A REVIEW OF TISSUE INHIBITOR OF METALLOPROTEINASES-3 (TIMP-3) AND EXPERIMENTAL-ANALYSIS OF ITS EFFECT ON PRIMARY TUMOR-GROWTH

The family of tissue inhibitors of metalloproteinases (TIMPs) presentl y numbers four distinct gene products that are specific inhibitors of the matrix metalloproteinases (MMPs). The local balance between MMPs a nd TIMPs is believed to play a major role in extracellular matrix (ECM ) remodeling during development and in diseases such as cancer and art hritis. Unlike the other TIMPs, which are soluble, TIMP-3 is unique in being a component of ECM. Mutations in the human TIMP-3 gene cause a dominantly inherited, adult-onset blindness (Sorsby's fundus dystrophy or SFD). In this article, we summarize what is currently known about TIMP-3, discuss possible mechanisms leading up to SFD, and investigate the effect of TIMP-3 on tumor growth. Breast carcinoma and malignant melanoma cell lines were transfected with TIMP-3 expression plasmids a nd injected subcutaneously into nude mice. Growth curves of the result ing tumors over a period of 6 to 8 weeks demonstrated that increased e xpression of TIMP-3 resulted in a statistically significant suppressio n of tumor growth. Deposition of TIMP-3 in the surrounding ECM by tumo r cells may inhibit tumor growth by preventing local expansion of tumo r, retarding the release of growth factors sequestered in ECM, or inhi biting angiogenesis. TIMP-3 over-expression had no effect on the growt h of the two tumor cell lines in vitro. Because recombinant TIMP-3 inh ibits endothelial cell migration and tube formation in response to ang iogenic factors, we believe that the effect of TIMP-3 on tumor growth seen in this study may be a consequence of its angiostatic action.