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The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic promoting effects

Lorin Host1, Alexandra Paye, Benoit Detry

  • 1Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, GIGA-Cancer, University of Liege, Liège, Belgium.

International Journal of Cancer
|January 21, 2012
PubMed

Insights

The catalytic activity of membrane-type 4 matrix metalloprotease (MT4-MMP) drives breast cancer growth and metastasis. Inactivating MT4-MMP

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Membrane-type 4 matrix metalloprotease (MT4-MMP) is linked to breast adenocarcinoma progression and metastasis.
  • The precise mechanism, particularly the role of MT4-MMP's proteolytic activity, in promoting tumor growth and spread remains unclear.

Purpose of the Study:

  • To investigate whether the pro-tumorigenic and pro-metastatic effects of MT4-MMP are dependent on its catalytic activity.
  • To elucidate the contribution of tumor-derived versus host-derived MT4-MMP in angiogenesis and tumor promotion.

Main Methods:

  • Site-directed mutagenesis was employed to inactivate MT4-MMP by substituting Glutamic acid 249 with Alanine in the active site.
  • Tumor growth, lung metastasis, and angiogenesis were assessed in vivo using genetically modified mice (recombination activating gene-1-deficient and MT4-MMP-deficient).
  • The requirement for a permissive microenvironment, including host angio-promoting factors like plasminogen activator inhibitor-1, was evaluated.

Main Results:

  • Active MT4-MMP significantly accelerated tumor growth and lung metastasis, alongside triggering an angiogenic switch.
  • These pro-tumorigenic effects were completely abolished upon MT4-MMP inactivation, highlighting the importance of its catalytic activity.
  • Tumor-derived MT4-MMP, not host-derived MT4-MMP, was found to contribute to angiogenesis, though it required host factors like PAI-1 to promote tumors.

Conclusions:

  • The catalytic activity of MT4-MMP within the tumor compartment is crucial for stimulating tumor growth and metastasis.
  • MT4-MMP acts as an intrinsic tumor cell determinant that shapes a permissive microenvironment conducive to cancer dissemination.
  • Targeting MT4-MMP's proteolytic function represents a potential therapeutic strategy for breast cancer.

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