A microphysiological system model of therapy for liver micrometastases.
A microphysiological system model of therapy for liver micrometastases.
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DOI：
10.1177/1535370214532596
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发表时间：
2014-09
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;Wheeler SE;Taylor DP;Pillai VC;Young CL;Prantil-Baun R;Nguyen T;Stolz DB;Borenstein JT;Lauffenburger DA;Venkataramanan R;Griffith LG;Wells A
转移占癌症相关死亡率的近90%。癌症治疗的有效性受到转移性小生境的保护性微环境的限制，因此这些播散性肿瘤仍然无法治愈。由于缺乏适当的模型系统，转移性疾病进展仍然知之甚少。为了解决这一认识上的差距，我们提出了一个全人类的微生理系统，以促进在肝转移小生境的癌症行为的调查。现有的LiverChip是一种模拟肝脏生态位的3D系统;它包含了完整的人类实质和非实质细胞，并有效地重现了微转移。此外，该系统允许实时监测微转移和评估人类特异性信号传导。它被用来进一步我们的化疗药物的疗效的理解，通过检查活动的建立和新的代理人对微转移的条件下复制昼夜变化的激素，营养和轻度炎症状态使用可编程的微分配器。这些输入影响支配肿瘤细胞反应的线索。针对三个关键的信号组：葡萄糖/胰岛素反应，应激激素皮质醇和与炎症线索相关的肠道微生物组。目前，该系统可维持功能性肝细胞至少15天;通过监测肝功能（尿素、α-1-抗胰蛋白酶、纤维蛋白原和细胞色素P450）和损伤（AST和ALT）进行确认。乳腺癌细胞系有效地整合到肝小生境中，而不会对组织造成可检测的破坏，初步证据表明乳腺癌细胞亚群中的生长衰减。结合系统生物学建模的xMAP技术也被用来评估细胞串扰并说明微转移早期微环境中的通信网络。该模型预计将通过阐明肝细胞和转移细胞之间的旁分泌效应来确定新的转移治疗策略，同时评估药物对转移、代谢和耐受性的疗效。
Metastasis accounts for almost 90% of cancer-associated mortality. The effectiveness of cancer therapeutics is limited by the protective microenvironment of the metastatic niche and consequently these disseminated tumors remain incurable. Metastatic disease progression continues to be poorly understood due to the lack of appropriate model systems. To address this gap in understanding, we propose an all-human microphysiological system that facilitates the investigation of cancer behavior in the liver metastatic niche. This existing LiverChip is a 3D-system modeling the hepatic niche; it incorporates a full complement of human parenchymal and non-parenchymal cells and effectively recapitulates micrometastases. Moreover, this system allows for real-time monitoring of micrometastasis and assessment of human-specific signaling. It is being utilized to further our understanding of the efficacy of chemotherapeutics by examining the activity of established and novel agents on micrometastases under conditions replicating diurnal variations in hormones, nutrients and mild inflammatory states using programmable microdispensers. These inputs affect the cues that govern tumor cell responses. Three critical signaling groups are targeted: the glucose/insulin responses, the stress hormone cortisol and the gut microbiome in relation to inflammatory cues. Currently, the system sustains functioning hepatocytes for a minimum of 15 days; confirmed by monitoring hepatic function (urea, α-1-antitrypsin, fibrinogen, and cytochrome P450) and injury (AST and ALT). Breast cancer cell lines effectively integrate into the hepatic niche without detectable disruption to tissue and preliminary evidence suggests growth attenuation amongst a subpopulation of breast cancer cells. xMAP technology combined with systems biology modeling are also employed to evaluate cellular crosstalk and illustrate communication networks in the early microenvironment of micrometastases. This model is anticipated to identify new therapeutic strategies for metastasis by elucidating the paracrine effects between the hepatic and metastatic cells, while concurrently evaluating agent efficacy for metastasis, metabolism and tolerability.