Tissue inhibitors of metalloproteinases (TIMP) in invasion and proliferation
Tissue inhibitors of metalloproteinases (TIMP) in invasion and proliferation
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DOI：
10.1111/j.1699-0463.1999.tb01533.x
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发表时间：
1999-01-01
期刊：
影响因子：
2.8
通讯作者：
DeClerck, YA
中科院分区：
文献类型：
--
作者：
Henriet, P;Blavier, L;DeClerck, YA
基质金属蛋白酶组织抑制剂（TIMPs）是一类控制细胞外基质（ECM）中基质金属蛋白酶（MMPs）活性的天然抑制剂。到目前为止，这个科的四个成员在各种各样的物种中都有特征。这些抑制剂具有相似的结构特征，其特征是存在涉及二硫键的12个半胱氨酸残基，并且具有与MMPs形成抑制复合物的类似功能。TIMPs在癌症中的作用一直是一些研究人员报道的抗肿瘤活性和另一些研究人员报道的生长刺激活性相矛盾的报道的主题。在这里，我们将讨论我们实验室获得的一系列数据，这些数据支持TIMPs不仅作为入侵抑制剂，而且作为细胞生长调节剂的作用。以胎盘发育为例，我们观察到TIMP-2和TIMP-3的水平在交合后14.5天至17.5天之间稳步上升。TIMPs由海绵滋养层细胞选择性表达，这些细胞将富含胎儿血管和母体血窦的迷路区与形成胎儿和母体组织边界的巨细胞区分开。TIMPs也是体内肿瘤生长的有效抑制剂。在黑色素瘤细胞中，我们之前报道过表达TIMP-2抑制植入scid小鼠皮肤的肿瘤生长。这种生长抑制似乎与血管生成无关，但依赖于胶原基质。我们观察到，在纤维状I型胶原存在的情况下，黑色素瘤细胞在细胞周期的G(1)到S间期转变时发生生长停滞。这种阻滞是胶原蛋白纤维结构所特有的，因为在非纤维性胶原蛋白或其他ECM成分存在时不会观察到这种阻滞。它与细胞周期蛋白抑制剂p27（KIP1）的特异性上调有关。因此，这些数据表明，锚定独立细胞仍然对来自ECM的生长调节信号敏感，并且这些信号可以特异性地阻断肿瘤细胞周期。因此，我们对蛋白酶抑制剂（如TIMPs）在癌症中的作用的概念已经从最初的关注肿瘤侵袭和转移的抑制转变为更广泛的关注，即通过其作为ECM稳态调节剂的功能来控制肿瘤细胞生长的分子。
Tissue inhibitors of matrix metalloproteinases (TIMPs) are a family of natural inhibitors that control the activity of matrix metalloproteinases (MMPs) in the extracellular matrix (ECM). Four members of this family have been so far characterized in a variety of species. These inhibitors share a similar structural feature characterized by the presence of 12 cysteine residues involved in disulfide bonds and a similar function by their ability to form inhibitory complexes with MMPs. The role of TIMPs in cancer has been the subject of conflicting reports with an antitumor activity reported by some investigators and a growth stimulation activity reported by others. Here we will discuss a series of data obtained in our laboratory supporting a role of TIMPs not only as inhibitors of invasion but also as regulators of cell growth. Using placental development as an example of a regulated invasive process, we have observed that the levels of TIMP-2 and TIMP-3 steadily increase between day 14.5 and 17.5 post-coitus. TIMPs are selectively expressed by spongiotrophoblastic cells that separate the labyrinthine zone, rich in fetal blood vessels and maternal blood sinuses, from the zone of giant cells forming the border between fetal and maternal tissues. TIMPs are also potent inhibitors of tumor growth in vivo. In melanoma cells, we have previously reported that over-expression of TIMP-2 inhibits the growth of tumors implanted in the skin of scid mice. This growth inhibition seems independent of angiogenesis but dependent on the collagen matrix. We observed that in the presence of fibrillar type I collagen, melanoma cells undergo a growth arrest at the G(1) to S interphase transition of the cell cycle. This arrest is specific to the fibrillar structure of collagen because it is not observed in the presence of non-fibrillar collagen or other ECM components. It is associated with a specific upregulation of the cyclin inhibitor p27(KIP1). The, data therefore indicate that anchorage independent cells remain sensitive to growth regulatory signals that originate from the ECM and that these signals can specifically block tumor cell cycle. Thus our concept of the role of protease inhibitors such as TIMPs in cancer has substantially changed from an initial focus on inhibition of tumor invasion and metastasis to a broader focus on being molecules that - via their function as regulators of the ECM homeostasis - can control tumor cell growth.