Cargando…

Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins

Central nervous system (CNS) involvement remains an important cause of morbidity and mortality in acute leukemia, the mechanisms of leukemic cell infiltration into the CNS have not yet been elucidated. The blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resourc...

Descripción completa

Detalles Bibliográficos
Autores principales: Feng, Saran, Cen, Jiannong, Huang, Yihong, Shen, Hongjie, Yao, Li, Wang, Yuanyuan, Chen, Zixing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157343/
https://www.ncbi.nlm.nih.gov/pubmed/21857898
http://dx.doi.org/10.1371/journal.pone.0020599
_version_ 1782210284629262336
author Feng, Saran
Cen, Jiannong
Huang, Yihong
Shen, Hongjie
Yao, Li
Wang, Yuanyuan
Chen, Zixing
author_facet Feng, Saran
Cen, Jiannong
Huang, Yihong
Shen, Hongjie
Yao, Li
Wang, Yuanyuan
Chen, Zixing
author_sort Feng, Saran
collection PubMed
description Central nervous system (CNS) involvement remains an important cause of morbidity and mortality in acute leukemia, the mechanisms of leukemic cell infiltration into the CNS have not yet been elucidated. The blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. How can the leukemic cells disrupt this barrier and invasive the CNS, even if many of the currently available chemotherapies can not cross the BBB? Tight junction in endothelial cells occupies a central role in the function of the BBB. Except the well known role of degrading extracellular matrix in metastasis of cancer cells, here we show matrix metalloproteinase (MMP)-2 and -9, secreted by leukemic cells, mediate the BBB opening by disrupting tight junction proteins in the CNS leukemia. We demonstrated that leukemic cells impaired tight junction proteins ZO-1, claudin-5 and occludin resulting in increased permeability of the BBB. However, these alterations reduced when MMP-2 and -9 activities were inhibited by RNA interference strategy or by MMP inhibitor GM6001 in an in vitro BBB model. We also found that the disruption of the BBB in company with the down-regulation of ZO-1, claudin-5 and occludin and the up-regulation of MMP-2 and -9 in mouse brain tissues with leukemic cell infiltration by confocal imaging and the assay of in situ gelatin zymography. Besides, GM6001 protected all mice against CNS leukemia. Our findings suggest that the degradation of tight junction proteins ZO-1, claudin-5 and occludin by MMP-2 and -9 secreted by leukemic cells constitutes an important mechanism in the BBB breakdown which contributes to the invasion of leukemic cells to the CNS in acute leukemia.
format Online
Article
Text
id pubmed-3157343
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-31573432011-08-19 Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins Feng, Saran Cen, Jiannong Huang, Yihong Shen, Hongjie Yao, Li Wang, Yuanyuan Chen, Zixing PLoS One Research Article Central nervous system (CNS) involvement remains an important cause of morbidity and mortality in acute leukemia, the mechanisms of leukemic cell infiltration into the CNS have not yet been elucidated. The blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. How can the leukemic cells disrupt this barrier and invasive the CNS, even if many of the currently available chemotherapies can not cross the BBB? Tight junction in endothelial cells occupies a central role in the function of the BBB. Except the well known role of degrading extracellular matrix in metastasis of cancer cells, here we show matrix metalloproteinase (MMP)-2 and -9, secreted by leukemic cells, mediate the BBB opening by disrupting tight junction proteins in the CNS leukemia. We demonstrated that leukemic cells impaired tight junction proteins ZO-1, claudin-5 and occludin resulting in increased permeability of the BBB. However, these alterations reduced when MMP-2 and -9 activities were inhibited by RNA interference strategy or by MMP inhibitor GM6001 in an in vitro BBB model. We also found that the disruption of the BBB in company with the down-regulation of ZO-1, claudin-5 and occludin and the up-regulation of MMP-2 and -9 in mouse brain tissues with leukemic cell infiltration by confocal imaging and the assay of in situ gelatin zymography. Besides, GM6001 protected all mice against CNS leukemia. Our findings suggest that the degradation of tight junction proteins ZO-1, claudin-5 and occludin by MMP-2 and -9 secreted by leukemic cells constitutes an important mechanism in the BBB breakdown which contributes to the invasion of leukemic cells to the CNS in acute leukemia. Public Library of Science 2011-08-17 /pmc/articles/PMC3157343/ /pubmed/21857898 http://dx.doi.org/10.1371/journal.pone.0020599 Text en Feng et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Feng, Saran
Cen, Jiannong
Huang, Yihong
Shen, Hongjie
Yao, Li
Wang, Yuanyuan
Chen, Zixing
Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins
title Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins
title_full Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins
title_fullStr Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins
title_full_unstemmed Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins
title_short Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins
title_sort matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157343/
https://www.ncbi.nlm.nih.gov/pubmed/21857898
http://dx.doi.org/10.1371/journal.pone.0020599
work_keys_str_mv AT fengsaran matrixmetalloproteinase2and9secretedbyleukemiccellsincreasethepermeabilityofbloodbrainbarrierbydisruptingtightjunctionproteins
AT cenjiannong matrixmetalloproteinase2and9secretedbyleukemiccellsincreasethepermeabilityofbloodbrainbarrierbydisruptingtightjunctionproteins
AT huangyihong matrixmetalloproteinase2and9secretedbyleukemiccellsincreasethepermeabilityofbloodbrainbarrierbydisruptingtightjunctionproteins
AT shenhongjie matrixmetalloproteinase2and9secretedbyleukemiccellsincreasethepermeabilityofbloodbrainbarrierbydisruptingtightjunctionproteins
AT yaoli matrixmetalloproteinase2and9secretedbyleukemiccellsincreasethepermeabilityofbloodbrainbarrierbydisruptingtightjunctionproteins
AT wangyuanyuan matrixmetalloproteinase2and9secretedbyleukemiccellsincreasethepermeabilityofbloodbrainbarrierbydisruptingtightjunctionproteins
AT chenzixing matrixmetalloproteinase2and9secretedbyleukemiccellsincreasethepermeabilityofbloodbrainbarrierbydisruptingtightjunctionproteins