title: The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic promoting effects.
abstract: 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.
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, GIGA-Cancer, University of Liege, Liège, Belgium.
authors.forename: Lorin
authors.initials: L
authors.lastname: Host
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paye
authors.forename: Benoit
authors.initials: B
authors.lastname: Detry
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D053515:Matrix Metalloproteinase 17 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics; D059748:Proteolysis; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D053515:Matrix Metalloproteinase 17