Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1.
Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1.
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DOI：
10.1158/0008-5472.can-09-3094
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Yoon SS
中科院分区：
文献类型：
--
作者：
Lee YJ;Koch M;Karl D;Torres-Collado AX;Fernando NT;Rothrock C;Kuruppu D;Ryeom S;Iruela-Arispe ML;Yoon SS
转移到任何器官部位都需要血管生成来进行肿瘤扩张。肿瘤血管生成受到多种内源性抑制剂的抑制，包括血小板反应蛋白1（TSP 1）。TSP 1的主要抗血管生成活性存在于含有3个TSP 1重复序列（3 TSR）的结构域中，并且TSP 1切割部分地由金属蛋白酶ADAMTS 1调节。在这里，我们研究了TSP 1和ADAMTS 1在控制肝和肺转移性疾病中的作用。过表达TSP 1的CT 26结肠癌细胞和RenCa肾癌细胞在肝脏中的生长受到抑制，但在肺中不受抑制。与对照组相比，B16 F10黑色素瘤肝转移在Tsp 1缺失小鼠中表现出加速生长，而B16 F10肺转移在Tsp 1缺失小鼠和对照组中生长相似。我们比较了肝和肺裂解物对重组TSP 1的裂解，发现肝裂解物比肺裂解物更有效地裂解TSP 1。这种切割活性可以用针对ADAMTS 1的中和抗体或RNA干扰来阻断，并且当使用来自Adamts 1-null小鼠的肝裂解物时，切割活性被显著废除。最后，为了证实缺乏TSP 1切割导致肺中无效的抗血管生成功能，我们产生了仅稳定分泌3 TSR结构域的表达CT 26的结肠癌细胞。3 TSR对CT 26肝转移和肺转移均有抑制作用。总的来说，这些数据表明，TSP 1的抗血管生成活性在肝脏和肺中受到ADAMTS 1的差异调节，并强调了不同宿主器官环境中血管生成调节的变化。
Metastases to any organ site require angiogenesis for tumor expansion. Tumor angiogenesis is restrained by a variety of endogenous inhibitors including thrombospondin 1 (TSP1). The principal anti-angiogenic activity of TSP1 resides in a domain containing 3 TSP1 repeats (3TSR), and TSP1 cleavage is regulated, in part, by the metalloproteinase ADAMTS1. Here we examine the role of TSP1 and ADAMTS1 in controlling metastatic disease in the liver and lung. The growth of CT26 colon carcinoma cells and RenCa renal carcinoma cells over-expressing TSP1 was inhibited in the liver but not in the lung. B16F10 melanoma liver metastases demonstrated accelerated growth in Tsp1-null mice compared to controls, while B16F10 lung metastases grew similarly in Tsp1-null mice and controls. We compared cleavage of recombinant TSP1 by liver and lung lysates, and found that liver lysate cleaved TSP1 much more efficiently that lung lysate. This cleavage activity could be blocked with neutralizing antibody or RNA interference directed at ADAMTS1, and cleavage activity was significantly abrogated when liver lysates from Adamts1-null mice were used. Finally to confirm that lack of TSP1 cleavage resulted in ineffective anti-angiogenic function in the lung, we generated CT26 expressing colon cancer cells stably secreting only the 3TSR domain. 3TSR secretion from CT26 cells inhibited both CT26 liver and lung metastases. Collectively, these data indicate that the anti-angiogenic activity of TSP1 is differentially regulated by ADAMTS1 in the liver and lung, and emphasize the notion of variations in the regulation of angiogenesis in different host organ environments.