Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis.

  title={Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis.},
  author={Laetitia Devy and Lili Huang and Laurent Naa and Niranjan Yanamandra and Henk Pieters and Nicolas Frans and Edward F. Chang and Qi Tao and Marc Vanhove and Annabelle Lejeune and Reinoud van Gool and Daniel J. Sexton and Guannan Kuang and Douglas Rank and Shannon Hogan and Csaba Pazmany and Yu Lu Ma and Sonia Schoonbroodt and Andrew E. Nixon and Robert Charles Ladner and René M. A. Hoet and Paula Henderikx and Christopher Tenhoor and Shafaat A. Rabbani and M. L. Valentino and Clive Ross Wood and Daniel T. Dransfield},
  journal={Cancer research},
  volume={69 4},
Inhibition of specific matrix metalloproteinases (MMP) is an attractive noncytotoxic approach to cancer therapy. MMP-14, a membrane-bound zinc endopeptidase, has been proposed to play a central role in tumor growth, invasion, and neovascularization. Besides cleaving matrix proteins, MMP-14 activates proMMP-2 leading to an amplification of pericellular proteolytic activity. To examine the contribution of MMP-14 to tumor growth and angiogenesis, we used DX-2400, a highly selective fully human MMP… 

Figures from this paper

Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer.

Two studies provide a preclinical proof-of-concept for MMP-14 targeting as an adjuvant treatment strategy for advanced ovarian cancer by inhibiting the migratory and invasive properties of aggressive ovarian cancer cells in vitro.

Mechanisms of Action of Novel Drugs Targeting Angiogenesis-Promoting Matrix Metalloproteinases

  • G. Fields
  • Biology, Chemistry
    Front. Immunol.
  • 2019
The mechanistically non-traditional MMP inhibitors offer treatment strategies for tumor angiogenesis that avoid the off-target toxicities and lack of specificity that plagued Zn2+-chelating inhibitors.

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

Current strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion are discussed, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold.

Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting

This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of M MPIs.

Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer

The structural character of MMP-2 is described followed by a review of the recent development of selective M MP-2 inhibitors based on their basic structures, which would be helpful for the treatment of cancer.

Matrix metalloproteinases in tumorigenesis: an evolving paradigm

The complex roles of MMPs and their endogenous inhibitors such as tissue inhibitors of metalloproteinase in tumorigenesis and strategies in suppressing M MPs are reviewed.

A new gallium complex inhibits tumor cell invasion and matrix metalloproteinase MMP-14 expression and activity.

Overall, these data show that GS2 is a promising compound for anti-invasive and anticancer therapy.

Syddansk Universitet Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo Botkjaer,

This is the first demonstration that an inhibitory antibody targeting sites outside the catalytic cleft of MT1-MMP can effectively abrogate its in vivo activity during tumorigenesis and metastasis.

Matrix metalloproteinase contribution in management of cancer proliferation, metastasis and drug targeting

This review will discuss both types of MMPs and current inhibitors, which target them in different aspects, including, biosynthesis, activation, secretion and catalytic activity.



Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis.

Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis.

Because of batimastat treatment, human breast carcinoma cells metastasized to the liver in nude mice and that an increase of liver metastases of murine T-cell lymphoma cells was observed in syngeneic mice.

Anti-Invasive, Antitumoral, and Antiangiogenic Efficacy of a Pyrimidine-2,4,6-trione Derivative, an Orally Active and Selective Matrix Metalloproteinases Inhibitor

Ro-28-2653, a selective and orally bioavailable MMPI with inhibitory activity against MMPs expressed by tumor and/or stromal cells, is a potent antitumor and antiangiogenic agent.

Preclinical and Clinical Studies of MMP Inhibitors in Cancer

Comparing the ability of broad‐spectrum and various types of selective matrix metalloproteinase inhibitors to induce tendinitis and to exhibit anticancer effects in an animal cancer model shows that under conditions in which both systemic exposure and inhibitor potency are controlled, selective inhibitors are less pro‐tendinitic, but are weaker anticancer agents than broad-spectrum agents such as marimastat.

Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations

The studies that brought MPIs into clinical testing are reviewed and the design and outcome of the trials are discussed in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression.

Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo.

The findings demonstrate that the inhibition pattern of cellular proteolytic activity achieved in vitro by a serine protease and an MMP inhibitor may lead to predictions that are not necessarily verified in vivo and may even have adverse effects.

Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas.

The results indicate that one mechanism of EGFR-mediated invasiveness in gliomas may involve the induction of MT1-MMP, and compounds additionally inhibited EGF-stimulated invasion in Matrigel Transwell assays.

Expression of membrane-type matrix metalloproteinase 1 (MT1-MMP) in tumor cells enhances pulmonary metastasis in an experimental metastasis assay.

Immunostaining of the consecutive tissue sections revealed that lung nodules expressing MT1-MMP were positive for gelatinase A as well, whereas MT1,MMP-negative cells were not stained for collagenase A at all, indicating that MT1 -MMP -expressing cells acquire specific ability to bind exogenous progelatinase A.

MT1-MMP Controls Tumor-induced Angiogenesis through the Release of Semaphorin 4D*

The results suggest that the proteolytic cleavage of Semaphorin 4D may provide a novel molecular mechanism by which membrane type 1-matrix metalloproteinase controls tumor-induced angiogenesis.

Type IV collagen induces matrix metalloproteinase 2 activation in HT1080 fibrosarcoma cells.

It is shown here that type IV collagen, a major component of basement membranes, promotes MMP-2 activation by HT1080 cells, consistent with the previous report that TIMP-2 degradation is probably linked to the MT1-MMP-dependent MMP -2 activation mechanism.