期刊
NEURO-ONCOLOGY
卷 19, 期 4, 页码 503-513出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/now230
关键词
glioblastoma; microfluidics; migration; pseudopalisades; SU-8
资金
- Junta de Comunidades de Castilla-La Mancha/FEDER [PEII-2014-031-P]
- Ministerio de Economia y Competitividad, Fondo de Investigacion Sanitaria [PI12/00775, PI13/01258]
- Ministerio de Economia y Competitividad, Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0027]
- National Institutes of Health [CA189647, CA154130, CA171652, CA169117, NS087913, NS089272]
- Research Program Committees of Cleveland Clinic
- James S. McDonnell Foundation
- James S. Mc. Donnell Foundation (USA) 21st Century Science Initiative in Mathematical and Complex Systems approaches for Brain Cancer (Special Initiative Collaborative Planning Grant [220020420, 220020450]
- [DPI2011-28262c04-01]
- [DPI2015-65401-C3-1-R]
- [BIO2016-79092-R]
- [MTM2015-71200-R]
- [BES-2012-059940]
Background: 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. Methods: 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. Results: 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. Conclusions: This paper shows the potential of microfluidic devices as advanced artificial systems capable of modeling in vivo nutrient and oxygen gradients during tumor evolution.
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