Transmigration of melanoma cells through the blood-brain barrier: Role of endothelial tight junctions and melanoma-released serine proteases

Csilla Fazakas, I. Wilhelm, Péter Nagyoszi, Attila E. Farkas, János Haskó, Judit Molnár, Hannelore Bauer, Hans Christian Bauer, F. Ayaydin, Ngo Thi Khue Dung, L. Siklós, I. Krizbai

Research output: Article

68 Citations (Scopus)

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.

Original languageEnglish
Article numbere20758
JournalPLoS One
Volume6
Issue number6
DOIs
Publication statusPublished - 2011

Fingerprint

blood-brain barrier
tight junctions
Tight Junctions
Endothelial cells
Serine Proteases
serine proteinases
melanoma
Blood-Brain Barrier
Melanoma
Brain
endothelial cells
Endothelial Cells
cells
brain
Monolayers
Serine Proteinase Inhibitors
Disintegration
Neurology
Cell culture
metastasis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Transmigration of melanoma cells through the blood-brain barrier : Role of endothelial tight junctions and melanoma-released serine proteases. / Fazakas, Csilla; Wilhelm, I.; Nagyoszi, Péter; Farkas, Attila E.; Haskó, János; Molnár, Judit; Bauer, Hannelore; Bauer, Hans Christian; Ayaydin, F.; Dung, Ngo Thi Khue; Siklós, L.; Krizbai, I.

In: PLoS One, Vol. 6, No. 6, e20758, 2011.

Research output: Article

Fazakas, Csilla ; Wilhelm, I. ; Nagyoszi, Péter ; Farkas, Attila E. ; Haskó, János ; Molnár, Judit ; Bauer, Hannelore ; Bauer, Hans Christian ; Ayaydin, F. ; Dung, Ngo Thi Khue ; Siklós, L. ; Krizbai, I. / Transmigration of melanoma cells through the blood-brain barrier : Role of endothelial tight junctions and melanoma-released serine proteases. In: PLoS One. 2011 ; Vol. 6, No. 6.
@article{71c5e1379652408eb428ed3a7d1b28f9,
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{\circledR} 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.",
author = "Csilla Fazakas and I. Wilhelm and P{\'e}ter Nagyoszi and Farkas, {Attila E.} and J{\'a}nos Hask{\'o} and Judit Moln{\'a}r and Hannelore Bauer and Bauer, {Hans Christian} and F. Ayaydin and Dung, {Ngo Thi Khue} and L. Sikl{\'o}s and I. Krizbai",
year = "2011",
doi = "10.1371/journal.pone.0020758",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Transmigration of melanoma cells through the blood-brain barrier

T2 - Role of endothelial tight junctions and melanoma-released serine proteases

AU - Fazakas, Csilla

AU - Wilhelm, I.

AU - Nagyoszi, Péter

AU - Farkas, Attila E.

AU - Haskó, János

AU - Molnár, Judit

AU - Bauer, Hannelore

AU - Bauer, Hans Christian

AU - Ayaydin, F.

AU - Dung, Ngo Thi Khue

AU - Siklós, L.

AU - Krizbai, I.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79957976779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79957976779&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0020758

DO - 10.1371/journal.pone.0020758

M3 - Article

C2 - 21674054

AN - SCOPUS:79957976779

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e20758

ER -