ROLES OF MEMBRANE TYPE MATRIX METALLOPROTEINASE IN BREAST TUMOR METASTASIS

明胶酶A(Gela)被认为对癌细胞的侵袭和转移起重要作用。明胶酶A是以一种不活跃的前酶(ProGelA)的形式产生的，并被癌细胞上的细胞表面激活剂激活。我们在1994年确定膜型基质金属蛋白酶是一种可能的细胞表面激活剂，并扩大了研究范围以阐明其与包括乳腺癌在内的癌症的相关性。在这三年中，我们取得了以下成果，得到了赠款的支持。结论：1.MT1-MMP1在乳腺癌、胃癌、结肠癌、头颈部癌和鼻咽癌中均有表达。MT1-MMPs在癌组织中的表达与Gela在组织中的激活有很好的相关性，提示MT1-MMPs可能是肿瘤中Gela的激活剂。免疫组织化学将MT1-MMPs和明胶酶A定位于癌细胞及其周围的间质成纤维细胞。而癌细胞不表达Gela，但在周围成纤维细胞中有表达。结果表明，MT1-MMP能以TIMP-2为接头与proGelA结合。因此，认为癌细胞表面形成了三个分子复合体。该复合体中的ProGelA被认为是被邻近的游离MT1-基质金属蛋白酶激活的。

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.