Membrane-Type 4 Matrix Metalloproteinase (MT4-MMP) induces lung metastasis by alteration of primary breast tumor vascular architecture

The present study aims at investigating the mechanism by which MT4-MMP, a membrane-anchored MMP expressed by human breast tumor cells promotes the metastatic dissemination into lung. We applied experimental (intravenous) and spontaneous (subcutaneous) models of lung metastasis using human breast adenocarcinoma MDA-MB-231 cells overexpressing or not MT4-MMP. We found that MT4-MMP does not affect lymph node colonization nor extravasation of cells from the bloodstream, but increases the intravasation step leading to metastasis. Ultrastructural and fluorescent microscopic observations coupled with automatic computer-assisted quantifications revealed that MT4-MMP expression induces blood vessel enlargement and promotes the detachment of mural cells from the vascular tree, thus causing an increased tumor vascular leak. On this basis, we propose that MT4-MMP promotes lung metastasis by disturbing the tumor vessel integrity and thereby facilitating tumor cell intravasation.