70737 20200324135213.0 doi 10.1093/neuonc/nox036.228 sideral 101470 ART-2017-101470 eng Martínez-González, Alicia Combined in-silico and on-chip validation of pseudopalisade formation hypothesis in Glioblastoma 2017 Access copy available to the general public Unrestricted Introduction: Hypercellular regions surrounding necrotic areas in glioblastoma (GBM), named pseudopalisades, are characteristic of these tumors and have been hypothesized to be waves of migrating GBM cells. These structures are thought to be induced by oxygen depletion caused by the accumulation of cells far from nutrient supplies (chronic hypoxia) and/or tumor-induced blood vessel occlusion (acute hypoxia). The universal appearance of these structures in GBM suggests that they may play an instrumental role in their spreading and invasion. However the validation of the mechanisms of pseudopalisade formation has remained challenging. Materials and methods: A mathematical model was developed incorporating the main mechanisms of pseudopalisade formation. Oxygen coming from straight vessels drives phenotype changes. A third phenotype was included accounting for hypoxic cells switching back to a more proliferative phenotype in regions of normoxia. Experiments were done by embedding different densities of U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we mimic and control blood-vessel obstruction events associated with this disease. Results: Nutrient and oxygen starvation triggered a strong migratory process leading to pseudopalisade generation in silico and in vitro. Also, cells at greatest distance from oxygen supply became hypoxic after a critical point in tumor growth was reached (due to increased metabolism) forming pseudopalisades both in silico and in vitro. All the elements included in the mathematical model were necessary to describe both types of phenomena pointing out to the insufficiency of the go-or-grow hypothesis to describe pseudopalisade formation on-chip. Conclusions: Using a combination of computational and experimental techniques, we proved the feasibility of the two hypotheses of pseudopalisade formation, driven by either acute or chronic hypoxia. Additionally, we verified the potential of microfluidic devices as advanced artificial systems capable of experimentally modeling nutrient and oxygen gradients during tumor evolution. info:eu-repo/grantAgreement/ES/FIS/PI12-00775 info:eu-repo/grantAgreement/ES/FIS/PI13-01258 info:eu-repo/grantAgreement/ES/ISCIII/RD12-0036-0027 info:eu-repo/grantAgreement/ES/MICINN/MTM2012-31073 info:eu-repo/grantAgreement/ES/MINECO/BES-2012-059940 info:eu-repo/grantAgreement/ES/MINECO/BIO2016-79092-R info:eu-repo/grantAgreement/ES/MINECO/DPI2015-65401-C3-1-R info:eu-repo/grantAgreement/ES/MINECO/MTM2015-71200-R info:eu-repo/semantics/openAccess All rights reserved http://www.europeana.eu/rights/rr-f/ 9.384 2017 ONCOLOGY 15 / 223 = 0.067 2017 Q1 T1 CLINICAL NEUROLOGY 9 / 197 = 0.046 2017 Q1 T1 4.064 2017 Cancer Research 2017 Q1 Oncology 2017 Q1 Neurology (clinical) 2017 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Ayuso, Jose Maria Monge, Rosa (orcid)0000-0003-3660-8651 Virumbrales-Muñoz, Maria Universidad de Zaragoza (orcid)0000-0002-5731-8840 Llamazares, Guillermo A. Hernández-Laín, A. Sánchez-Gómez, Pilar Pérez-García, Victor (orcid)0000-0001-5376-4440 Fernández, Luis Universidad de Zaragoza (orcid)0000-0003-2410-5678 Ochoa, Ignacio Universidad de Zaragoza 1003 443 Universidad de Zaragoza Dpto. Anatom.Histolog.Humanas Area Histología 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 5004 605 Universidad de Zaragoza Dpto. Ingeniería Mecánica Área Mec.Med.Cont. y Teor.Est. 19, Suppl. 3 (2017), [7 pp.] Neuro-oncology NEURO-ONCOLOGY 1522-8517 438812 http://zaguan.unizar.es/record/70737/files/texto_completo.pdf Postprint 80946 http://zaguan.unizar.es/record/70737/files/texto_completo.jpg?subformat=icon icon Postprint oai:zaguan.unizar.es:70737 articulos driver 2020-03-24-10:01:14 ARTICLE