Matrix metalloproteinases: Pro- and anti-angiogenic activities
Matrix metalloproteinases: Pro- and anti-angiogenic activities
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DOI：
10.1046/j.1087-0024.2000.00004.x
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发表时间：
2000-12-01
影响因子：
--
通讯作者：
Cornelius, LA
中科院分区：
文献类型：
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作者：
Raza, SL;Cornelius, LA
基质金属蛋白酶(MMPs)是一类结构相关的蛋白水解酶，因其降解细胞外基质的能力而被广泛认识，尽管最近的研究表明这些酶还有其他生物学功能。基质金属蛋白酶通常不是结构性表达的，但受以下因素的调控：(1)控制基因表达的细胞因子、生长因子以及细胞-细胞-基质相互作用；(2)它们的酶原形式的激活；(3)基质金属蛋白酶抑制物[TIMP]的存在，基质金属蛋白酶在正常过程中发挥重要作用，包括发育、伤口愈合、乳腺和子宫退缩，但也参与血管生成、肿瘤生长和转移。血管生成是指从原有的血管系统中建立新的血管，是伤口愈合等生物过程和关节炎、肿瘤生长和转移等病理过程所必需的。阻断基质金属蛋白酶的活性被研究为控制这种病理过程的潜在治疗效果。人工合成的基质金属蛋白酶抑制剂，最著名的是羟基化合物，已经为此目的而设计，目前正在进行临床试验。这些抑制剂可能具有广泛的相对于特定的基质金属蛋白酶抑制活性。然而，随着基质金属蛋白酶非基质降解能力的增强，即细胞因子的激活，蛋白质被加工成具有不同生物功能的分子，对于涉及基质金属蛋白酶的所有病理过程，是否是非选择性地抑制基质金属蛋白酶活性变得不太清楚。本文综述了基质金属蛋白酶在肿瘤侵袭和血管生成过程中的作用，并讨论了在这些过程中作为治疗剂的基质金属蛋白酶抑制剂的设计和使用。
Matrix metalloproteinases (MMP) are a family of structurally related proteinases most widely recognized for their ability to degrade extracellular matrix, although recent investigations have demonstrated other biologic functions for these enzymes. MMP are typically not constitutively expressed, but are regulated by: (1) cytokines, growth factors, and cell-cell and cell-matrix interactions that control gene expression; (2) activation of their proenzyme form; and (3) the presence of MMP inhibitors [tissue inhibitors of metalloproteinases, (TIMP)], MMP have important roles in normal processes including development, wound healing, mammary gland, and uterine involution, but are also involved in angiogenesis, tumor growth, and metastasis. Angiogenesis, characteristically defined as the establishment of new vessels from pre-existing vasculature, is required for biologic processes such as wound healing and pathologic processes such as arthritis, tumor growth, and metastasis. Blocking of MMP activity has been studied for potential therapeutic efficacy in controlling such pathologic processes. Synthetic MMP inhibitors, most notably the hydroxymates, have been engineered for this purpose and are presently in clinical trial. These inhibitors may have broad versus specific MMP inhibitory activity. As increased nonmatrix degrading capabilities of MMP are recognized, however, i.e., cytokine activation, processing of proteins to molecules of distinct biologic function, it becomes less clear whether the nonselective inhibition of MMP activity for all pathologic processes involving MMP is appropriate. This review focuses upon the contribution of MMP to the process of tumor invasion and angiogenesis, and discusses the design and use of MMP inhibitors as therapeutic agents in these processes.