Remillard Taylor C, Bratslavsky Gennady, Jensen-Taubman Sandra, Stetler-Stevenson William G, Bourboulia Dimitra
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 USA.
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Advanced Technology Center, 8717 Grovemont Circle, Bethesda, MD 20892-4605 USA.
Mol Cell Ther. 2014 Jun 3;2:17. doi: 10.1186/2052-8426-2-17. eCollection 2014.
There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease. Their endogenous inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs), primarily function to prevent degradation of the ECM via inhibition of MMPs. However, recent studies demonstrate that TIMP family members also possess MMP-independent functions. One TIMP member in particular, TIMP-2, has many distinct properties and functions, that occur independent of MMP inhibition, including the inhibition of tumor growth and reduction of angiogenesis through decreased endothelial cell proliferation and migration. The MMP-independent molecular mechanisms and signaling pathways elicited by TIMP-2 in the TME are described in this review.
近年来，我们针对癌症的方式发生了范式转变，更加关注肿瘤微环境（TME）在癌症发生、发展和转移中的作用。在TME中，恶性细胞与周围细胞外基质之间存在信号传导和通讯的相互作用。基质金属蛋白酶（MMPs）是锌依赖性内切蛋白酶，能够降解肿瘤周围的基质并介导肿瘤生长、血管生成和转移性疾病。它们的内源性抑制剂——金属蛋白酶组织抑制剂（TIMPs），主要功能是通过抑制MMPs来防止细胞外基质的降解。然而，最近的研究表明，TIMP家族成员还具有不依赖MMP的功能。特别是一种TIMP成员TIMP-2，具有许多独特的特性和功能，这些特性和功能独立于MMP抑制作用而发生，包括通过减少内皮细胞增殖和迁移来抑制肿瘤生长和减少血管生成。本文综述了TIMP-2在TME中引发的不依赖MMP的分子机制和信号通路。
