文章：

基质金属蛋白酶在癌症进展中的新功能

New functions for the matrix metalloproteinases in cancer progression

原文发布日期：2002-03-01

DOI: 10.1038/nrc745

类型: Review Article

开放获取: 否

要点：

1. The matrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases that consist of more than 21 human MMPs and numerous homologues from other species. They can be divided into eight structural classes, three of which are membrane bound.
2. The MMPs are synthesized as inactive zymogens and activated by proteinase cleavage. Their activity is regulated by endogenous inhibitors, including α2-macroglobulin; tissue inhibitors of metalloproteinases (TIMPs); small molecules with TIMP-like domains; and the membrane-bound inhibitor RECK (reversion-inducing cysteine-rich protein with kazal motifs).
3. Direct evidence for a role of MMPs in tumour progression comes from xenograft experiments using cancer cells with decreased and increased expression levels of MMPs or TIMPs, and from carcinogenesis experiments with mice that either lack a specific Mmp or Timp-1 or have organ-specific Mmp or Timp-1 overexpression.
4. MMPs are upregulated in almost every type of human cancer, and their expression is often associated with poor survival. Whereas some of the MMPs (for example, MMP-7) are expressed by the cancer cells, other MMPs (for example, MMP-2 and MMP-9) are synthesized by the tumour stromal cells, including fibroblasts, myofibroblasts, inflammatory cells and endothelial cells.
5. MMPs can promote cancer progression by increasing cancer-cell growth, migration, invasion, metastasis and angiogenesis. MMPs exert these effects by cleaving a diverse group of substrates, which include not only structural components of the extracellular matrix, but also growth-factor-binding proteins, growth-factor precursors, receptor tyrosine kinases, cell-adhesion molecules and other proteinases.
6. Several synthetic MMP inhibitors are undergoing Phase III clinical trials. Although a few encouraging results have been reported, some trials were prematurely terminated due to either lack of benefits or major adverse effects.
7. The clinical trials have so far focused on patients with advanced-stage disease. Based on animal experiments, we would expect, however, that clinical efficacy might be improved either by using MMP inhibitors in the treatment of early disease (in combination with conventional therapy), or as preoperative and postoperative treatment to prevent surgical-induced micrometastatic spread and recurrence of the disease.

要点翻译：

1. 基质金属蛋白酶（MMPs）是一个锌依赖性内肽酶家族，包含超过21种人类MMP及其他物种的同源物。根据结构特征可将其分为八类，其中三类为膜结合型。
2. MMPs以无活性的酶原形式合成，经蛋白酶切割后激活。其活性受内源性抑制剂调控，包括α2-巨球蛋白、金属蛋白酶组织抑制剂（TIMPs）、具有TIMP样结构域的小分子物质以及膜结合型抑制剂RECK（具有kazal基序的逆转诱导富含半胱氨酸蛋白）。
3. MMPs在肿瘤进展中作用的直接证据来自两方面：一是通过异种移植实验，采用MMPs或TIMPs表达水平降低或升高的癌细胞；二是通过致癌实验，使用缺乏特定Mmp或Timp-1基因，或具有器官特异性Mmp或Timp-1过表达的小鼠。
4. MMPs在几乎所有人类癌症类型中均出现上调表达，且其表达常与不良预后相关。部分MMPs（如MMP-7）由癌细胞表达，而其他MMPs（如MMP-2和MMP-9）则由肿瘤基质细胞（包括成纤维细胞、肌成纤维细胞、炎症细胞和内皮细胞）合成。
5. MMPs通过增强癌细胞生长、迁移、侵袭、转移和血管生成来促进癌症进展。这些效应是通过切割多种底物实现的，不仅包括细胞外基质的结构成分，还涉及生长因子结合蛋白、生长因子前体、受体酪氨酸激酶、细胞粘附分子及其他蛋白酶。
6. 目前有数种合成MMP抑制剂正在进行III期临床试验。虽已有部分令人鼓舞的结果报道，但一些试验因缺乏疗效或严重不良反应而提前终止。
7. 现有临床试验主要针对晚期疾病患者。但基于动物实验，我们预期通过以下方式可能提升临床疗效：将MMP抑制剂用于早期疾病治疗（联合常规疗法），或作为术前术后治疗手段，以预防手术引发的微转移扩散及疾病复发。

英文摘要：

Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?

摘要翻译： 

基质金属蛋白酶（MMPs）长期以来被认为与癌细胞的侵袭和转移有关。这为MMP抑制剂的临床试验提供了理论基础，然而结果却令人失望。然而我们现在知道，MMPs除了促进侵袭外还有其他功能，其底物不仅仅是细胞外基质成分，而且在癌症发展的侵袭前期就发挥作用。掌握这些知识后，我们是否可以重新思考MMP抑制剂在临床上的应用？

原文链接：

New functions for the matrix metalloproteinases in cancer progression