Ayuso Jose M, Monge Rosa, Martínez-González Alicia, Virumbrales-Muñoz María, Llamazares Guillermo A, Berganzo Javier, Hernández-Laín Aurelio, Santolaria Jorge, Doblaré Manuel, Hubert Christopher, Rich Jeremy N, Sánchez-Gómez Pilar, Pérez-García Víctor M, Ochoa Ignacio, Fernández Luis J
Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.
Neuro Oncol. 2017 Apr 1;19(4):503-513. doi: 10.1093/neuonc/now230.
Glioblastoma (GBM) is one of the most lethal tumor types. Hypercellular regions, named pseudopalisades, are characteristic in these tumors and have been hypothesized to be waves of migrating glioblastoma cells. These "waves" of cells are thought to be induced by oxygen and nutrient depletion caused by tumor-induced blood vessel occlusion. Although the universal presence of these structures in GBM tumors suggests that they may play an instrumental role in GBM's spread and invasion, the recreation of these structures in vitro has remained challenging.
Here we present a new microfluidic model of GBM that mimics the dynamics of pseudopalisade formation. To do this, we embedded U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we can mimic and control blood-vessel obstruction events associated with this disease.
Through the use of this new system, we show that nutrient and oxygen starvation triggers a strong migratory process leading to pseudopalisade generation in vitro. These results validate the hypothesis of pseudopalisade formation and show an excellent agreement with a systems-biology model based on a hypoxia-driven phenomenon.
This paper shows the potential of microfluidic devices as advanced artificial systems capable of modeling in vivo nutrient and oxygen gradients during tumor evolution.
胶质母细胞瘤（GBM）是最致命的肿瘤类型之一。在这些肿瘤中，名为假栅栏的高细胞区域具有特征性，并且据推测是胶质母细胞瘤细胞的迁移波。这些细胞“波”被认为是由肿瘤诱导的血管闭塞导致的氧气和营养物质耗竭所诱导的。尽管这些结构在GBM肿瘤中普遍存在表明它们可能在GBM的扩散和侵袭中起重要作用，但在体外重建这些结构仍然具有挑战性。
在此，我们展示了一种模拟假栅栏形成动态的新型GBM微流控模型。为此，我们将U-251 MG细胞嵌入定制设计的微流控装置中的胶原蛋白水凝胶内。通过控制通过侧向微通道的介质流动，我们可以模拟和控制与该疾病相关的血管阻塞事件。
通过使用这个新系统，我们表明营养物质和氧气饥饿会触发一个强烈的迁移过程，导致体外假栅栏的产生。这些结果验证了假栅栏形成的假设，并与基于缺氧驱动现象的系统生物学模型显示出极好的一致性。
本文展示了微流控装置作为先进的人工系统在模拟肿瘤演变过程中体内营养物质和氧气梯度方面的潜力。
