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Tumor‐derived TIMP‐2 mediates endothelial barrier dysfunction and breast cancer cell transmigration by activating endothelial MMP‐2
Author(s) -
Shen Qiang,
Lee Eugene S,
Pitts Robert L,
Wu Mack H,
Yuan Sarah Y
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.592.2
Subject(s) - angiogenesis , matrix metalloproteinase , endothelial stem cell , cancer research , metastasis , vascular endothelial growth inhibitor , cancer cell , cancer , chemistry , microbiology and biotechnology , biology , medicine , immunology , vascular endothelial growth factor a , vascular endothelial growth factor , in vitro , vegf receptors , biochemistry
Accumulating evidence suggests a dual role of tissue inhibitor of metalloproteinase‐2 (TIMP‐2) in regulating the activity of matrix metalloproteinase‐2 (MMP‐2), which has long been associated with tumor angiogenesis and metastasis. By forming a complex with pro‐MMP‐2 and its cell surface activator MMP‐14, TIMP‐2 can either induce or restrain MMP‐2 activation. Our recent work has shown that breast cancer cell adhesion to vascular endothelial cells activates endothelial MMP‐2. The purpose of this study was to explore the underlying mechanism and its potential impact on endothelial barrier function and transendothelial migration. We found that MMP‐14 was expressed in both breast cancer cells (MDA‐231) and lung microvascular endothelial cells (HBMVEC‐L), whereas TIMP‐2 was exclusively expressed in cancer cells. Importantly, the tumor cell‐derived TIMP‐2 was identified as a major determinant of MMP‐2 activation during tumor cell transmigration in the presence of MMP‐14. This response was associated with endothelial barrier dysfunction, as evidenced by a significant decrease in transendothelial electric resistance and endothelial cell‐cell junction disruption. These findings suggest a cooperative mechanism between metastatic breast cancer cells and microvascular endothelial cells in promoting MMP‐2 activation and tumor cell transmigration. NIH grants HL61507, HL70753, HL73324, HL84852