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

TY - JOUR

T1 - MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease

AU - Szabova, L

AU - Chrysovergis, K

AU - Yamada, S S

AU - Holmbeck, K

PY - 2008/5/22

Y1 - 2008/5/22

N2 - 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.

AB - 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.

KW - Animals

KW - Carcinoma, Ductal, Breast/genetics

KW - Cell Proliferation

KW - Collagen/metabolism

KW - Disease Progression

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Mammary Neoplasms, Experimental/genetics

KW - Matrix Metalloproteinase 14/genetics

KW - Mice

KW - Models, Biological

KW - Neoplasm Invasiveness

KW - Neoplasm Metastasis

KW - Protein Processing, Post-Translational

KW - Stromal Cells/metabolism

KW - Tumor Cells, Cultured

KW - Up-Regulation

U2 - 10.1038/sj.onc.1210982

DO - 10.1038/sj.onc.1210982

M3 - Journal article

C2 - 18071307

SN - 0950-9232

VL - 27

SP - 3274

EP - 3281

JO - Oncogene

JF - Oncogene

IS - 23

ER -