Tags

Type your tag names separated by a space and hit enter

Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins.
PLoS One 2011; 6(8):e20599Plos

Abstract

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.

Authors+Show Affiliations

Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21857898

Citation

Feng, Saran, et al. "Matrix Metalloproteinase-2 and -9 Secreted By Leukemic Cells Increase the Permeability of Blood-brain Barrier By Disrupting Tight Junction Proteins." PloS One, vol. 6, no. 8, 2011, pp. e20599.
Feng S, Cen J, Huang Y, et al. Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS ONE. 2011;6(8):e20599.
Feng, S., Cen, J., Huang, Y., Shen, H., Yao, L., Wang, Y., & Chen, Z. (2011). Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PloS One, 6(8), pp. e20599. doi:10.1371/journal.pone.0020599.
Feng S, et al. Matrix Metalloproteinase-2 and -9 Secreted By Leukemic Cells Increase the Permeability of Blood-brain Barrier By Disrupting Tight Junction Proteins. PLoS ONE. 2011;6(8):e20599. PubMed PMID: 21857898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. AU - Feng,Saran, AU - Cen,Jiannong, AU - Huang,Yihong, AU - Shen,Hongjie, AU - Yao,Li, AU - Wang,Yuanyuan, AU - Chen,Zixing, Y1 - 2011/08/17/ PY - 2011/01/10/received PY - 2011/05/05/accepted PY - 2011/8/23/entrez PY - 2011/8/23/pubmed PY - 2012/2/16/medline SP - e20599 EP - e20599 JF - PloS one JO - PLoS ONE VL - 6 IS - 8 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21857898/Matrix_metalloproteinase_2_and__9_secreted_by_leukemic_cells_increase_the_permeability_of_blood_brain_barrier_by_disrupting_tight_junction_proteins_ L2 - http://dx.plos.org/10.1371/journal.pone.0020599 DB - PRIME DP - Unbound Medicine ER -