INHIBITION OF STROMAL MATRIX METALLOPROTEASES - EFFECTS ON BREAST-TUMOR PROMOTION BY FIBROBLASTS

Go-injection of fibroblasts with human epithelial breast-tumor MCF7 ce lls in the presence of Matrigel enhances tumor growth in nude mice. Wh ile most of the matrix metalloproteinases (MMPs) have been shown to be produced by stromal cells, tumor cells such as MCF7 cells are unable to produce MMPs. We therefore, hypothesized that the tumor-promoting e ffect of fibroblasts could be related to their production of MMPs. In order to inhibit stromal proteases, over-production of TIMP-2 was indu ced in MCF7 cells by in vitro retroviral-mediated gene transfer. TIMP- 2-producing MCF7 cells were then co-injected with fibroblasts into nud e mice. Alternatively, we evaluated the effect of Batimastat, a synthe tic inhibitor of MMPs, on the tumorigenicity of MCF7 cells co-inoculat ed with fibroblasts into nude mice. Both physiological (TIMP-2) and sy nthetic (Batimastat) inhibitors of MMPs were able to abolish the tumor -promoting effect of fibroblasts. On the contrary, they failed to modu late the tumorigenicity of MCF7 cells injected alone. Interestingly, M atrigel from which low-molecular-weight proteins or growth factors had been removed failed to favor the tumorigenicity of MCF7 cells inocula ted with fibroblasts. These findings emphasize the importance of fibro blasts in cancer progression, and suggest that their role could be rel ated at least in part to production of proteases which can induce the release of factors from the extracellular matrix. (C) 1998 Wiley-Liss, Inc.