The Autocrine FGF/FGFR System in both Skin and Uveal Melanoma: FGF Trapping as a Possible Therapeutic Approach
The Autocrine FGF/FGFR System in both Skin and Uveal Melanoma: FGF Trapping as a Possible Therapeutic Approach
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DOI：
10.3390/cancers11091305
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发表时间：
2019-09-01
期刊：
影响因子：
5.2
通讯作者：
Presta, Marco
中科院分区：
文献类型：
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作者：
Rezzola, Sara;Ronca, Roberto;Presta, Marco
成纤维细胞生长因子（FGFs）在各种人类癌症中发挥非冗余的自分泌/旁分泌功能。癌症基因组图谱（TCGA）数据挖掘表明，高水平的FGF和/或FGF受体（FGFR）表达与人葡萄膜黑色素瘤（UM）的总生存率降低、3号染色体单体性和BAP 1突变相关，指出FGF/FGFR系统是UM治疗的靶点。在这里，我们研究了不同的FGF捕获方法对肝转移衍生的小鼠黑色素瘤B16-LS 9细胞的致瘤性和肝转移活性的影响，该细胞类似于人UM，其特征在于具有独特的肝向性。体外和体内实验证明，天然FGF陷阱抑制剂长正五聚蛋白3（PTX 3）的过表达抑制B16-LS 9细胞的致癌活性。此外，B16-LS 9细胞在移植到过表达PTX 3的转基因小鼠中时显示出降低的肿瘤生长和肝转移活性。FGF捕获方法的功效通过PTX 3衍生的泛FGF捕获小分子NSC 12在斑马鱼胚胎原位肿瘤模型和肝转移实验模型中体外抑制B16-LS 9细胞生长的能力来证实。NSC 12抑制人UM Mel 285、Mel 270、92.1和OMM 2.3细胞中FGF信号传导和细胞增殖的能力提供了这些观察结果的可能的翻译含义。此外，NSC 12引起半胱天冬酶-3活化和PARP裂解，随后是凋亡性细胞死亡以及β-连环蛋白降解和UM细胞迁移的抑制。总之，我们的研究结果表明，成纤维细胞生长因子捕获可能代表一种新的治疗策略在UM。
Fibroblast growth factors (FGFs) play non-redundant autocrine/paracrine functions in various human cancers. The Cancer Genome Atlas (TCGA) data mining indicates that high levels of FGF and/or FGF receptor (FGFR) expression are associated with reduced overall survival, chromosome 3 monosomy and BAP1 mutation in human uveal melanoma (UM), pointing to the FGF/FGFR system as a target for UM treatment. Here, we investigated the impact of different FGF trapping approaches on the tumorigenic and liver metastatic activity of liver metastasis-derived murine melanoma B16-LS9 cells that, similar to human UM, are characterized by a distinctive hepatic tropism. In vitro and in vivo experiments demonstrated that the overexpression of the natural FGF trap inhibitor long-pentraxin 3 (PTX3) inhibits the oncogenic activity of B16-LS9 cells. In addition, B16-LS9 cells showed a reduced tumor growth and liver metastatic activity when grafted in PTX3-overexpressing transgenic mice. The efficacy of the FGF trapping approach was confirmed by the capacity of the PTX3-derived pan-FGF trap small molecule NSC12 to inhibit B16-LS9 cell growth in vitro, in a zebrafish embryo orthotopic tumor model and in an experimental model of liver metastasis. Possible translational implications for these observations were provided by the capacity of NSC12 to inhibit FGF signaling and cell proliferation in human UM Mel285, Mel270, 92.1, and OMM2.3 cells. In addition, NSC12 caused caspase-3 activation and PARP cleavage followed by apoptotic cell death as well as beta-catenin degradation and inhibition of UM cell migration. Together, our findings indicate that FGF trapping may represent a novel therapeutic strategy in UM.