Increased stromal expression of murine urokinase plasminogen activator in a human breast cancer xenograft model following treatment with the matrix metalloprotease inhibitor, batimastat

The matrix metalloprotease (MMP) family of enzymes and the urokinase plasmi nogen activator (uPA) pathway have both been implicated in tumor invasion a nd metastasis and in poor prognosis of cancer. We have previously shown tha t treatment with batimastat, a synthetic MMP inhibitor, leads to significan t retardation but not regression of tumor growth in a human breast cancer x enograft model. In addition, batimastat treatment did not inhibit local tum or invasion, nor did it encourage stromal encapsulation of the tumor, sugge sting the additional involvement of non-MMP proteolytic mechanisms. To inve stigate the presence of an alternative extracellular matrix protease whose activity is known to be important in breast cancer, but which is not inhibi ted by batimastat, expression of murine and human uPA were examined by in s itu hybridization and ELISA. No differences were observed between untreated and batimastat-treated tumors regarding human uPA mRNA and protein. In con trast, murine uPA mRNA expression was increased at the tumor-stromal juncti on in batimastat-treated tumors in comparison with the control tumors. In a greement with these results, batimastat treatment was shown to significantl y induce murine uPA protein content in the tumors. Inoculating MDA435/LCC-6 cells into immunodeficient, uPA-deficient mice resulted in tumor growth re tardation as compared to tumor growth in littermate wild-type controls, whi le addition of batimastat treatment to uPA-/- mice did not result in furthe r growth inhibition. The increased expression of stromal uPA may represent a cellular response to MMP inhibition and may demonstrate a new level of pl asticity in the malignant progression of the disease. These results may hav e important implications for the clinical applications of MMP inhibitors, a s well as for development of other anti-invasion drugs.