Opposite effects of tissue inhibitor of metalloproteinases-1 (TIMP-1) over-expression and knockdown on colorectal liver metastases

BACKGROUND: Tissue inhibitors of metalloproteinases (TIMPs) and the corresponding metalloproteinases are integral parts of the protease network and have been shown to be involved in cancer development and metastasis. Paradoxically, for TIMP-1, tumor promoting as well as tumor inhibitory effects have been observed. METHODS: To address this paradox, we utilized the BALB/c/CT26 mouse model that reliably leads to liver metastasis after splenic tumor cell injection and variegated the type of target cells for therapeutic intervention and the modalities of gene transfer. Since we have observed before that over-expression of TIMP-1 in liver host cells leads to efficient tumor growth inhibition in this model, we now examined whether targeting the tumor cells themselves will have a similar effect. RESULTS: In concordance with the earlier results, TIMP-1 over-expression in tumor cells led to a dramatic reduction of tumor growth as well. To evaluate any influence of treatment modality, we further examined whether TIMP-1 knockdown in the same animal model would have the opposite effect on tumor growth than TIMP-1 over-expression. Indeed, TIMP-1 knockdown led to a marked increase in tumor burden. CONCLUSION: These data indicate that in the BALB/c/CT26 model, the modification of TIMP-1 has concordant effects irrespective of the type of target cell or the technique of modulation of TIMP-1 activity, and that TIMP-1 is unequivocally tumor inhibitory in this model.