title: Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases.
abstract: 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.
authors.affiliation: Institute of Biophysics, Biological Research Center, Szeged, Hungary.
authors.forename: Csilla
authors.initials: C
authors.lastname: Fazakas
authors.forename: Imola
authors.initials: I
authors.lastname: Wilhelm
authors.forename: Péter
authors.initials: P
authors.lastname: Nagyoszi
authors.forename: Attila E
authors.initials: AE
authors.lastname: Farkas
authors.forename: János
authors.initials: J
authors.lastname: Haskó
authors.forename: Judit
authors.initials: J
authors.lastname: Molnár
authors.forename: Hannelore
authors.initials: H
authors.lastname: Bauer
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Bauer
authors.forename: Ferhan
authors.initials: F
authors.lastname: Ayaydin
authors.forename: Ngo Thi Khue
authors.initials: NT
authors.lastname: Dung
authors.forename: László
authors.initials: L
authors.lastname: Siklós
authors.forename: István A
authors.initials: IA
authors.lastname: Krizbai
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000473:pathology*; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D051381:Rats; D057057:Serine Proteases / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration
chemical_list: D057057:Serine Proteases