Polette M, Birembaut P
INSERM U.314, Unité de Biologie Cellulaire, Laboratoire Pol Bouin, CHU Maison Blanche, Reims, France.
Int J Biochem Cell Biol. 1998 Nov;30(11):1195-202. doi: 10.1016/s1357-2725(98)00083-1.
Matrix metalloproteinases (MMPs) are members of a multigene family of zinc-dependent enzymes involved in the degradation of numerous extracellular matrix (ECM) components. Among these enzymes, membrane-type MMPs (MT-MMPs) play a major role in the activation of progelatinase A (MMP-2). The molecular structure of these enzymes is characterized by a transmembrane domain and the presence of an insertion of 11 amino-acids between the pro-peptide and the catalytic domains, which may be cleaved by furin-like enzymes leading to the activated form of the enzymes. MT1-MMP appears to play a dual role in extracellular matrix remodeling through activation of progelatinase A and procollagenase 3 and direct cleavage of some ECM macromolecules such as gelatin, type I collagen and fibronectin. Tissue inhibitor of MMPs-2 (TIMP-2) serves as an intermediate in progelatinase A activation by binding to MT1-MMP and progelatinase A on the plasma membrane. In vivo, MT1-MMP is overexpressed in malignant tumor tissues in which it was mainly localized in stromal cells surrounding the neoplastic tissue. These peritumoral fibroblasts, under particular stimuli, would be induced to overexpress MT1-MMP and consequently activate gelatinase A leading to ECM degradation. The expression of MT1-MMP is however observed in vitro in the invasive tumor cells which might represent an late stage of tumor progression. All these data confirm the important role of MT-MMPs in tumor invasion and highlight a cooperation between tumor and stromal cells for the production of these enzymes. The contribution of MMPs in a metastatic process leads to the development of novel therapies using inhibitors of these enzymes. Among a multitude of synthetic inhibitors generated, Marimastat is already clinically employed in cancer treatment.
基质金属蛋白酶（MMPs）是一个多基因家族的成员，属于锌依赖性酶，参与多种细胞外基质（ECM）成分的降解。在这些酶中，膜型MMPs（MT-MMPs）在明胶酶原A（MMP-2）的激活中起主要作用。这些酶的分子结构的特征是具有一个跨膜结构域，并且在原肽和催化结构域之间存在11个氨基酸的插入序列，该序列可能被弗林蛋白酶样酶切割，从而导致酶的活化形式。MT1-MMP似乎在细胞外基质重塑中发挥双重作用，它通过激活明胶酶原A和原胶原酶3以及直接切割一些ECM大分子，如明胶、I型胶原和纤连蛋白。MMPs-2的组织抑制剂（TIMP-2）通过与质膜上的MT1-MMP和明胶酶原A结合，在明胶酶原A的激活过程中起中间体的作用。在体内，MT1-MMP在恶性肿瘤组织中过度表达，主要定位于肿瘤组织周围的基质细胞中。这些肿瘤周围的成纤维细胞在特定刺激下会被诱导过度表达MT1-MMP，从而激活明胶酶A，导致ECM降解。然而，在体外侵袭性肿瘤细胞中也观察到MT1-MMP的表达，这可能代表肿瘤进展的晚期阶段。所有这些数据证实了MT-MMPs在肿瘤侵袭中的重要作用，并突出了肿瘤细胞与基质细胞在这些酶产生过程中的协同作用。MMPs在转移过程中的作用促使人们开发使用这些酶抑制剂的新型疗法。在众多合成抑制剂中，马立马司他已在临床上用于癌症治疗。
