Over-expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma.

The balance between matrix metalloproteinases and their inhibitors is a critical factor which affects tumor invasion and metastasis. We have established a rat bladder carcinoma cell line, LMC19, which is tumorigenic, invasive and metastatic to the retroperitoneal lymph nodes and to the lungs in nude mice. LMC19 cells secrete pro-gelatinases A and B as well as tissue inhibitors of matrix metalloproteinase (TIMP1 and TIMP2). We conducted the present study to determine whether or not over-expression of TIMP1 and TIMP2 can affect the metastatic potential of LMC19 cells. We transfected the cells with an expression vector containing TIMP1 or TIMP2 cDNA, isolated several clones over-expressing TIMP1 or TIMP2 and assessed their invasive and metastatic potential by inoculation at an orthotopic site (urinary bladder) in nude mice. Our results show that the transfectants over-expressing TIMP1 and TIMP2 marginally affect primary tumor growth, local invasion or metastasis to the retroperitoneal lymph nodes but significantly inhibit extravascular growth of pulmonary tumor emboli. Our results suggest that the net activity of matrix metalloproteinases of tumor cells may be a critical factor that controls extravasation at this distant metastatic site.