VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption.
Details
Serval ID
serval:BIB_EE6F7DC01F05
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption.
Journal
Journal of cerebral blood flow and metabolism
ISSN
1559-7016 (Electronic)
ISSN-L
0271-678X
Publication state
Published
Issued date
10/2019
Peer-reviewed
Oui
Volume
39
Number
10
Pages
1995-2010
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
Keywords
Animals, Blood-Brain Barrier/metabolism, Blood-Brain Barrier/pathology, Brain Neoplasms/metabolism, Brain Neoplasms/pathology, Brain Neoplasms/secondary, Capillary Permeability, Cell Adhesion, Cell Line, Tumor, Cells, Cultured, Endothelial Cells/metabolism, Endothelial Cells/pathology, Humans, Integrin alpha4beta1/analysis, Integrin alpha4beta1/metabolism, Melanoma/metabolism, Melanoma/pathology, Mice, Inbred C57BL, Transendothelial and Transepithelial Migration, BBB leakage, Blood–brain barrier, in vitro live cell imaging, melanoma brain metastasis, tissue microarray, very late antigen-4
Pubmed
Web of science
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Create date
31/08/2020 13:02
Last modification date
10/11/2020 7:26