ROLES OF MEMBRANE TYPE MATRIX METALLOPROTEINASE IN BREAST TUMOR METASTASIS

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Gelatinase A (GelA) is believed to be important for cancer cell invasion and metastasis. Gelatinase A is produced as an inactive proenzyme (proGelA) and activated by a cell surface activator on cancer cells. We identified membrane-type 1 matrix metalloproteinase as a possible cell surface activator in 1994 and have extended the study to elucidate its relevance to cancer including breast carcinomas. During the three years we obtained the following results supported by the grant.1. MT1-MMP expression was demonstrated in various types of human cancers such as breast, gastric, colon, head and neck, and nasophagial carcinomas.2. Expression of MT1-MMP in carcinomas correlated well to the activation of GelA in the tissue suggesting that MT1-MMP is surely the GelA activator in cancers.3. Immunohistochmistry localized both MT1-MMP and gelatinase A to the cancer cells and also surrounding stromal fibroblasts.4. However carcinoma cells did not express GelA but it was expressed in the surrounding fibroblasts.5. MT1-MMP was shown to bind proGelA by using TIMP-2 as a adapter. Thus Three molecular complex is thought to be formed on cancer cell surface. ProGelA in the complex is thought to be activated by the neighboring free MT1- MMP.