Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells
Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells
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DOI：
10.1038/sj.onc.1205341
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发表时间：
2002-04-11
期刊：
影响因子：
8
通讯作者：
Fidler, IJ
中科院分区：
文献类型：
--
作者：
Huang, SY;Bucana, CD;Fidler, IJ
Stat 1在许多类型的人类肿瘤中是缺乏或无活性的，而一些肿瘤已经激活了Stat 1。Stat 1是否影响肿瘤生长和转移尚不清楚。在本研究中，我们使用Stat 1基因敲除的肿瘤细胞来确定（1）Stat 1是否可以调节肿瘤细胞的血管生成，生长和转移;（2）Stat 1是否是IFN-β对血管生成因子bFGF表达的抑制作用所必需的。来源于Stat 1敲除小鼠的纤维肉瘤的高度致瘤性和转移性RAD-105肿瘤细胞用Stat 1表达载体重建。Stat 1的重建抑制RAD-105细胞在裸鼠体内的成瘤性和转移，这与体内微血管密度降低和促血管生成分子bFGF、MMP-2和MMP-9的表达降低相关。此外，非细胞毒性浓度的IFN-β显着抑制bFGF在体外表达的Stat 1重建的细胞，但不是在Stat 1缺陷的细胞，这是一致的Stat 1重建的肿瘤在体内的bFGF表达减少。因此，Stat 1对于IFN介导的bFGF产生的抑制是必不可少的，这表明肿瘤内源性Stat 1是抗血管生成信号（如IFN）的重要介质。总的来说，这些数据表明，由肿瘤细胞表达的Stat 1是肿瘤血管生成的负调控因子，因此，肿瘤生长和转移。
Stat1 is deficient or inactive in many types of human tumors whereas some tumors have activated Stat1. Whether Stat1 affects tumor growth and metastasis is unclear. In the present study, we used Stat1 knockout tumor cells to determine (1) whether Stat1 can regulate angiogenesis, growth, and metastasis of tumor cells; and (2) whether Stat1 is required for the inhibitory effect of IFN-beta on the expression of angiogenic factor bFGF. Highly tumorigenic and metastatic RAD-105 tumor cells derived from a fibrosarcoma of a Stat1 knockout mouse were reconstituted with a Stat1 expression vector. The reconstitution of Stat1 suppressed the tumorigenicity and metastasis of RAD-105 cells in nude mice which correlated with a decreased microvessel density and decreased expression of proangiogenic molecules bFGF, MMP-2, and MMP-9 in vivo. Moreover, noncytotoxic concentrations of IFN-beta significantly inhibited the in vitro expression of bFGF in the Stat1-reconstituted cells but not in the Stat1-deficient cells, which was consistent with decreased bFGF expression of Stat1-reconstituted tumors in vivo. Therefore, Stat1 is essential for IFN-mediated inhibition of bFGF production, suggesting that tumor-intrinsic Stat1 is an important mediator for antiangiogenic signals, such as IFN. Collectively, these data demonstrate that Stat1 expressed by tumor cells is a negative regulator of tumor angiogenesis and, hence, tumor growth and metastasis.