HOST TIMP-1 OVEREXPRESSION CONFERS RESISTANCE TO EXPERIMENTAL BRAIN METASTASIS OF A FIBROSARCOMA CELL-LINE

Within the tumor-stromal microenvironment a disrupted balance between matrix metalloproteinases (MMPs) and their inhibitors compromises the integrity of the extracellular matrix and promotes malignancy. Tissue inhibitors of metalloproteinases (TIMPs) have been linked to tumor sup pression in studies of genetically altered tissue culture cells and in analyses of clinical specimens in situ. We generated transgenic mice as a model system to test the relationship between TIMP-1 levels in a host organ and susceptibility to experimentally targeted metastasis. E ctopically overexpressed TIMP-1 in the brain resulted in a tissue micr oenvironment with elevated protein levels of this natural MMP inhibito r. Metastatic challenge provided by lacZ-tagged fibrosarcoma cells per mitted high-resolution analysis of metastatic load and pattern. We fou nd that elevated host TIMP-1 imposed resistance to experimental metast asis of fibrosarcoma: In TIMP-1 overexpressing mice, brain metastases were significantly reduced by 75% compared to wild-type littermates. O ur findings demonstrate that ectopic TIMP-1 expression efficiently exe rts a suppressive effect on metastasizing tumor cells.