Liver metastases: Microenvironments and ex-vivo models.
Liver metastases: Microenvironments and ex-vivo models.
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DOI：
10.1177/1535370216658144
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Wells A
中科院分区：
文献类型：
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作者：
Clark AM;Ma B;Taylor DL;Griffith L;Wells A
肝脏是一个高度允许转移的器官，肿瘤的发生通常预示着死亡。其独特而多样的结构和细胞组成使肝脏能够承担许多专门的功能，然而，这种独特的生物学特性，特别是其血流动力学特征和独特的微环境，使肝脏本质上适合播散性肿瘤细胞。这一观点特别关注的是播散性肿瘤细胞和肝脏独特的常驻细胞群之间的双向相互作用；特别是肝实质细胞和非实质肝窦内皮细胞（LSEC）、库普弗细胞（KC）和肝星状细胞（HSC）。由于许多限制，很难在二维培养系统和动物中研究转移性播种的早期步骤，包括决定进行休眠还是生长。作为回应，组织工程仿生系统已经出现。在这些发展的前沿是离体“微生理系统”（MPS），它是一种细胞结构，旨在忠实地概括人体器官或器官区域在毫微米尺度上的结构和功能，并且可以使所有人类维持物种特异性相互作用。肝脏mps对于研究转移尤其有吸引力，因为肝脏除了是转移播种的主要部位外，也是药物代谢和治疗限制性毒性的主要部位。因此，使用这些肝脏mps不仅可以增强对转移的基本方面的理解，而且还可以充分研究治疗药物的疗效，同时还可以监测药理学方面和预测毒性。本文讨论了目前可用的一些肝脏MPS模型，尽管只有一种MPS已被证实可用于相关的转移模型，但预计其他肝脏模型将很快适应肿瘤。
The liver is a highly metastasis-permissive organ, tumor seeding of which usually portends mortality. Its unique and diverse architectural and cellular composition enable the liver to undertake numerous specialized functions, however, this distinctive biology, notably its hemodynamic features and unique microenvironment, renders the liver intrinsically hospitable to disseminated tumor cells. The particular focus for this perspective is the bidirectional interactions between the disseminated tumor cells and the unique resident cell populations of the liver; notably, parenchymal hepatocytes and non-parenchymal liver sinusoidal endothelial (LSEC), Kupffer (KC), and hepatic stellate cells (HSC). Understanding the early steps in the metastatic seeding, including the decision to undergo dormancy versus outgrowth, has been difficult to study in 2D culture systems and animals due to numerous limitations. In response, tissue-engineered biomimetic systems have emerged. At the cutting-edge of these developments are ex vivo ‘Microphysiological Systems’ (MPS) which are cellular constructs designed to faithfully recapitulate the structure and function of a human organ or organ region on a milli- to micro-scale level and can be made all human to maintain species-specific interactions. Hepatic MPSs are particularly attractive for studying metastases as in addition to the liver being a main site of metastatic seeding, it is also the principal site of drug metabolism and therapy-limiting toxicities. Thus, using these hepatic MPSs will enable not an enhanced understanding of the fundamental aspects of metastasis but also allow for therapeutic agents to be fully studied for efficacy while also monitoring pharmacologic aspects and predicting toxicities. The review discusses some of the hepatic MPS models currently available and although only one MPS has been validated for relevantly modeling metastasis, it is anticipated that the adaptation of the other hepatic models to include tumors will not be long in coming.