The fibroblast growth factor (FGF)/FGF receptor (FGFR) system plays a crucial role in cancer by affecting tumor growth, angiogenesis, drug resistance, and escape from anti-angiogenic anti-vascular endothelial growth factor therapy. The soluble pattern recognition receptor long-pentraxin 3 (PTX3) acts as a multi-FGF antagonist. Here we demonstrate that human PTX3 overexpression in transgenic mice driven by the Tie2 promoter inhibits tumor growth, angiogenesis, and metastasis in heterotopic, orthotopic, and autochthonous FGF-dependent tumor models. Using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2, we identified a small-molecule chemical (NSC12) that acts as an extracellular FGF trap with significant implications in cancer therapy. Ronca et al. show that overexpression of long-pentraxin 3 (PTX3) in mice inhibits the growth of FGF-dependent tumor models. On the basis of pharmacophore modeling of PTX3-FGF2 interaction, they identify a small molecule that acts as an extracellular FGF trap and inhibits FGF-dependent tumor growth in mice.
Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy
Pagano Katiuscia;Ragona Laura;Moroni Elisabetta;Colombo Giorgio;
2015
Abstract
The fibroblast growth factor (FGF)/FGF receptor (FGFR) system plays a crucial role in cancer by affecting tumor growth, angiogenesis, drug resistance, and escape from anti-angiogenic anti-vascular endothelial growth factor therapy. The soluble pattern recognition receptor long-pentraxin 3 (PTX3) acts as a multi-FGF antagonist. Here we demonstrate that human PTX3 overexpression in transgenic mice driven by the Tie2 promoter inhibits tumor growth, angiogenesis, and metastasis in heterotopic, orthotopic, and autochthonous FGF-dependent tumor models. Using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2, we identified a small-molecule chemical (NSC12) that acts as an extracellular FGF trap with significant implications in cancer therapy. Ronca et al. show that overexpression of long-pentraxin 3 (PTX3) in mice inhibits the growth of FGF-dependent tumor models. On the basis of pharmacophore modeling of PTX3-FGF2 interaction, they identify a small molecule that acts as an extracellular FGF trap and inhibits FGF-dependent tumor growth in mice.File | Dimensione | Formato | |
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Descrizione: Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy
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