组织金属蛋白酶抑制因子（TIMPs）是一组保守的蛋白质家族，最初被鉴定为细胞因子样红细胞生长因子。随后，TIMPs被确定为基质金属蛋白酶的内源性抑制剂。这些蛋白酶是病理条件下如癌症侵袭和转移中细胞外基质代谢的主要调节因子。因此，TIMPs立即被认识为组织稳态的重要调节因子。然而，TIMPs还表现出与金属蛋白酶调控无关的独特生物活性。尽管经常被忽视，这些非蛋白酶介导的TIMP功能展示了一系列潜在治疗价值的直接细胞效应。TIMP2是表达最丰富的TIMP家族成员，并且进行中的研究显示它的肿瘤抑制活性不仅限于蛋白酶抑制，还包括对肿瘤、内皮细胞和成纤维细胞在肿瘤微环境中的直接调节。最近的数据表明，TIMP2能够抑制原发肿瘤生长和转移巢生成。TIMP2直接与细胞受体和基质元素相互作用，调节细胞信号转导通路，从而减少肿瘤、内皮细胞和成纤维细胞人群的增殖和迁移。这些效应导致细胞粘附和重点接触的形成增强，同时减少肿瘤和内皮细胞的增殖、迁移和上皮间质转变。这些发现与TIMP2除了简单的金属蛋白酶活性抑制之外的稳态功能一致。本综述文章讨论了TIMP2功能的持续演化、TIMP研究的未来展望以及TIMP2的治疗潜力。 Elsevier Inc.出版。

Tissue inhibitors of metalloproteinases (TIMPs) are a conserved family of proteins that were originally identified as cytokine-like erythroid growth factors. Subsequently, TIMPs were characterized as endogenous inhibitors of Matrixin proteinases. These proteinases are the primary mediators of extracellular matrix turnover in pathologic conditions such as cancer invasion and metastasis. Thus, TIMPs were immediately recognized as important regulators of tissue homeostasis. However, TIMPs also demonstrate unique biological activities that are independent of metalloproteinase regulation. Although often overlooked, these non-protease-mediated TIMP functions demonstrate a variety of direct cellular effects of potential therapeutic value. TIMP2 is the most abundantly expressed TIMP family member, and ongoing studies show that its tumor suppressor activity extends beyond protease inhibition to include direct modulation of tumor, endothelial, and fibroblast cellular responses in the tumor microenvironment. Recent data suggest that TIMP2 can suppress both primary tumor growth and metastatic niche formation. TIMP2 directly interacts with cellular receptors and matrisome elements to modulate cell signaling pathways that result in reduced proliferation and migration of neoplastic, endothelial, and fibroblast cell populations. These effects result in enhanced cell adhesion and focal contact formation while reducing tumor and endothelial proliferation, migration, and epithelial-to-mesenchymal transitions. These findings are consistent with TIMP2 homeostatic functions beyond simple inhibition of metalloprotease activity. This review examines the ongoing evolution of TIMP2 function, future perspectives in TIMP research, and the therapeutic potential of TIMP2.Published by Elsevier Inc.