Integral Role of Transcription Factor 8 in the Negative Regulation of Tumor Angiogenesis
Integral Role of Transcription Factor 8 in the Negative Regulation of Tumor Angiogenesis
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DOI：
10.1158/0008-5472.can-08-3620
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Ohba, Yusuke
中科院分区：
文献类型：
--
作者：
Inuzuka, Takayuki;Tsuda, Masumi;Ohba, Yusuke
血管生成涉及各种生理和病理条件，包括肿瘤生长，并受到促血管生成和抗血管生成因子的密切调控。抑制血管内皮生长因子（VEGF），最好的抗血管生成治疗癌症，已显示出一定的效果;然而，新的监管机构，其功能是独立的VEGF的鉴定，需要实现更好的结果。在这里，我们表明，转录因子8（TCF 8）是上调血管生成过程中的内皮细胞，作为一个负调节。此外，TCF 8特异性表达于肿瘤血管内皮。1cf 8-杂合敲除小鼠比野生型小鼠更容易在皮下形成肿瘤血管。移植的黑色素瘤，这似乎有助于更积极的增长和肺转移的肿瘤在突变小鼠。TCF 8的抑制在体外和离体模型中促进血管生成，并显示出全面的细胞表型，包括增强的细胞侵袭、受损的细胞粘附和增加的细胞单层通透性，这至少部分地分别归因于MMPI过表达、粘着斑形成的减弱和VE-钙粘蛋白募集不足。总之，我们的研究结果定义了TCF 8在病理性血管生成调节中的一种新的、不可或缺的作用，并提出TCF 8作为癌症治疗干预的靶点。[癌症研究2009;69（4）：1678-84]
Angiogenesis is involved in various physiologic and pathological conditions, including tumor growth, and is tightly regulated by the orchestration of proangiogenic and antiangiogenic factors. Inhibition of vascular endothelial growth factor (VEGF), the best-established antiangiogenic treatment in cancer, has shown some effectiveness; however, the identification of novel regulators, whose function is independent of VEGF, is required to achieve better outcomes. Here, we show that transcription factor 8 (TCF8) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator. Furthermore, TCF8 is specifically expressed in the endothelium of tumor vessels. 1cf8-heterozygous knockout mice are more permissive than wildtype mice to the formation of tumor blood vessels in s.c. implanted melanoma, which seems to contribute to the more aggressive growth and the lung metastases of the tumor in mutant mice. Suppression of TCF8 facilitates angiogenesis in both in vitro and ex vivo models, and displays comprehensive cellular phenotypes, including enhanced cell invasion, impaired cell adhesion, and increased cell monolayer permeability due to, at least partly, MMPI overexpression, attenuation of focal adhesion formation, and insufficient VE-cadherin recruitment, respectively. Taken together, our findings define a novel, integral role for TCF8 in the regulation of pathologic angiogenesis, and propose TCF8 as a target for therapeutic intervention in cancer. [Cancer Res 2009;69(4):1678-84]