OVEREXPRESSION OF TISSUE INHIBITOR OF METALLOPROTEINASES-2 BY RETROVIRAL-MEDIATED GENE-TRANSFER IN-VIVO INHIBITS TUMOR-GROWTH AND INVASION

We have demonstrated previously that overexpression of tissue inhibito r of metalloproteinases-2 (TIMP-2), an inhibitor of matrix-degrading m etalloproteinases, not only inhibits the invasive and metastatic behav ior of tumor cells but also significantly decreases tumor growth ill v ivo (Y. A. DeClerck et al., Cancer Res., 52: 701-708, 1992). This latt er effect was found to be dependent on the ability of TIMP-2 to preven t the degradation of the collagen matrix (A. M. Montgomery et al., Can cer Res., 54: 5467-5473, 1994). In this report, we have overexpressed TIMP-2 in tumor tissue by retroviral-mediated gene transfer into tumor cells by co-injecting s.c. in nude mice tumorigenic c-Ha-ras-transfec ted rat embryo fibroblasts with irradiated packaging cells producing h igh titer retroviral vectors containing the human TIMP-2 cDNA. The gro wth rate of tumors derived from cells co-injected with the TIMP-2 vect or producer cells was significantly slower than the growth rate of tum ors derived from cells co-injected with packaging cells producing a re trovirus containing the Escherichia coil beta-galactosidase gene. The transduction efficiency was estimated at 13%, and the production of a functional human TIMP-2 in tumor cells transduced with the TIMP-2-cont aining vector was documented. Furthermore, histological analysis of tu mors derived from tumor cells co-injected with the TIMP-2 vector produ cer cells revealed the presence of a thick connective tissue capsule a nd a lack of local invasion, The data indicate that retroviral-mediate d transduction of TIMP-2 cDNA into a limited population of tumor cells in vivo is sufficient to increase the accumulation of connective tiss ue proteins in tumor tissue, to inhibit growth, and to prevent local i nvasion.