A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth
A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth
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DOI：
10.1139/o96-090
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发表时间：
1996-01-01
期刊：
影响因子：
--
通讯作者：
Apte, SS
中科院分区：
文献类型：
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作者：
AnandApte, B;Bao, L;Apte, SS
金属蛋白酶的组织抑制剂（TIMPs）家族目前有四种不同的基因产物，它们是基质金属蛋白酶（MMPs）的特异性抑制剂。据信，MMPs和TIMP之间的局部平衡在发育过程中以及癌症和关节炎等疾病中的细胞外基质（ECM）重塑中发挥重要作用。与其他可溶性TIMP不同，TIMP-3是ECM的独特组分。人类TIMP-3基因的突变导致显性遗传的成人型失明（Sorsby眼底营养不良或SFD）。在这篇文章中，我们总结了什么是目前已知的TIMP-3，讨论可能导致SFD的机制，并调查TIMP-3对肿瘤生长的影响。用TIMP-3表达质粒转染乳腺癌和恶性黑色素瘤细胞系，并皮下注射到裸鼠体内。在6至8周的时间内所得肿瘤的生长曲线表明，TIMP-3的表达增加导致肿瘤生长的统计学显著抑制。肿瘤细胞在周围ECM中沉积TIMP-3可通过防止肿瘤的局部扩张、延迟ECM中隔离的生长因子的释放或抑制血管生成来抑制肿瘤生长。TIMP-3过表达对两种肿瘤细胞株的体外生长无影响。由于重组TIMP-3抑制内皮细胞迁移和管形成的血管生成因子的反应，我们认为，TIMP-3对肿瘤生长的影响，在这项研究中看到的可能是其血管生成抑制作用的结果。
The family of tissue inhibitors of metalloproteinases (TIMPs) presently numbers four distinct gene products that are specific inhibitors of the matrix metalloproteinases (MMPs). The local balance between MMPs and TIMPs is believed to play a major role in extracellular matrix (ECM) remodeling during development and in diseases such as cancer and arthritis. Unlike the other TIMPs, which are soluble, TIMP-3 is unique in being a component of ECM. Mutations in the human TIMP-3 gene cause a dominantly inherited, adult-onset blindness (Sorsby's fundus dystrophy or SFD). In this article, we summarize what is currently known about TIMP-3, discuss possible mechanisms leading up to SFD, and investigate the effect of TIMP-3 on tumor growth. Breast carcinoma and malignant melanoma cell lines were transfected with TIMP-3 expression plasmids and injected subcutaneously into nude mice. Growth curves of the resulting tumors over a period of 6 to 8 weeks demonstrated that increased expression of TIMP-3 resulted in a statistically significant suppression of tumor growth. Deposition of TIMP-3 in the surrounding ECM by tumor cells may inhibit tumor growth by preventing local expansion of tumor, retarding the release of growth factors sequestered in ECM, or inhibiting angiogenesis. TIMP-3 over-expression had no effect on the growth of the two tumor cell lines in vitro. Because recombinant TIMP-3 inhibits endothelial cell migration and tube formation in response to angiogenic factors, we believe that the effect of TIMP-3 on tumor growth seen in this study may be a consequence of its angiostatic action.