Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases.
Open accessAbstract
Malignant melanoma represents the third common cause of brain metastasis, having the highest propensity to metastasize to the brain of all primary neoplasms in adults. Since the central nervous system lacks a lymphatic system, the only possibility for melanoma cells to reach the brain is via the blood stream and the blood-brain barrier. Despite the great clinical importance, mechanisms of transmigration of melanoma cells through the blood-brain barrier are incompletely understood. In order to investigate this question we have used an in vitro experimental setup based on the culture of cerebral endothelial cells (CECs) and the A2058 and B16/F10 melanoma cell lines, respectively. Melanoma cells were able to adhere to confluent brain endothelial cells, a process followed by elimination of protrusions and transmigration from the luminal to the basolateral side of the endothelial monolayers. The transmigration process of certain cells was accelerated when they were able to use the routes preformed by previously transmigrated melanoma cells. After migrating through the endothelial monolayer several melanoma cells continued their movement beneath the endothelial cell layer. Melanoma cells coming in contact with brain endothelial cells disrupted the tight and adherens junctions of CECs and used (at least partially) the paracellular transmigration pathway. During this process melanoma cells produced and released large amounts of proteolytic enzymes, mainly gelatinolytic serine proteases, including seprase. The serine protease inhibitor Pefabloc® was able to decrease to 44-55% the number of melanoma cells migrating through CECs. Our results suggest that release of serine proteases by melanoma cells and disintegration of the interendothelial junctional complex are main steps in the formation of brain metastases in malignant melanoma.
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Proteolytic enzymes such as heparanase and seprase are important for the capacity of metastatic cells to traverse the BBB and occupy the brain, and micrometastases give rise to macrometastases through proliferation along brain microvessels.
“proteolytic enzymes such as heparanase and seprase are important for the capacity of metastatic cells to traverse the BBB and occupy the brain”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Fazakas et al., 2011
To cross the BBB, tumor cells bind endothelial cells and disrupt their tight junctions, and melanoma cells adhere to and disturb the interaction of brain endothelial cells through a disruption of tight and adherence junction proteins such as Claudin 5 and ZO-1.
“To cross the BBB, tumor cells bind endothelial cells and disrupt their tight junctions”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Fazakas et al., 2011
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Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120 · see citing works
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- Authors
- Fazakas, C., Wilhelm, I., Nagyőszi, P., Farkas, A. E., Haskó, J., Molnár, J., Bauer, H., Bauer, H.-C., Ayaydin, F., Dung, N. T. K., Siklós, L., & Krizbai, I. A.
- Affiliations
- HUN-REN Szegedi Biológiai Kutatóközpont (HU)
- University of Salzburg (AT)
- Corresponding author
- Krizbai, István A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-06-02
- Volume
- 6
- Issue
- 6
- Pages
- e20758
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3107231
- OpenAlex
- W1985649889
- Cited by
- 147
- References
- 43
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 12 · 2022: 5 · 2021: 12 · 2020: 11 · 2019: 17 · 2018: 12 · 2017: 5 · 2016: 13 · 2015: 13 · 2014: 13 · 2013: 16 · 2012: 2
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- melanoma, brain metastases, blood-brain barrier, endothelial transmigration, tight junctions, serine protease, seprase, paracellular pathway, adherens junctions, brain endothelial cells, protease inhibitors, tumor cell adhesion
- MeSH terms
- Animals, Blood-Brain Barrier, Humans, Melanoma, Tight Junctions, Endothelial Cells, Cell Line, Tumor, Mice, Rats, Serine Proteases, Transendothelial and Transepithelial Migration
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