Nelson A R, Fingleton B, Rothenberg M L, Matrisian L M
Department of Hematology, Vanderbilt University Medical Center, Nashville, TN, USA.
J Clin Oncol. 2000 Mar;18(5):1135-49. doi: 10.1200/JCO.2000.18.5.1135.
Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.
肿瘤进展是一个复杂的多阶段过程，在此过程中，正常细胞经历基因变化，导致表型改变，并获得在体内远处部位扩散和定植的能力。尽管许多因素调节恶性肿瘤的生长和扩散，但肿瘤与其周围微环境之间的相互作用会产生对肿瘤进展的每个步骤都至关重要的重要蛋白质产物。基质金属蛋白酶（MMPs）是一类与恶性肿瘤有明确联系的降解酶。这些酶与肿瘤细胞侵袭基底膜和基质、穿透血管以及转移有关。最近，它们还与原发性和转移性肿瘤的生长及血管生成有关，甚至可能在肿瘤促进中发挥作用。本综述概述了我们目前对MMP家族的理解，包括特定MMP与恶性表型的关联以及MMP在转移级联反应特定步骤中的作用。随着对MMPs科学认识的不断进步，利用阻断这些酶的治疗策略迅速发展。本文还研究了合成MMP抑制剂（MMPIs）的临床前和临床进展，讨论内容包括与确定MMPIs和其他新型治疗药物临床疗效相关的重要方法学问题。
