title: Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins.
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.affiliation: Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China.
authors.forename: Saran
authors.initials: S
authors.lastname: Feng
authors.forename: Jiannong
authors.initials: J
authors.lastname: Cen
authors.forename: Yihong
authors.initials: Y
authors.lastname: Huang
authors.forename: Hongjie
authors.initials: H
authors.lastname: Shen
authors.forename: Li
authors.initials: L
authors.lastname: Yao
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zixing
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D062507:Claudin-5; D057167:Claudins / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D062793:Occludin; D010539:Permeability / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D020298:U937 Cells; D062826:Zonula Occludens-1 Protein
chemical_list: C107466:CLDN5 protein, human; D062507:Claudin-5; D057167:Claudins; D004151:Dipeptides; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D011480:Protease Inhibitors; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9