All-human microphysical model of metastasis therapy.
All-human microphysical model of metastasis therapy.
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转移治疗的全人类微物理模型。
DOI：
10.1186/scrt372
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发表时间：
2013
影响因子：
7.5
通讯作者：
Young C
中科院分区：
文献类型：
--
作者：
Wheeler SE;Borenstein JT;Clark AM;Ebrahimkhani MR;Fox IJ;Griffith L;Inman W;Lauffenburger D;Nguyen T;Pillai VC;Prantil-Baun R;Stolz DB;Taylor D;Ulrich T;Venkataramanan R;Wells A;Young C
绝大多数癌症死亡是由于远处转移。转移性微环境为异位肿瘤提供了独特的保护，因为原发性肿瘤通常对特异性药物有反应。虽然在原发性肿瘤上已经取得了显着的干预性进展，但缺乏研究转移的相关可及体外系统模型一直困扰着转移性治疗的发展-特别是在微转移中。一个实时的、全人类的转移性接种和癌细胞模型，重现了转移性生长，并且可以通过各种测量和挑战在真实的时间内进行探测，这将为转移的病理生理学和转移性肿瘤抗性的药理学提供一个关键的窗口。为了实现这一目标，我们正在推进我们的微型生物反应器，该生物反应器结合了人肝细胞，人非实质肝细胞和人乳腺癌细胞，以模拟具有功能组织的三维肝脏生态位。该生物反应器配备有氧传感器和微型泵，能够生成营养素和激素的日变化曲线，同时能够进行实时采样。由于肝脏是各种癌症和其他肿瘤的主要转移部位，因此该生物反应器独特地使我们能够更准确地重建人类转移微环境，并探测肝实质和转移细胞之间的旁分泌效应。此外，由于肝脏是异生物质代谢的主要场所，该反应器将帮助我们研究代谢挑战的肝脏微环境内的化疗反应。该模型预计将产生转移行为和药理学代谢的标志物，从而实现更好的临床监测，并将指导临床研究的设计，以了解癌症治疗中的药物疗效和安全性。这种高度仪器化的生物反应器形式，在微环境中容纳生长的肿瘤并监测其反应，很容易转移到其他器官，使这项工作的影响超越肝脏。
The vast majority of cancer mortalities result from distant metastases. The metastatic microenvironment provides unique protection to ectopic tumors as the primary tumors often respond to specific agents. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model in vitro systems in which to study metastases has plagued metastatic therapeutic development - particularly among micrometastases. A real-time, all-human model of metastatic seeding and cancer cells that recapitulate metastatic growth and can be probed in real time by a variety of measures and challenges would provide a critical window into the pathophysiology of metastasis and pharmacology of metastatic tumor resistance. To achieve this we are advancing our microscale bioreactor that incorporates human hepatocytes, human nonparenchymal liver cells, and human breast cancer cells to mimic the hepatic niche in three dimensions with functional tissue. This bioreactor is instrumented with oxygen sensors, micropumps capable of generating diurnally varying profiles of nutrients and hormones, while enabling real-time sampling. Since the liver is a major metastatic site for a wide variety of carcinomas and other tumors, this bioreactor uniquely allows us to more accurately recreate the human metastatic microenvironment and probe the paracrine effects between the liver parenchyma and metastatic cells. Further, as the liver is the principal site of xenobiotic metabolism, this reactor will help us investigate the chemotherapeutic response within a metabolically challenged liver microenvironment. This model is anticipated to yield markers of metastatic behavior and pharmacologic metabolism that will enable better clinical monitoring, and will guide the design of clinical studies to understand drug efficacy and safety in cancer therapeutics. This highly instrumented bioreactor format, hosting a growing tumor within a microenvironment and monitoring its responses, is readily transferable to other organs, giving this work impact beyond the liver.
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影响因子：
4.3
作者：
Aldridge BB;Saez-Rodriguez J;Muhlich JL;Sorger PK;Lauffenburger DA
通讯作者：
Lauffenburger DA
影响因子：
11.4
作者：
Ma, Di;Panda, Satchidananda;Lin, Jiandie D.
通讯作者：
Lin, Jiandie D.
DOI：
10.1073/pnas.1106750109
发表时间：
2012-01-10
影响因子：
11.1
作者：
Gibbs, Julie E.;Blaikley, John;Loudon, Andrew S. I.
通讯作者：
Loudon, Andrew S. I.
DOI：
10.1158/1078-0432.ccr-12-3180
发表时间：
2013-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Taylor DP;Wells JZ;Savol A;Chennubhotla C;Wells A
通讯作者：
Wells A
影响因子：
3.8
作者：
Ideker, T;Winslow, LR;Lauffenburger, AD
通讯作者：
Lauffenburger, AD