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dc.contributor.authorGonzalez-Gomez, Pilar 
dc.contributor.authorCrecente-Campo, Jose
dc.contributor.authorZahonero, Cristina 
dc.contributor.authorFuente, Maria de la
dc.contributor.authorHernández-Laín, Aurelio
dc.contributor.authorMira, Helena
dc.contributor.authorSánchez-Gómez, Pilar 
dc.contributor.authorGarcia-Fuentes, Marcos
dc.identifier.citationOncotarget. 2015 May 10; 6(13): 10950–10963es_ES
dc.description.abstractGlioblastoma tumor initiating cells are believed to be the main drivers behind tumor recurrence, and therefore therapies that specifically manage this population are of great medical interest. In a previous work, we synthesized controlled release microspheres optimized for intracranial delivery of BMP7, and showed that these devices are able to stop the in vitro growth of a glioma cell line. Towards the translational development of this technology, we now explore these microspheres in further detail and characterize the mechanism of action and the in vivo therapeutic potential using tumor models relevant for the clinical setting: human primary glioblastoma cell lines. Our results show that BMP7 can stop the proliferation and block the self-renewal capacity of those primary cell lines that express the receptor BMPR1B. BMP7 was encapsulated in poly (lactic-co-glycolic acid) microspheres in the form of a complex with heparin and Tetronic, and the formulation provided effective release for several weeks, a process controlled by carrier degradation. Data from xenografts confirmed reduced and delayed tumor formation for animals treated with BMP7-loaded microspheres. This effect was coincident with the activation of the canonical BMP signaling pathway. Importantly, tumors treated with BMP7-loaded microspheres also showed downregulation of several markers that may be related to a malignant stem cell-like phenotype: CD133(+), Olig2, and GFAPδ. We also observed that tumors treated with BMP7-loaded microspheres showed enhanced expression of cell cycle inhibitors and reduced expression of the proliferation marker PCNA. In summary, BMP7-loaded controlled release microspheres are able to inhibit GBM growth and reduce malignancy markers. We envisage that this kind of selective therapy for tumor initiating cells could have a synergistic effect in combination with conventional cytoreductive therapy (chemo-, radiotherapy) or with immunotherapy.es_ES
dc.description.sponsorshipThis study was supported by grants from: Ministerio de Economía y Competitividad, Fondo de Investigación Sanitaria (PI12/101 to HM; PI12/00775 to PSG; PS09/1786 to MGF and PI13/01258 to AHL), Comunidad de Madrid (S2010/BMD-2336 to HM), Xunta de Galicia (EM2013/042 to MGF), Fundación BBVA (2014-PO010 to MGF) and Ministerio de Economía y Competitividad, Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0027 to PSG and AHL). PGG was recipient of a “Sara Borell” postdoctoral fellowship, and MdF of a “Miguel Servet” contract from Ministerio de Economía y Competitividades_ES
dc.publisherImpact Journals es_ES
dc.subjectBone morphogenetic proteines_ES
dc.subjectControlled releasees_ES
dc.subjectTumor initiating cellses_ES
dc.subject.meshAnimals es_ES
dc.subject.meshBlotting, Western es_ES
dc.subject.meshBone Morphogenetic Protein 7 es_ES
dc.subject.meshBrain Neoplasms es_ES
dc.subject.meshCell Movement es_ES
dc.subject.meshCell Proliferation es_ES
dc.subject.meshDelayed-Action Preparations es_ES
dc.subject.meshGlioblastoma es_ES
dc.subject.meshHumans es_ES
dc.subject.meshImmunoenzyme Techniques es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Nude es_ES
dc.subject.meshRNA, Messenger es_ES
dc.subject.meshReal-Time Polymerase Chain Reaction es_ES
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction es_ES
dc.subject.meshTumor Cells, Cultured es_ES
dc.subject.meshXenograft Model Antitumor Assays es_ES
dc.subject.meshApoptosis es_ES
dc.subject.meshMicrospheres es_ES
dc.titleControlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastomaes_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderXunta de Galicia (España) 
dc.contributor.funderFundación BBVA 
dc.contributor.funderRed Temática de Investigación Cooperativa en Cáncer (España) 
dc.repisalud.centroISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)es_ES
dc.rights.accessRightsopen accesses_ES

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Atribución 4.0 Internacional
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