VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption.

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.

• Authors: Ana B García-Martín, Pascale Zwicky, Thomas Gruber, Christoph Matti, Federica Moalli, Jens V Stein, David Francisco, Gaby Enzmann, Mitchell P Levesque, Ekkehard Hewer, Ruth Lyck
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 39 Issue 10 Pg. 1995-2010 (10 2019) ISSN: 1559-7016 [Electronic] United States
• PMID: 29762071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin alpha4beta1

Topics

• Animals
• Blood-Brain Barrier (metabolism, pathology)
• Brain Neoplasms (metabolism, pathology, secondary)
• Capillary Permeability
• Cell Adhesion
• Cell Line, Tumor
• Cells, Cultured
• Endothelial Cells (metabolism, pathology)
• Humans
• Integrin alpha4beta1 (analysis, metabolism)
• Melanoma (metabolism, pathology)
• Mice, Inbred C57BL
• Transendothelial and Transepithelial Migration