Long Pentraxin-3 inhibits FGF-dependent angiogenesis andgrowth of steroid hormone-regulated tumors

Steroid hormone-regulated tumors, including breast and prostate cancers, represent a class of epithelial lesions whose growth is finely tuned by steroid hormones. However, as these tumors progress, they may become independent from steroid hormones for growth, limiting the effectiveness of hormonal ablation therapies. Fibroblast growth factors (FGFs) are potent angiogenic factors that exert non-redundant autocrine/paracrine functions in various tumors types. Experimental and clinical evidences indicate that the FGF/FGF receptor (FGFR) axis can drive the progression of steroid hormone-dependent cancers to a hormone-independent state, thus representing a possible alternative target for the treatment of hormonal cancers. Previous observations had shown that the soluble pattern recognition receptor long pentraxin-3 (PTX3) is a natural selective antagonist for a restricted number of FGF family members, inhibiting FGF2 but not FGF1 and FGF4 activity. Here, we extended these findings and assessed the capacity of PTX3 to antagonize also FGF8b and to inhibit the vascularization and growth of steroid hormone-regulated breast and prostate cancers. Surface plasmon resonance analysis demonstrates that PTX3 binds FGF8b with high affinity. As a consequence, PTX3 prevents the binding of FGF8b to its receptors, inhibits FGF8b-driven ERK1/2 activation, cell proliferation and chemotaxis in endothelial cells, and suppresses FGF8b-induced neovascularization in vivo. Also, PTX3 inhibits testosterone and FGF8b-driven proliferation in androgen-regulated Shionogi 115 (S115) mouse breast and LNCaP human prostate tumor cells and the FGF8b/FGF2-driven proliferation of TRAMP-C2 murine prostate cancer cells. Furthermore, when transfected into S115 or TRAMP-C2 cells, PTX3 impairs FGF/testosterone induced cell proliferation and angiogenic activity in the chick embryo chorioallantoic membrane (CAM) assay. Accordingly, hPTX3_S115 and hPTX3_TRAMP-C2 cells show a dramatic decrease of their tumorigenic capacity in vivo. These results identify PTX3 as a novel FGF2/FGF8b antagonist endowed with antiangiogenic and antineoplastic activity with possible implications for the therapy of breast and prostate steroid hormone-regulated tumors.