Cargando…

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

Breast 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Godinho-Pereira, Joana, Garcia, Ana Rita, Figueira, Inês, Malhó, Rui, Brito, Maria Alexandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268492/
https://www.ncbi.nlm.nih.gov/pubmed/34209088
http://dx.doi.org/10.3390/ijms22137057
_version_ 1783720370407211008
author Godinho-Pereira, Joana
Garcia, Ana Rita
Figueira, Inês
Malhó, Rui
Brito, Maria Alexandra
author_facet Godinho-Pereira, Joana
Garcia, Ana Rita
Figueira, Inês
Malhó, Rui
Brito, Maria Alexandra
author_sort Godinho-Pereira, Joana
collection PubMed
description Breast 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.
format Online
Article
Text
id pubmed-8268492
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-82684922021-07-10 Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption Godinho-Pereira, Joana Garcia, Ana Rita Figueira, Inês Malhó, Rui Brito, Maria Alexandra Int J Mol Sci Article Breast 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. MDPI 2021-06-30 /pmc/articles/PMC8268492/ /pubmed/34209088 http://dx.doi.org/10.3390/ijms22137057 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Godinho-Pereira, Joana
Garcia, Ana Rita
Figueira, Inês
Malhó, Rui
Brito, Maria Alexandra
Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
title Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
title_full Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
title_fullStr Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
title_full_unstemmed Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
title_short Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
title_sort behind brain metastases formation: cellular and molecular alterations and blood–brain barrier disruption
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268492/
https://www.ncbi.nlm.nih.gov/pubmed/34209088
http://dx.doi.org/10.3390/ijms22137057
work_keys_str_mv AT godinhopereirajoana behindbrainmetastasesformationcellularandmolecularalterationsandbloodbrainbarrierdisruption
AT garciaanarita behindbrainmetastasesformationcellularandmolecularalterationsandbloodbrainbarrierdisruption
AT figueiraines behindbrainmetastasesformationcellularandmolecularalterationsandbloodbrainbarrierdisruption
AT malhorui behindbrainmetastasesformationcellularandmolecularalterationsandbloodbrainbarrierdisruption
AT britomariaalexandra behindbrainmetastasesformationcellularandmolecularalterationsandbloodbrainbarrierdisruption