MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease.
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.
Szabova
L
L
Matrix Metalloproteinase Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892-4380, USA.
Chrysovergis
K
K
Yamada
S S
SS
Holmbeck
K
K
D000818:Animals; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011499:Protein Processing, Post-Translational; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C507096:Mmp14 protein, mouse; D003094:Collagen; D053511:Matrix Metalloproteinase 14