s10439-019-02269-2
复制
发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Skardal, Aleksander
中科院分区：
文献类型：
--
作者：
Forsythe, Steven;Mehta, Naren;Skardal, Aleksander
结直肠癌的突变率很高，晚期肿瘤通常含有许多突变。这些肿瘤很难治疗，即使最近在现代医院实施了旨在缩小治疗范围的个性化医疗方法，仍然存在差距。这些肿瘤的正确建模可能有助于为个体患者推荐最佳治疗，优选地利用维持关于衍生的母体组织的适当信号传导的模型。在这项研究中，我们利用细胞外基质衍生的水凝胶来创建一个3D微肿瘤构建平台，该平台能够长时间支持细胞并进行高通量药物筛选。细胞系的实验证明了细胞增殖维持的长期活力。此外，利用不同作用机制的几种化疗药物的研究在比较3D和2D培养物时显示出疗效差异。最后，获得患者结直肠肿瘤组织并用于重建微肿瘤构建体，从而提供用于以患者特异性方式测试针对肿瘤的新型化疗剂的系统。总的来说，这些结果描述了一种能够进行高通量测试同时保持母体组织的重要特征的系统。
Colorectal cancer is subject to a high rate of mutations, with late stage tumors often containing many mutations. These tumors are difficult to treat, and even with the recently implemented methods of personalized medicine at modern hospitals aiming to narrow treatments, a gap still exists. Proper modeling of these tumors may help to recommend optimal treatments for individual patients, preferably utilizing a model that maintains proper signaling in respect to the derived parent tissue. In this study, we utilized an extracellular matrix-derived hydrogel to create a 3D micro-tumor construct platform capable of both supporting cells for long time durations and for high throughput drug screening. Experiments with cell lines demonstrated long-term viability with maintenance of cell proliferation. Furthermore, studies with several chemotherapeutics utilizing different mechanisms of action displayed differences in efficacy in comparing 3D and 2D cultures. Finally, patient colorectal tumor tissue was acquired and employed to reconstruct micro-tumor constructs, providing a system for the testing of novel chemotherapeutics against tumors in a patient-specific manner. Collectively, the results describe a system capable of high throughput testing while maintaining important characteristics of the parent tissue.