Tissue Inhibitor of Metalloproteinase-2 Regulates Matrix Metalloproteinase-2–Mediated Endothelial Barrier Dysfunction and Breast Cancer Cell Transmigration through Lung Microvascular Endothelial Cells

Abstract

Matrix metalloproteinases (MMP) have been implicated in multiple stages of cancer metastasis. Tissue inhibitor of metalloproteinase-2 (TIMP-2) plays an important role in regulating MMP-2 activity. By forming a ternary complex with pro-MMP-2 and its activator MMP-14 on the cell surface, TIMP-2 can either initiate or restrain the cleavage and subsequent activation of MMP-2. Our recent work has shown that breast cancer cell adhesion to vascular endothelial cells activates endothelial MMP-2, promoting tumor cell transendothelial migration (TEME). However, the mechanism of MMP-2 regulation during TEME remains unclear. In the current study, we present evidence that MMP-14 is expressed in both invasive breast cancer cells (MDA-MB-231 and MDA-MB-436) and lung microvascular endothelial cells (HBMVEC-L), whereas TIMP-2 is exclusively expressed and released from the cancer cells. The tumor cell–derived TIMP-2 was further identified as a major determinant of endothelial MMP-2 activity during tumor cell transmigration in the presence of MMP-14. This response was associated with endothelial barrier dysfunction because coculture of MDA-MB-231 or MDA-MB-436 with HBMVEC-L caused a significant decrease in transendothelial electrical resistance concomitantly with endothelial cell-cell junction disruption and tumor cell transmigration. Knockdown of TIMP-2 or inhibition of TIMP-2/MMP-14 attenuated MMP-2–dependent transendothelial electrical resistance response and TEME. These findings suggest a novel interactive role of breast cancer cells and vascular endothelial cells in regulating the TIMP-2/MMP-14/MMP-2 pathway during tumor metastasis.

Role of MMP2 and MMP9 in TRPV4-induced lung injury

“…Thus, TRPV4-mediated increases in the availability of active MMP2 and MMP9 in the alveolar septal compartment could initiate cellular detachment and/or development of intercellular gaps. Indeed, active MMP2 and MMP9 alter barrier integrity in cultured lung epithelial and microvascular endothelial cells (38,49). Similarly, TRPV4 activation is known to elicit endothelial cell detachment in vitro and detachment/disruption of the lung septal endothelial barrier in vivo (2,50,56).…”

“…Active MMP2 and MMP9 degrade components of the alveolar basement membrane (10,52), nonmatrix components such as integrins (16,47), and intercellular targets such as E-cadherin (29,43). Indeed, active MMP2 and MMP9 alter barrier integrity in cultured lung epithelial and microvascular endothelial cells (38,49). Furthermore, increased MMP2 and MMP9 in bronchoalveolar lavage fluid (BALF) have been noted in patients with ARDS (8,28,46).…”

Melatonin inhibits IL1β-induced MMP9 expression and activity in human umbilical vein endothelial cells by suppressing NF-κB activation

“…MMP9, secreted by endothelial cells, disrupted the blood-brain barrier and made leukocyte recruitment because it was able to degrade components of the basal membrane of cerebral vessels (Sulik & Chyczewski 2008). Endothelial MMP2, which is activated by breast cancer cell adhesion to VE cells, could degrade interendothelial junctional protein VE-cadherin and promote cancer cell transendothelial migration (Shen et al 2010). Moreover, oxidants, inflammatory cytokines, and pharmacological agents can spur the activation of MMPs to destroy the adherens junctional protein VE-cadherin and the tight junctional protein occludin (Alexander & Elrod 2002, Navaratna et al 2007.…”

Therapy with Multipotent Mesenchymal Stromal Cells Protects Lungs from Radiation-Induced Injury and Reduces the Risk of Lung Metastasis

“…In particular matrix metalloproteinases (Mmps) have previously been shown to degrade the extracellular matrix and the basement membrane in the process of metastasis (49). Interestingly invasive breast cancer cells foster endothelial barrier dysfunction by the activation of endothelial Mmp2 production and thereby facilitate tumor cell extravasation through lung microvascular endothelial cells (36,54). We therefore speculated that the primary damage and functional impairment of the endothelial cell (EC) facilitates the formation of micrometastasis in the irradiated lung tissue.…”