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.

Curcumin induces apoptosis and suppresses invasion through MAPK and MMP signaling in human monocytic leukemia SHI-1 cells

“…Studies have confirmed that MMP-2 and MMP-9 play an important role in the invasion process of various solid tumors (Ray et al, 1994) and are also abnormally expressed in AML; their expression levels are correlated with extramedullary infiltration by leukemia cells (Reikvam et al, 2010). Feng reported that tight junction proteins were more obviously disrupted in SHI-1 cells than in the HL-60 and U937 leukemic cell lines, which is consistent with the higher rate of invasion of SHI-1 cells and the high constitutive expression of MMP-2 and MMP-9 in this cell line (Feng et al, 2011;Wang et al, 2010). MMP-2 and MMP-9 are tightly regulated at the levels of transcription and secretion by multiple factors.…”

Pericellular proteolysis in cancer

“…Consistently, genetic or pharmacological inhibition of cathepsin S significantly impaired the development of experimental breast-to-brain metastasis . Similarly, degradation of the tight junction proteins claudin-5 and occludin by MMP2 and MMP9 secreted by leukemic cells led to BBB breakdown and contributed to CNS involvement in acute leukemia (Feng et al 2011). As these representative examples indicate, proteases can promote invasion and metastasis to multiple organ sites through a plethora of different molecular mechanisms.…”

De Novo Meningitis Caused by Propionibacterium acnes in a Patient with Metastatic Melanoma

“…Feng and others have hypothesized that matrix metalloproteinases secreted by leukemic cells may facilitate the breakdown of the blood-brain barrier (BBB), which may lead to seeding of the CSF during transient bacteremia (20). Additionally, melanoma is known to disrupt the BBB, and in our patient, disruption of the BBB by metastatic melanoma might have facilitated P. acnes to enter the CSF; however, it is unclear why P. acnes and not another organism might cause disease in this setting (21,22).…”