REQUIREMENT FOR MATRIX METALLOPROTEINASE-9 (GELATINASE-B) EXPRESSION IN METASTASIS BY MURINE PROSTATE CARCINOMA

Although a number of effective therapies are available for localized p rostate cancer, metastatic prostate cancer is difficult to treat and i mpossible to cure. Identification of the gene products that enable a p rostatic carcinoma cell to metastasize should facilitate an understand ing of the processes leading to metastasis. To characterize the contri bution of matrix metalloproteinase-9 (MMP-9, gelatinase B or the 92-kd type IV gelatinase/collagenase) to the development of metastasis in p rostate cancer, we reduced MMP-9 expression in metastatic murine prost atic carcinoma cells using a ribozyme. The ribozyme transfected cells had lower basal levels of MMP-9 as well as decreased levels after stim ulation by transforming growth factor-beta or phorbol 12-myristate 13- acetate when compared with the parental cells or with control transfec tants. The cells with down-regulated MMP-9 were unable to form lung co lonies in the experimental metastasis assay, whereas the controls and parental cells readily formed metastases. All cell types readily forme d tumors after injection and down-regulation of MMP-9 did not adversel y affect the rate of tumor growth. Thus, MMP-9 expression is required for hematogenous metastasis in a murine prostate model system raising the possibility that it may play an equivalent role in human prostate cancer.