Co-Culture of Tumor Spheroids and Fibroblasts in a Collagen Matrix-Incorporated Microfluidic Chip Mimics Reciprocal Activation in Solid Tumor Microenvironment.
Co-Culture of Tumor Spheroids and Fibroblasts in a Collagen Matrix-Incorporated Microfluidic Chip Mimics Reciprocal Activation in Solid Tumor Microenvironment.
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DOI：
10.1371/journal.pone.0159013
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kuh HJ
中科院分区：
文献类型：
--
作者：
Jeong SY;Lee JH;Shin Y;Chung S;Kuh HJ
多细胞3D培养和与基质成分的相互作用被认为是建立“更具临床相关性”的肿瘤模型的基本要素。使用微流控芯片平台的基质包埋3D培养物可以重现肿瘤微环境内的微尺度相互作用。肿瘤相关成纤维细胞（CAFs）作为肿瘤微环境的重要组成部分，在肿瘤的发生、发展和耐药过程中发挥重要作用。在这里，我们提出了一种基于微流控芯片的肿瘤组织培养模型，该模型将3D肿瘤球体（TS）与水凝胶支架内的CAF接近。HT-29人结肠直肠癌细胞生长成3D TS，并且当与成纤维细胞共培养时，生长受到刺激，如5天内直径变化%增加1.5倍所示。与单独培养的TS相比，当与成纤维细胞共培养时，培养6天的TS显示Ki-67沿着降低的表达以及纤连蛋白的增加的表达。成纤维细胞在共培养条件下活化，如α-SMA表达和迁移活性增加所示。当暴露于紫杉醇时，在与活化的成纤维细胞共培养的TS中观察到存活优势。总之，我们证明了TS和成纤维细胞之间的相互作用，在我们的7通道微流控芯片。三维TS-CAF在胶原基质微流控芯片中的共培养可能有助于研究肿瘤微环境以及药物筛选和评价。
Multicellular 3D culture and interaction with stromal components are considered essential elements in establishing a ‘more clinically relevant’ tumor model. Matrix-embedded 3D cultures using a microfluidic chip platform can recapitulate the microscale interaction within tumor microenvironments. As a major component of tumor microenvironment, cancer-associated fibroblasts (CAFs) play a role in cancer progression and drug resistance. Here, we present a microfluidic chip-based tumor tissue culture model that integrates 3D tumor spheroids (TSs) with CAF in proximity within a hydrogel scaffold. HT-29 human colorectal carcinoma cells grew into 3D TSs and the growth was stimulated when co-cultured with fibroblasts as shown by 1.5-folds increase of % changes in diameter over 5 days. TS cultured for 6 days showed a reduced expression of Ki-67 along with increased expression of fibronectin when co-cultured with fibroblasts compared to mono-cultured TSs. Fibroblasts were activated under co-culture conditions, as demonstrated by increases in α-SMA expression and migratory activity. When exposed to paclitaxel, a survival advantage was observed in TSs co-cultured with activated fibroblasts. Overall, we demonstrated the reciprocal interaction between TSs and fibroblasts in our 7-channel microfluidic chip. The co-culture of 3D TS-CAF in a collagen matrix-incorporated microfluidic chip may be useful to study the tumor microenvironment and for evaluation of drug screening and evaluation.