VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption.
J Cereb Blood Flow Metab
; 39(10): 1995-2010, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-29762071
ABSTRACT
Melanoma is the most aggressive skin cancer in humans. One severe complication is the formation of brain metastasis, which requires extravasation of melanoma cells across the tight blood-brain barrier (BBB). Previously, VLA-4 has been assigned a role for the adhesive interaction of melanoma cells with non-BBB endothelial cells. However, the role of melanoma VLA-4 for breaching the BBB remained unknown. In this study, we used a mouse in vitro BBB model and imaged the shear resistant arrest of melanoma cells on the BBB. Similar to effector T cells, inflammatory conditions of the BBB increased the arrest of melanoma cells followed by a unique post-arrest behavior lacking immediate crawling. However, over time, melanoma cells intercalated into the BBB and compromised its barrier properties. Most importantly, antibody ablation of VLA-4 abrogated melanoma shear resistant arrest on and intercalation into the BBB and protected the BBB from barrier breakdown. A tissue microarray established from human brain metastasis revealed that indeed a majority of 92% of all human melanoma brain metastases stained VLA-4 positive. We propose VLA-4 as a target for the inhibition of brain metastasis formation in the context of personalized medicine identifying metastasizing VLA-4 positive melanoma.
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MEDLINE
Assunto principal:
Neoplasias Encefálicas
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Barreira Hematoencefálica
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Integrina alfa4beta1
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Células Endoteliais
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Melanoma
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Cereb Blood Flow Metab
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
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