ALTERED TUMOR-GROWTH AND METASTASIS OF A T-CELL LYMPHOMA IN TIMP-1 TRANSGENIC MICE

The concept of tumor suppression by tissue inhibitor of metalloprotein ases (TIMPs) has evolved primarily from studies of genetically modulat ed tumor cells. The next step is to focus on the host and assess the p rotective potential of host TIMP-1 on primary tumor growth and metasta sis. We generated two transgenic mouse lines with altered Timp-1 expre ssion in skin and liver: one overexpressed Timp-1 (Timp-1(high)), and the other had antisense RNA-mediated Timp-1 reduction (Timp-1(low)), E SbL-lacZ T-lymphoma cells provided the tumor challenge, as they form p rimary tumors upon intradermal injection with spontaneous metastasis t o liver. Metastases were examined in X-Gal-stained whole-organ mounts. Timp-1 overexpression inhibited intradermal tumor growth and spontane ous metastasis, leading to prolonged survival of the mice. The opposit e effects occurred in Timp-1(low) mice, leading to shorter host surviv al, Experimental metastasis assays showed that Timp-1-compromised live rs in Timp-1(low) mice showed at least a doubling of metastatic foci a nd numerous additional micrometastases, indicative of increased host s usceptibility. However, Timp-1(high) mouse livers showed an unaltered metastatic load in the experimental metastasis assay. In conclusion, t hese data demonstrate that Timp-1 levels within a tissue predetermine the development and progression of T-cell lymphoma. (C) 1997 by The Am erican Society of Hematology.