000070737 001__ 70737
000070737 005__ 20200324135213.0
000070737 0247_ $$2doi$$a10.1093/neuonc/nox036.228
000070737 0248_ $$2sideral$$a101470
000070737 037__ $$aART-2017-101470
000070737 041__ $$aeng
000070737 100__ $$aMartínez-González, Alicia
000070737 245__ $$aCombined in-silico and on-chip validation of pseudopalisade formation hypothesis in Glioblastoma
000070737 260__ $$c2017
000070737 5060_ $$aAccess copy available to the general public$$fUnrestricted
000070737 5203_ $$aIntroduction:
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.
000070737 536__ $$9info:eu-repo/grantAgreement/ES/FIS/PI12-00775$$9info:eu-repo/grantAgreement/ES/FIS/PI13-01258$$9info:eu-repo/grantAgreement/ES/ISCIII/RD12-0036-0027$$9info:eu-repo/grantAgreement/ES/MICINN/MTM2012-31073$$9info:eu-repo/grantAgreement/ES/MINECO/BES-2012-059940$$9info:eu-repo/grantAgreement/ES/MINECO/BIO2016-79092-R$$9info:eu-repo/grantAgreement/ES/MINECO/DPI2015-65401-C3-1-R$$9info:eu-repo/grantAgreement/ES/MINECO/MTM2015-71200-R
000070737 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000070737 590__ $$a9.384$$b2017
000070737 591__ $$aONCOLOGY$$b15 / 223 = 0.067$$c2017$$dQ1$$eT1
000070737 591__ $$aCLINICAL NEUROLOGY$$b9 / 197 = 0.046$$c2017$$dQ1$$eT1
000070737 592__ $$a4.064$$b2017
000070737 593__ $$aCancer Research$$c2017$$dQ1
000070737 593__ $$aOncology$$c2017$$dQ1
000070737 593__ $$aNeurology (clinical)$$c2017$$dQ1
000070737 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000070737 700__ $$aAyuso, Jose Maria
000070737 700__ $$aMonge, Rosa
000070737 700__ $$0(orcid)0000-0003-3660-8651$$aVirumbrales-Muñoz, Maria$$uUniversidad de Zaragoza
000070737 700__ $$0(orcid)0000-0002-5731-8840$$aLlamazares, Guillermo A.
000070737 700__ $$aHernández-Laín, A.
000070737 700__ $$aSánchez-Gómez, Pilar
000070737 700__ $$aPérez-García, Victor
000070737 700__ $$0(orcid)0000-0001-5376-4440$$aFernández, Luis$$uUniversidad de Zaragoza
000070737 700__ $$0(orcid)0000-0003-2410-5678$$aOchoa, Ignacio$$uUniversidad de Zaragoza
000070737 7102_ $$11003$$2443$$aUniversidad de Zaragoza$$bDpto. Anatom.Histolog.Humanas$$cArea Histología
000070737 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000070737 7102_ $$15004$$2605$$aUniversidad de Zaragoza$$bDpto. Ingeniería Mecánica$$cÁrea Mec.Med.Cont. y Teor.Est.
000070737 773__ $$g19, Suppl. 3 (2017), [7 pp.]$$pNeuro-oncology$$tNEURO-ONCOLOGY$$x1522-8517
000070737 8564_ $$s438812$$uhttps://zaguan.unizar.es/record/70737/files/texto_completo.pdf$$yPostprint
000070737 8564_ $$s80946$$uhttps://zaguan.unizar.es/record/70737/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000070737 909CO $$ooai:zaguan.unizar.es:70737$$particulos$$pdriver
000070737 951__ $$a2020-03-24-10:01:14
000070737 980__ $$aARTICLE