VanMeter T E, Rooprai H K, Kibble M M, Fillmore H L, Broaddus W C, Pilkington G J
Department of Neuropathology, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
J Neurooncol. 2001 Jun;53(2):213-35. doi: 10.1023/a:1012280925031.
Matrix metalloproteinases (MMPs) are cation-dependent endopeptidases which have been implicated in the malignancy of gliomas. It is thought that the MMPs play a critical role in both metastasis and angiogenesis, and that interference with proteases might therefore deter local tumor dissemination and neovascularization. However, the attempt to control tumor-associated proteolysis will rely on better definition of the normal tissue function of MMPs, an area of study still in its infancy in the central nervous system (CNS). Understanding the role of MMP-mediated proteolysis in the brain relies heavily on advances in other areas of molecular neuroscience, most notably an understanding of extracellular matrix (ECM) composition and the function of cell adhesion molecules such as integrins, which communicate knowledge of ECM composition intracellularly. Recently, protease expression and function has been shown to be strongly influenced by the functional state and signaling properties of integrins. Here we review MMP function and expression in gliomas and present examples of MMP profiling studies in glioma tissues and cell lines by RT-PCR and Western blotting. Co-expression of MMPs and certain integrins substantiates the gathering evidence of a functional intersection between the two, and inhibition studies using recombinant TIMP-1 and integrin antisera demonstrate significant inhibition of glioma invasion in vitro. Use of promising new therapeutic compounds with anti-MMP and anti-invasion effects are discussed. These data underline the importance of functional interaction of MMPs with accessory proteins such as integrins during invasion, and the need for further studies to elucidate the molecular underpinnings of this process.
基质金属蛋白酶（MMPs）是一类阳离子依赖性内肽酶，与胶质瘤的恶性程度有关。人们认为MMPs在转移和血管生成中都起着关键作用，因此干扰蛋白酶可能会阻止肿瘤的局部扩散和新血管形成。然而，控制肿瘤相关蛋白水解的尝试将依赖于对MMPs正常组织功能的更清晰定义，而这一研究领域在中枢神经系统（CNS）仍处于起步阶段。理解MMP介导的蛋白水解在大脑中的作用很大程度上依赖于分子神经科学其他领域的进展，最显著的是对细胞外基质（ECM）组成以及整合素等细胞粘附分子功能的理解，整合素可将ECM组成的信息传递到细胞内。最近，蛋白酶的表达和功能已被证明受到整合素功能状态和信号特性的强烈影响。在此，我们综述了MMPs在胶质瘤中的功能和表达，并通过RT-PCR和蛋白质印迹法展示了胶质瘤组织和细胞系中MMP分析研究的实例。MMPs与某些整合素的共表达证实了两者之间功能交叉的证据不断增多，使用重组TIMP-1和整合素抗血清的抑制研究表明，在体外可显著抑制胶质瘤的侵袭。本文还讨论了具有抗MMP和抗侵袭作用的新型有前景治疗化合物的应用。这些数据强调了MMPs与诸如整合素等辅助蛋白在侵袭过程中功能相互作用的重要性，以及进一步研究阐明这一过程分子基础的必要性。
