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MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease

L Szabova1, K Chrysovergis, S S Yamada

  • 1Matrix Metalloproteinase Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892-4380, USA.

Oncogene
|December 12, 2007
PubMed

Insights

Membrane-type I matrix metalloproteinase (MT1-MMP) is crucial for mammary cancer progression. MT1-MMP deficiency reduced tumor metastasis by 50%, highlighting its role in cancer cell dissemination.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Membrane-type I matrix metalloproteinase (MT1-MMP) is implicated in various cancers, including mammary cancer.
  • Understanding MT1-MMP's role in tumor progression and metastasis is critical for developing targeted therapies.

Purpose of the Study:

  • To investigate the direct impact of MT1-MMP deficiency on mammary tumor progression and metastasis.
  • To elucidate the mechanism by which MT1-MMP influences cancer cell dissemination.

Main Methods:

  • Generation of a genetically engineered mouse model by crossing MT1-MMP-deficient mice with MMTV-PyMT mice.
  • Orthotopic transplantation of mammary tumors into syngeneic recipient mice.
  • Assessment of tumor growth, metastasis to the lungs, and MT1-MMP expression in tumor stroma and metastatic sites.

Main Results:

  • MT1-MMP-deficient tumors showed earlier palpation and faster growth to experimental endpoint compared to wild-type tumors.
  • A significant reduction (50%) in lung metastasis was observed in MT1-MMP-deficient mice.
  • MT1-MMP was exclusively expressed in the tumor stroma, and metastatic nodules lacked MT1-MMP expression.
  • Stromal fibroblasts from MT1-MMP-deficient tumors exhibited impaired type I collagen degradation.

Conclusions:

  • Stromal MT1-MMP expression is essential for efficient mammary tumor cell metastasis.
  • MT1-MMP-mediated stromal remodeling of the tumor microenvironment is critical for cancer cell dissemination.
  • Targeting stromal MT1-MMP may represent a therapeutic strategy to inhibit cancer metastasis.

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