Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo

Detalhes bibliográficos
Autor(a) principal: Trindade, A.
Data de Publicação: 2017
Outros Autores: Djokovic, D., Gigante, J., Mendonça, L., Duarte, A.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: https://doi.org/10.1186/s12885-017-3171-2
Resumo: This work was supported by the Portuguese Foundation for Science and Technology (FCT; http://www.fct.pt/index.phtml.en), Project PTDC/CVT/115703/2009 to AD; PTDC/SAU-ONC/116164/2009 and PTDC/SAU-ONC/121742/2010 to AT. DD, JG and LM are PhD students supported by grants SFRH/BD/29447/2006, SFRH/BD/73264/2010 and SFRH/BD/74229/2010 from FCT. AT is a Postdoctoral Researcher supported by grants SFRH/BPD/47079/2008 and SFRH/BPD/110174/2015 from FCT. CIISA has provided support through Project UID/CVT/00276/2013, funded by FCT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Editor
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spelling Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivoAngiogenesisDll4Drug-deliveryMetastasisNotchOverexpressionTumorSDG 3 - Good Health and Well-beingThis work was supported by the Portuguese Foundation for Science and Technology (FCT; http://www.fct.pt/index.phtml.en), Project PTDC/CVT/115703/2009 to AD; PTDC/SAU-ONC/116164/2009 and PTDC/SAU-ONC/121742/2010 to AT. DD, JG and LM are PhD students supported by grants SFRH/BD/29447/2006, SFRH/BD/73264/2010 and SFRH/BD/74229/2010 from FCT. AT is a Postdoctoral Researcher supported by grants SFRH/BPD/47079/2008 and SFRH/BPD/110174/2015 from FCT. CIISA has provided support through Project UID/CVT/00276/2013, funded by FCT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EditorBackground: The inhibition of Delta-like 4 (Dll4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic Dll4/Notch blockade. Alternatively, we explored the endothelial Dll4 overexpression using different mouse tumor models. Methods: We used a transgenic mouse model of endothelial-specific Dll4 overexpression, previously produced. Growth kinetics and vascular histopathology of several types of solid tumors was evaluated, namely Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas and RIP1-Tag2 insulinomas. Results: We found that increased Dll4/Notch signaling reduces tumor growth by reducing vascular endothelial growth factor (VEGF)-induced endothelial proliferation, tumor vessel density and overall tumor blood supply. In addition, Dll4 overexpression consistently improved tumor vascular maturation and functionality, as indicated by increased vessel calibers, enhanced mural cell recruitment and increased network perfusion. Importantly, the tumor vessel normalization is not more effective than restricted vessel proliferation, but was found to prevent metastasis formation and allow for increased delivery to the tumor of concomitant chemotherapy, improving its efficacy. Conclusions: By reducing endothelial sensitivity to VEGF, these results imply that Dll4/Notch stimulation in tumor microenvironment could be beneficial to solid cancer patient treatment by reducing primary tumor size, improving tumor drug delivery and reducing metastization. Endothelial specific Dll4 overexpression thus appears as a promising anti-angiogenic modality that might improve cancer control. © 2017 The Author(s).NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)RUNTrindade, A.Djokovic, D.Gigante, J.Mendonça, L.Duarte, A.2017-10-26T22:03:14Z2017-03-142017-03-14T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article13application/pdfhttps://doi.org/10.1186/s12885-017-3171-2eng1471-2407PURE: 3226914https://www.scopus.com/inward/record.uri?eid=2-s2.0-85014885082&doi=10.1186%2fs12885-017-3171-2&partnerID=40&md5=640eba5e412bd9bc328336a9702c4f77https://doi.org/10.1186/s12885-017-3171-2info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:12:51Zoai:run.unl.pt:10362/24650Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:28:05.943933Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
title Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
spellingShingle Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
Trindade, A.
Angiogenesis
Dll4
Drug-delivery
Metastasis
Notch
Overexpression
Tumor
SDG 3 - Good Health and Well-being
title_short Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
title_full Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
title_fullStr Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
title_full_unstemmed Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
title_sort Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
author Trindade, A.
author_facet Trindade, A.
Djokovic, D.
Gigante, J.
Mendonça, L.
Duarte, A.
author_role author
author2 Djokovic, D.
Gigante, J.
Mendonça, L.
Duarte, A.
author2_role author
author
author
author
dc.contributor.none.fl_str_mv NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
RUN
dc.contributor.author.fl_str_mv Trindade, A.
Djokovic, D.
Gigante, J.
Mendonça, L.
Duarte, A.
dc.subject.por.fl_str_mv Angiogenesis
Dll4
Drug-delivery
Metastasis
Notch
Overexpression
Tumor
SDG 3 - Good Health and Well-being
topic Angiogenesis
Dll4
Drug-delivery
Metastasis
Notch
Overexpression
Tumor
SDG 3 - Good Health and Well-being
description This work was supported by the Portuguese Foundation for Science and Technology (FCT; http://www.fct.pt/index.phtml.en), Project PTDC/CVT/115703/2009 to AD; PTDC/SAU-ONC/116164/2009 and PTDC/SAU-ONC/121742/2010 to AT. DD, JG and LM are PhD students supported by grants SFRH/BD/29447/2006, SFRH/BD/73264/2010 and SFRH/BD/74229/2010 from FCT. AT is a Postdoctoral Researcher supported by grants SFRH/BPD/47079/2008 and SFRH/BPD/110174/2015 from FCT. CIISA has provided support through Project UID/CVT/00276/2013, funded by FCT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Editor
publishDate 2017
dc.date.none.fl_str_mv 2017-10-26T22:03:14Z
2017-03-14
2017-03-14T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://doi.org/10.1186/s12885-017-3171-2
url https://doi.org/10.1186/s12885-017-3171-2
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1471-2407
PURE: 3226914
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85014885082&doi=10.1186%2fs12885-017-3171-2&partnerID=40&md5=640eba5e412bd9bc328336a9702c4f77
https://doi.org/10.1186/s12885-017-3171-2
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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