Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma

Glioblastoma 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 B...

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Autores: González-Gómez, P., Crecente-Campo, J., Zahonero, C., De La Fuente Freire, María, Hernández-Laín, A., Mira, H., Sánchez-Gómez, P., Garcia-Fuentes, M.
Tipo de recurso: artículo
Fecha de publicación:2015
País:España
Institución:Servizo Galego de Saúde (SERGAS)
Repositorio:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/8228
Acceso en línea:http://hdl.handle.net/20.500.11940/8228
Access Level:acceso abierto
Palabra clave:Animals
Apoptosis
Blotting, Western
Bone Morphogenetic Protein 7
Brain Neoplasms
Cell Movement
Cell Proliferation
Delayed-Action Preparations
Glioblastoma
Humans
Immunoenzyme Techniques
Mice
Mice, Nude
Microspheres
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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spelling Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastomaGonzález-Gómez, P.Crecente-Campo, J.Zahonero, C.De La Fuente Freire, MaríaHernández-Laín, A.Mira, H.Sánchez-Gómez, P.Garcia-Fuentes, M.AnimalsApoptosisBlotting, WesternBone Morphogenetic Protein 7Brain NeoplasmsCell MovementCell ProliferationDelayed-Action PreparationsGlioblastomaHumansImmunoenzyme TechniquesMiceMice, NudeMicrospheresRNA, MessengerReal-Time Polymerase Chain ReactionReverse Transcriptase Polymerase Chain ReactionTumor Cells, CulturedXenograft Model Antitumor AssaysGlioblastoma 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 GFAPdelta. 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.Gobierno de EspañaInstituto de Salud Carlos IIIComunidad de MadridXunta de GaliciaComisión EuropeaBBVA FoundationMinisterio de Economia y Competitividad, Red Tematica de Investigacion Cooperativa en Cancer"Sara Borell" postdoctoral fellowshipInstituto de Salud Carlos III/PI12/101Instituto de Salud Carlos III/PI12/00775Instituto de Salud Carlos III/PS09/1786Instituto de Salud Carlos III/PI13/01258Comunidad de Madrid/S2010/BMD-2336Xunta de Galicia/European Commission/EM2013/042BBVA Foundation/2014-PO010Ministerio de Economia y Competitividad, Red Tematica de Investigacion Cooperativa en Cancer/RD12/0036/00272015info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.11940/8228reponame:RUNA. Repositorio da Consellería de Sanidade e Sergasinstname:Servizo Galego de Saúde (SERGAS)Inglésinfo:eu-repo/semantics/openAccessoai:runa.sergas.gal:20.500.11940/82282026-06-12T08:40:47Z
dc.title.none.fl_str_mv Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
title Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
spellingShingle Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
González-Gómez, P.
Animals
Apoptosis
Blotting, Western
Bone Morphogenetic Protein 7
Brain Neoplasms
Cell Movement
Cell Proliferation
Delayed-Action Preparations
Glioblastoma
Humans
Immunoenzyme Techniques
Mice
Mice, Nude
Microspheres
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
title_short Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
title_full Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
title_fullStr Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
title_full_unstemmed Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
title_sort Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma
dc.creator.none.fl_str_mv González-Gómez, P.
Crecente-Campo, J.
Zahonero, C.
De La Fuente Freire, María
Hernández-Laín, A.
Mira, H.
Sánchez-Gómez, P.
Garcia-Fuentes, M.
author González-Gómez, P.
author_facet González-Gómez, P.
Crecente-Campo, J.
Zahonero, C.
De La Fuente Freire, María
Hernández-Laín, A.
Mira, H.
Sánchez-Gómez, P.
Garcia-Fuentes, M.
author_role author
author2 Crecente-Campo, J.
Zahonero, C.
De La Fuente Freire, María
Hernández-Laín, A.
Mira, H.
Sánchez-Gómez, P.
Garcia-Fuentes, M.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Animals
Apoptosis
Blotting, Western
Bone Morphogenetic Protein 7
Brain Neoplasms
Cell Movement
Cell Proliferation
Delayed-Action Preparations
Glioblastoma
Humans
Immunoenzyme Techniques
Mice
Mice, Nude
Microspheres
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
topic Animals
Apoptosis
Blotting, Western
Bone Morphogenetic Protein 7
Brain Neoplasms
Cell Movement
Cell Proliferation
Delayed-Action Preparations
Glioblastoma
Humans
Immunoenzyme Techniques
Mice
Mice, Nude
Microspheres
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
description Glioblastoma 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 GFAPdelta. 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.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.11940/8228
url http://hdl.handle.net/20.500.11940/8228
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:RUNA. Repositorio da Consellería de Sanidade e Sergas
instname:Servizo Galego de Saúde (SERGAS)
instname_str Servizo Galego de Saúde (SERGAS)
reponame_str RUNA. Repositorio da Consellería de Sanidade e Sergas
collection RUNA. Repositorio da Consellería de Sanidade e Sergas
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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