Gelatinase B (MMP-9), but not its inhibitor (TIMP-1), dictates the growth rate of experimental thymic lymphoma

Dysregulation of metalloproteinase production at tumor sites contributes to the modification of local stromal tissue necessary for tumor development. Gelatinase B (matrix metalloproteinase-9, MMP-9) is one of the key enzymes that have been associated with the progression of several tumors. Paradoxic ally, MMP-9 expression by tumor cells, most notably by lymphoma cells, is c oncomitant with the expression of its physiological inhibitor, TIMP-1, Not only are both genes often co-expressed in the most aggressive forms of lymp homas but also both are up-regulated upon contact with stromal cells. Since TIMP-1 is known to regulate growth in several cell types and some aggressi ve lymphoma cells express TIMP-1 constitutively without MMP-9, it is unclea r whether the over-expression of MMP-9 is counterbalanced by TIMP-1 and whe ther TIMP-1 expression alone could favor the development of lymphoma. To ga in further insight into the respective roles of MMP-9 and TIMP-1 in lymphom a, we generated lymphoma cell lines expressing constitutively high levels o f MMP-9 or TIMP-1 and compared these cells for the ability to form thymic l ymphoma in vivo, Moreover, we generated lymphoma cell lines expressing cons titutively high levels of both MMP-9 and TIMP-1 to reproduce the net physio logical balance resulting from the expression of both genes simultaneously and to determine which gene overrides the other. Our results show that mice injected with lymphoma cells expressing MMP-9 constitutively developed thy mic lymphoma more rapidly than those injected with control lymphoma cells. Over-expression of TIMP-1 alone did not significantly influence tumor progr ession of lymphoma nor did it delay the capacity of MMP-9 to accelerate the development of thymic lymphoma, Int, J, Cancer 82:743-747, 1999, (C) 1999 Wiley-Liss, Inc.