A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis.
A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis.
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DOI：
10.1371/journal.pone.0057927
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Takada Y
中科院分区：
文献类型：
--
作者：
Mori S;Tran V;Nishikawa K;Kaneda T;Hamada Y;Kawaguchi N;Fujita M;Saegusa J;Takada YK;Matsuura N;Zhao M;Takada Y
成纤维细胞生长因子-1（FGF 1）和FGF 2在血管生成（从现有血管形成新血管）中起关键作用。整合素通过串扰关键地参与FGF信号传导。我们以前报道了FGF 1直接与整合素αvβ3结合并诱导FGF受体1（FGFR 1）-FGF 1-整合素αvβ3三元复合物。我们先前产生了整合素结合缺陷型FGF 1突变体（Arg-50至Glu，R50 E）。R50 E在诱导三元复合物形成、细胞增殖和细胞迁移方面有缺陷，并且在体外抑制由WT FGF 1诱导的FGF信号传导（显性负效应）。这些发现表明，FGFR和αvβ3通过直接整合素结合FGF而相互作用，并且R50 E充当FGFR的拮抗剂。我们研究了R50 E是否抑制肿瘤发生和血管生成。在这里，我们描述了R50 E抑制体内肿瘤生长，而WT FGF 1使用稳定表达WT FGF 1或R50 E的癌细胞增强肿瘤生长。由于R50 E在体外不影响癌细胞的增殖，我们推测R50 E通过抑制血管生成间接抑制肿瘤发生。因此，我们研究了R50 E在几种血管生成模型中对血管生成的影响。我们发现，过量的R50 E抑制FGF 1诱导的迁移和管形成的内皮细胞，FGF 1诱导的血管生成的基质胶塞试验，和生长的细胞在主动脉环试验。过量的R50 E抑制鸡胚绒毛尿囊膜（CAM）试验中FGF 1诱导的血管生成。有趣的是，过量的R50 E在CAM测定中也抑制了FGF 2诱导的血管生成，这表明R50 E可能独特地抑制来自FGF家族其他成员的信号传导。综上所述，我们的结果表明，R50 E抑制血管生成诱导的FGF 1或FGF 2，从而间接抑制肿瘤发生，除了其可能的直接影响肿瘤细胞的增殖在体内。我们提出R50 E具有作为抗癌和抗血管生成治疗剂（“FGF 1诱饵”）的潜力。
Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent (“FGF1 decoy”).
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影响因子：
4.8
作者：
Ieguchi, Katsuaki;Fujita, Masaaki;Takada, Yoshikazu
通讯作者：
Takada, Yoshikazu
DOI：
10.1038/nrd2792
发表时间：
2009-03
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Fujita, Masaaki;Ieguchi, Katsuaki;Takada, Yoshikazu
通讯作者：
Takada, Yoshikazu
影响因子：
4.8
作者：
Mori, Seiji;Wu, Chun-Yi;Takada, Yoshikazu
通讯作者：
Takada, Yoshikazu
影响因子：
5.8
作者：
Schreiber, I.;Buchfelder, M.;Strasburger, C. J.
通讯作者：
Strasburger, C. J.