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- Title
MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease.
- Authors
Szabova, L.; Chrysovergis, K.; Yamada, S. S.; Holmbeck, K.
- 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.Oncogene (2008) 27, 3274–3281; doi:10.1038/sj.onc.1210982; published online 10 December 2007
- Subjects
METASTASIS; CANCER invasiveness; CANCER cells; MOUSE mammary tumor virus; CYSTS (Pathology); CARDIOPULMONARY system; CONNECTIVE tissue cells; ONCOLOGY
- Publication
Oncogene, 2008, Vol 27, Issue 23, p3274
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210982