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.