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Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood–Brain Barrier Disruption
- Source :
- International Journal of Molecular Sciences, Vol 22, Iss 7057, p 7057 (2021), International Journal of Molecular Sciences, Volume 22, Issue 13
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- 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.
- Subjects :
- Caveolin 1
Cell Culture Techniques
Connexin
cellular communication
blood–brain barrier
Mice
Caveolae
Gene Regulatory Networks
breast cancer brain metastases
Phosphorylation
Transcellular
Biology (General)
beta Catenin
Spectroscopy
paracellular and transcellular migration
Brain Neoplasms
Chemistry
General Medicine
Extravasation
Computer Science Applications
Cell biology
Gene Expression Regulation, Neoplastic
adhesion
medicine.anatomical_structure
Blood-Brain Barrier
Invadopodia
cardiovascular system
Female
Shear Strength
Myosin light-chain kinase
QH301-705.5
Breast Neoplasms
Blood–brain barrier
Article
Catalysis
Inorganic Chemistry
Focal adhesion
Cell Line, Tumor
medicine
Animals
Humans
Physical and Theoretical Chemistry
Molecular Biology
QD1-999
Organic Chemistry
Transendothelial and Transepithelial Migration
Connexin 43
Zonula Occludens-1 Protein
extravasation
Subjects
Details
- Language :
- English
- ISSN :
- 16616596 and 14220067
- Volume :
- 22
- Issue :
- 7057
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....f0f9d3cc8c23c4770b00da5463848a0e