The concept of tumor suppression by tissue inhibitor of metalloproteinases (TIMPs) has evolved primarily from studies of genetically modulated tumor cells. The next step is to focus on the host and assess the protective potential of host TIMP-1 on primary tumor growth and metastasis. We generated two transgenic mouse lines with altered Timp-1 expression in skin and liver: one overexpressed Timp-1 (Timp-1(high)), and the other had antisense RNA-mediated Timp-1 reduction (Timp-1(low)). ESbL-lacZ T-lymphoma cells provided the tumor challenge, as they form primary tumors upon intradermal injection with spontaneous metastasis to liver. Metastases were examined in X-Gal-stained whole-organ mounts. Timp-1 overexpression inhibited intradermal tumor growth and spontaneous metastasis, leading to prolonged survival of the mice. The opposite effects occurred in Timp-1(low) mice, leading to shorter host survival. Experimental metastasis assays showed that Timp-1-compromised livers in Timp-1(low) mice showed at least a doubling of metastatic foci and numerous additional micrometastases, indicative of increased host susceptibility. However, Timp-1(high) mouse livers showed an unaltered metastatic load in the experimental metastasis assay. In conclusion, these data demonstrate that Timp-1 levels within a tissue predetermine the development and progression of T-cell lymphoma.

PMID: 9292534 [PubMed - in process]