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Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood Brain Barrier Disruption

2021-06-30Artigo científico Acesso aberto
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dc.contributor.authorPereira, Joana
dc.contributor.authorGarcia, Ana Rita
dc.contributor.authorFigueira, Inês
dc.contributor.authorMalhó, Rui
dc.contributor.authorBrito, Maria Alexandra
dc.date.accessioned2022-08-09T17:28:08Z
dc.date.available2022-08-09T17:28:08Z
dc.date.issued2021-06-30
dc.date.updated2022-06-29T11:35:01Z
dc.description.abstractBreast cancer (BC) brain metastases is a life-threatening condition to which accounts the poor understanding of BC cells’ (BCCs) extravasation into the brain, precluding the development of preventive strategies. Thus, we aimed to unravel the players involved in the interaction between BCCs and blood–brain barrier (BBB) endothelial cells underlying BBB alterations and the transendothelial migration of malignant cells. We used brain microvascular endothelial cells (BMECs) as a BBB in vitro model, under conditions mimicking shear stress to improve in vivo-like BBB features. Mixed cultures were performed by the addition of fluorescently labelled BCCs to distinguish individual cell populations. BCC–BMEC interaction compromised BBB integrity, as revealed by junctional proteins (β-catenin and zonula occludens-1) disruption and caveolae (caveolin-1) increase, reflecting paracellular and transcellular hyperpermeability, respectively. Both BMECs and BCCs presented alterations in the expression pattern of connexin 43, suggesting the involvement of the gap junction protein. Myosin light chain kinase and phosphorylated myosin light chain were upregulated, revealing the involvement of the endothelial cytoskeleton in the extravasation process. β4-Integrin and focal adhesion kinase were colocalised in malignant cells, reflecting molecular interaction. Moreover, BCCs exhibited invadopodia, attesting migratory properties. Collectively, hub players involved in BC brain metastases formation were unveiled, disclosing possible therapeutic targets for metastases prevention.pt_PT
dc.description.sponsorshipThis work was funded by the Portuguese Foundation for Science and Technology (FCT), Portugal, grant numbers PTDC/MED-ONC/29402/2017, UIDP/04138/2020 and UIDB/04138/2020. We also acknowledge FCT financial support of J.G.-P. (SFRH/BD/145522/2019) and of A.R.G. (2020.07115.BD). We acknowledge the Faculty of Sciences of the University of Lisbon’s Microscopy Facility, a node of the Portuguese Platform of BioImaging (PPBI-POCI-01-0145-FEDER-022122). We also acknowledge Luís Marques (Faculty of Sciences, University of Lisbon) for the excellent technical support with image acquisition.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationGodinho-Pereira J, Garcia AR, Figueira I, Malhó R, Brito MA. Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption. International Journal of Molecular Sciences 2021;22:7057. https://doi.org/10.3390/ijms22137057.pt_PT
dc.identifier.doi10.3390/ijms22137057pt_PT
dc.identifier.slugcv-prod-2763459
dc.identifier.urihttp://hdl.handle.net/10451/54095
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationThe blood-brain barrier in brain metastasization of breast cancer: a source of biomarkers, a target for modulation and an obstacle to overcome
dc.relationUnravelling and modulating the interplay between breast cancer cells and blood-brain barrier endothelial cells: a new hope to prevent brain metastasis formation
dc.relation.publisherversionhttps://www.mdpi.com/1422-0067/22/13/7057pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectBlood–brain barrierpt_PT
dc.subjectBreast cancer brain metastasespt_PT
dc.subjectExtravasationpt_PT
dc.subjectParacellular and transcellular migrationpt_PT
dc.subjectAdhesionpt_PT
dc.subjectCellular communicationpt_PT
dc.titleBehind Brain Metastases Formation: Cellular and Molecular Alterations and Blood Brain Barrier Disruptionpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleThe blood-brain barrier in brain metastasization of breast cancer: a source of biomarkers, a target for modulation and an obstacle to overcome
oaire.awardTitleUnravelling and modulating the interplay between breast cancer cells and blood-brain barrier endothelial cells: a new hope to prevent brain metastasis formation
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F29402%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F145522%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//2020.07115.BD/PT
oaire.citation.startPage7057pt_PT
oaire.citation.titleInternational Journal of Molecular Sciencespt_PT
oaire.citation.volume22pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNamePereira
person.familyNameLourenço Figueira
person.familyNameMalhó
person.familyNameBrito
person.givenNameJoana
person.givenNameInês Margarida
person.givenNameRui
person.givenNameMaria
person.identifier.ciencia-idC913-1CF6-111E
person.identifier.ciencia-id8618-519D-6DEB
person.identifier.ciencia-id021B-D302-CF83
person.identifier.ciencia-id411E-6373-496A
person.identifier.orcid0000-0002-8219-6240
person.identifier.orcid0000-0003-4639-6883
person.identifier.orcid0000-0001-5287-869X
person.identifier.orcid0000-0002-8493-4649
person.identifier.ridM-8278-2013
person.identifier.scopus-author-id7103088772
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.cv.cienciaid411E-6373-496A | Maria Alexandra de Oliveira Silva Braga Pedreira de Brito
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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FF - CiênciaVitae - Faculdade de Farmácia