Modelling liver cancer microenvironment: novel 3D culture system as a potential anti-cancer drug screening tool
Modelling liver cancer microenvironment: novel 3D culture system as a potential anti-cancer drug screening tool
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DOI：
10.1101/2021.11.04.467266
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
Al Hrout;Karla Cervantes-Gracia;Richard Chahwan;A. Amin
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文献类型：
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作者：
Al Hrout;Karla Cervantes-Gracia;Richard Chahwan;A. Amin
肿瘤微环境及其在肿瘤发生中的作用是近年来研究的热点。肿瘤与周围微环境之间的双向交流维持并促进肿瘤的生长和转移。据报道，肝细胞癌的进展和转移受到多种微环境因素的极大影响。在这项研究中，我们提出了肝癌的3d培养模型，以更好地模拟体内肿瘤环境。通过创建新的3D共培养模型，该模型结合了肝癌细胞和成纤维细胞的自由漂浮和基于支架的3D培养技术，我们旨在建立一个简单但可重复的离体癌症微环境模型，以捕获肿瘤-基质相互作用。与肝癌细胞的2D和3D单培养相比，本文提出的模型显示出独特的基因表达和蛋白质表达谱。我们的研究结果表明，体内的类似条件不能通过简单地将癌细胞培养成球形来模拟，而是通过将它们与3D成纤维细胞共培养来模拟，从而使它们能够相互作用。这可以通过HCC中涉及的几种途径的上调以及共培养癌细胞分泌因子的增加来证明，其中许多因子也参与肿瘤-基质相互作用。与传统的二维培养相比，该模型显示出与HCC发生、进展和预后不良相关基因的表达增加。我们的研究结果与一种更能反映体内HCC的侵袭性结果相关，因此，这是一种更可靠的平台，可以了解HCC的分子结构，并可能更好地进行抗癌药物筛选。
The tumor microenvironment and its contribution to tumorigenesis has been a focal highlight in recent years. A two-way communication between the tumor and the surrounding microenvironment sustains and contributes to the growth and metastasis of tumors. Progression and metastasis of hepatocellular carcinoma have been reported to be exceedingly influenced by diverse microenvironmental cues. In this study, we present a 3D-culture model of liver cancer to better mimic in vivo tumor settings. By creating novel 3D co-culture model that combines free-floating and scaffold based 3D-culture techniques of liver cancer cells and fibroblasts, we aimed to establish a simple albeit reproducible ex vivo cancer microenvironment model that captures tumor-stroma interactions. The model presented herein exhibited unique gene expression and protein expression profiles when compared to 2D and 3D mono-cultures of liver cancer cells. Our results showed that in vivo like conditions cannot be mimicked by simply growing cancer cells as spheroids, but by co-culturing them with 3D fibroblast with which they were able to cross-talk. This was evident by the upregulation of several pathways involved in HCC, and the increase in secreted factors by co-cultured cancer cells, many of which are also involved in tumor-stroma interactions. Compared to the conventional 2D culture, the proposed model exhibits an increase in the expression of genes associated with development, progression, and poor prognosis of HCC. Our results correlated with an aggressive outcome that better mirrors in vivo HCC, and therefore, a more reliable platform for molecular understanding of HCC and possibly better anti-cancer drug screening.