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The proteolytic activity of MT4‐MMP is required for its pro‐angiogenic and pro‐metastatic promoting effects
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<jats:title>Abstract</jats:title><jats:p>Membrane‐type 4 matrix metalloprotease (MT4‐MMP) expression in breast adenocarcinoma stimulates tumor growth and metastatic spreading to the lung. However, whether these pro‐tumorigenic and pro‐metastatic effects of MT4‐MMP are related to a proteolytic action is not yet known. Through site directed mutagenesis MT4‐MMP has been inactivated in cancer cells through Glutamic acid 249 substitution by Alanine in the active site. Active MT4‐MMP triggered an angiogenic switch at day 7 after tumor implantation and drastically accelerated subcutaneous tumor growth as well as lung colonization in recombination activating gene‐1‐deficient mice. All these effects were abrogated upon MT4‐MMP inactivation. In sharp contrast to most MMPs being primarily of stromal origin, we provide evidence that tumor‐derived MT4‐MMP, but not host‐derived MT4‐MMP contributes to angiogenesis. A genetic approach using MT4‐MMP‐deficient mice revealed that the status of MT4‐MMP produced by host cells did not affect the angiogenic response. Despite of this tumor intrinsic feature, to exert its tumor promoting effect, MT4‐MMP requires a permissive microenvironment. Indeed, tumor‐derived MT4‐MMP failed to circumvent the lack of an host angio‐promoting factor such as plasminogen activator inhibitor‐1. Overall, our study demonstrates the key contribution of MT4‐MMP catalytic activity in the tumor compartment, at the interface with host cells. It identifies MT4‐MMP as a key intrinsic tumor cell determinant that contributes to the elaboration of a permissive microenvironment for metastatic dissemination.</jats:p>
Journal
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- International Journal of Cancer
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International Journal of Cancer 131 (7), 1537-1548, 2012-04-04
Wiley
