A case of tumor betrayal: biphasic effects of TIMP-1 on Burkitt's lymphoma.
A case of tumor betrayal: biphasic effects of TIMP-1 on Burkitt's lymphoma.
复制标题
肿瘤背叛案例：TIMP-1 对伯基特淋巴瘤的双相作用。
DOI：
10.1016/s0002-9440(10)64067-9
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Moses,MA
中科院分区：
文献类型：
--
作者：
Yan,L;Moses,MA
在许多能够消化细胞外基质 (ECM) 成分的不同蛋白酶中，基质金属蛋白酶 (MMP)（锌依赖性内肽酶家族）发挥着重要作用。 1 总的来说，MMP 已被证明可以独立或以协作方式裂解大多数 ECM 组件。由于 ECM 的过度消化是包括肿瘤生长和转移在内的许多病理状况的标志，因此在空间和时间上精确调节 MMP 活性至关重要。除了生长激素/因子、细胞因子、细胞-ECM 或细胞-细胞接触以及癌基因表达对 MMP 表达的转录和翻译控制外，MMP 活性还受到其内源性抑制剂（基质金属蛋白酶组织抑制剂 (TIMP)）的调节。 TIMP不仅直接控制活性MMP的活性，而且对MMP酶原的激活过程有实质性影响。 2-5 鉴于 TIMP 能够抑制 MMP 的蛋白水解活性，因此发现 TIMP 能够通过抑制肿瘤对基底膜的侵袭或通过抑制肿瘤血管生成来阻断肿瘤转移也就不足为奇了。 6 然而，最近的研究表明，TIMP 对肿瘤进展的抑制作用不仅在于其抑制 MMP 活性的能力，还在于其能够直接调节肿瘤细胞以及宿主内皮细胞 (EC) 的生长和凋亡。在本期《美国病理学杂志》上发表的一项有趣的研究中，Guedez 及其同事报道了 TIMP-1 对裸鼠伯基特淋巴瘤生长的不同影响。 96 当 Epstein-Barr 病毒阴性的伯基特淋巴瘤细胞通过逆转录病毒转染被迫过度表达 TIMP-1 时，观察到双相肿瘤生长模式。注射入裸鼠后，由于TIMP-1刺激肿瘤细胞增殖和防止细胞凋亡，这些细胞显示出最初的快速增殖期。然而，一旦这些肿瘤达到一定大小（0.4 mm2），最初的快速生长阶段就会被肿瘤进展减慢所取代，并伴有肿瘤坏死和消退。作者提供了令人信服的证据来表明这种晚期抑制是由肿瘤诱导的宿主血管生成的抑制引起的。这些新颖的体内结果强调了 MMP 及其内源性抑制剂在肿瘤进展和血管生成过程中的重要性。
Among a number of different proteinases that are capable of digesting extracellular matrix (ECM) components, the matrix metalloproteinases (MMPs), a family of zincdependent endopeptidases, play a major role. 1 Collectively, MMPs have been shown to cleave most ECM components either independently or in a collaborative manner. Because excessive digestion of ECM is a hallmark of many pathological conditions including tumor growth and metastasis, it is critical that MMP activity be precisely regulated both spatially and temporally. In addition to the transcriptional and translational control of MMP expression by growth hormones/factors, cytokines, cell-ECM or cell-cell contacts, and oncogene expression, MMP activity is regulated by their endogenous inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs). TIMPs not only directly control the activity of active MMPs, but also have substantial influence on the activation process of MMP zymogens. 2–5 Given the ability of TIMPs to inhibit the proteolytic activity of MMPs, it is not surprising to find that TIMPs are capable of blocking tumor metastasis, either by inhibiting tumor invasion of basement membrane or by restraining tumor angiogenesis. 6 However, recent studies have suggested that the inhibitory effects of TIMPs on tumor progression are not only due to their ability to inhibit MMP activity, but also because of their ability to directly modulate the cell growth and apoptosis of tumor cells, as well as host endothelial cells (ECs). In an intriguing study published in this issue of The American Journal of Pathology, divergent effects of TIMP-1 on Burkitt’s lymphoma growth in nude mice are reported by Guedez and co-workers. 96 When Epstein-Barr virusnegative Burkitt’s lymphoma cells were forced to overexpress TIMP-1 by retroviral transfection, a biphasic tumor growth pattern was observed. After injection into nude mice, these cells showed an initial fast proliferation phase due to the stimulation of tumor cell proliferation and the protection from apoptosis elicited by TIMP-1. However, once these tumors reached a certain size (0.4 mm2), the initial fast growth phase was replaced by a slowdown of tumor progression accompanied by tumor necrosis and regression. The authors provide convincing evidence to show that this late stage inhibition was caused by the suppression of tumor-induced host angiogenesis. These novel in vivo results highlight the importance of MMPs and their endogenous inhibitors during tumor progression and angiogenesis.