Freije José M P, Balbín Milagros, Pendás Alberto M, Sánchez Luis M, Puente Xose S, López-Otín Carlos
Departamento de Bioquímica, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
Adv Exp Med Biol. 2003;532:91-107. doi: 10.1007/978-1-4615-0081-0_9.
The matrix metalloproteinases (MMPs) are a family of more than 20 distinct enzymes that are frequently overexpressed in human tumors. Functional studies have shown that MMPs play an important role in the proteolytic destruction of extracellular matrix and basement membranes, thereby facilitating tumor invasion and metastasis. In addition, these enzymes may also be important in other steps of tumor evolution including neoplastic cell proliferation and angiogenesis stimulation. On the basis of the relevance of MMPs in tumor progression, a number of different strategies aimed to block the unwanted activity of these enzymes in cancer have been developed. Unfortunately, most clinical trials with the first series of MMP inhibitors have failed to show clear benefit in patients with advanced cancer. Explanations for this lack of success include the failure to recognize the role of these enzymes in early stages of the disease as well as inadequacy of either the employed inhibitors or the proteases to be targeted. The introduction of novel concepts such as tumor degradome, and global approaches to protease analysis, may facilitate the identification of the relevant MMPs that must be targeted in each individual cancer patient. On the other hand, the finding that MMPs are enzymes whose effects on biologically active substrates can have profound consequences on cell behaviour, suggests that selective inhibition of a limited set of MMPs at early stages of tumor evolution might be much more effective than using wide-spectrum inhibitors active against most family members, and administered to patients at late stages of the disease. Further studies directed to elucidate these questions will be necessary to clarify whether any of the multiple strategies of MMP inhibition may be part of future therapeutic approaches to control tumor progression.
基质金属蛋白酶（MMPs）是一个由20多种不同酶组成的家族，在人类肿瘤中经常过度表达。功能研究表明，MMPs在细胞外基质和基底膜的蛋白水解破坏中起重要作用，从而促进肿瘤侵袭和转移。此外，这些酶在肿瘤演变的其他步骤中也可能很重要，包括肿瘤细胞增殖和刺激血管生成。基于MMPs与肿瘤进展的相关性，已经开发了许多不同的策略来阻断这些酶在癌症中的不良活性。不幸的是，首批MMP抑制剂的大多数临床试验未能在晚期癌症患者中显示出明显益处。对此缺乏成功的解释包括未能认识到这些酶在疾病早期阶段的作用，以及所用抑制剂或要靶向的蛋白酶的不足。诸如肿瘤降解组等新概念的引入以及蛋白酶分析的全局方法，可能有助于确定每个癌症患者必须靶向的相关MMPs。另一方面，MMPs是其对生物活性底物的作用可对细胞行为产生深远影响的酶这一发现表明，在肿瘤演变的早期阶段选择性抑制有限的一组MMPs可能比使用对大多数家族成员有活性的广谱抑制剂并在疾病晚期给予患者更有效。有必要进行进一步的研究以阐明这些问题，以弄清楚MMP抑制的多种策略中是否有任何一种可能成为未来控制肿瘤进展的治疗方法的一部分。
