Inhibition of liver metastasis from orthotopically implanted colon cancer in nude mice by transfection of the TIMP-1 gene into KM12SM cells

To determine whether the tissue inhibitor of metalloproteinases 1 (TIMP-1) can modulate in vivo tumor growth and metastasis, we transfected TIMP-1 cDN A into KM12SM human colon carcinoma cells and determined the implanted tumo r volume and incidence of liver metastasis in orthotopically implanted colo n cancer in nude mice. We also treated the implanted tumors with repeated i ntraperitoneal injections of recombinant human TIMP-1 (rTIMP-1), and compar ed the inhibitory efficacy on liver metastasis with that achieved by the TI MP-1 transfectants. The TIMP-1 transfectants had a significantly greater in hibitory effect, in association with TIMP-1 expression, on the growth of th e primary tumor and on liver metastasis as compared with the controls. Howe ver, the intraperitoneal administration of rTIMP-1 did not decrease the rat e of liver metastasis. In situ hybridization demonstrated that TIMP-1 mRNA in the cecal tumors implanted with the highly produced KM12SMT-2 cells with TIMP-1 was mainly expressed by the tumor cells. These results suggest that the increased expression of TIMP-1 in KM12SM cells was responsible for the ir decreased metastatic potential, and that the endogenous increase in TIMP -1 production by the tumor cells might be more effective for counteracting the matrix metalloproteinases (MMPs) in tumor tissue and for inhibiting liv er metastasis from colon cancer than the exogenous administration of TIMPs.