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

Oncogene volume 27, pages 3274–3281 (2008)Cite this article

Abstract

Membrane-type I matrix metalloproteinase (MT1-MMP) is associated with multiple forms of cancer including mammary cancer. To directly evaluate the significance of MT1-MMP expression in tumor progression and metastasis using a genetically induced cancer model, we crossed MT1-MMP-deficient mice to MMTV–polyoma virus middle T-antigen (PyMT) mice. Expression of PyMT in the MT1-MMP-deficient background consistently resulted in hyperplasia of the mammary gland as seen in wild-type PyMT littermates. Following orthotopic transplantation of PyMT+ glands into the cleared mammary fat pad of syngeneic recipient mice, MT1-MMP-deficient tumors were palpable earlier than wild-type tumors. Moreover, MT1-MMP-deficient tumors grew to the experimental end point size quicker than control tumors, but demonstrated markedly reduced ability to metastasize to the lungs of recipient mice. Accordingly, MT1-MMP-deficient mice displayed an overall reduction in metastasis count of 50%. MT1-MMP was expressed solely in the stroma of PyMT-induced tumors and those metastatic nodules that formed in the lungs were devoid of MT1-MMP expression. Stromal fibroblasts isolated from MT1-MMP-deficient tumors did not degrade type I collagen suggesting that efficient dissemination of tumor cells is dependent on stromal cell remodeling of the tumor environment. The data demonstrate directly that MT1-MMP-mediated proteolysis by stromal cells is important in the metastatic process.

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Acknowledgements

We thank Pamela Robey, Silvio Gutkind and Thomas Bugge for critical reading of the manuscript. This work was supported by the DIR, NIDCR of the IRP, NIH.

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Authors and Affiliations

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

    L Szabova, K Chrysovergis, S S Yamada & K Holmbeck

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  1. L Szabova
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  2. K Chrysovergis
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  3. S S Yamada
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  4. K Holmbeck
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Correspondence to K Holmbeck.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Szabova, L., Chrysovergis, K., Yamada, S. et al. MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene 27, 3274–3281 (2008). https://doi.org/10.1038/sj.onc.1210982

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