Abstract
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 β-catenin degradation and inhibition of UM cell migration. Together, our findings indicate that FGF trapping may represent a novel therapeutic strategy in UM.
Highlights
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults.Its occurrence increases with age and its incidence is more than 20 per million per year [1,2]
The Fibroblast growth factors (FGFs)/FGF receptor (FGFR) System Is Upregulated in Human Uveal Melanoma
FGFRs are overexpressed in 21% of UM cases, these alterations being associated to a poor prognosis when compared to UM cases without FGFR alterations (p = 0.023, log-rank test; median survival equal to 31 and 52 months for cases with or without FGFR alterations, respectively) (Figure 1A,B)
Summary
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults.Its occurrence increases with age and its incidence is more than 20 per million per year [1,2]. Current treatments of primary UM include enucleation, radiotherapy, transpupillary thermotherapy, and local resection, achieving a control of local tumor in up to 97% of treated cases. The mortality rate is high because of the frequent occurrence of metastases by hematogenous dissemination: almost 50% of all UM patients develop metastatic disease, mainly in the liver, with a current 5-year mortality ranging from 26% to 32% [1,2,3]. A better understanding of UM biology has provided new indications for the development of efficacious adjuvant therapies and for the treatment of the metastatic. As of today, no specific systemic treatment has been approved, indicating that novel biologically-based therapies are urgently required
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