Abstract
Fibroblast growth factor-8b (FGF8b) exerts nonredundant autocrine/paracrine functions in steroid hormone-regulated tumors. 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 assessed the capacity of PTX3 to antagonize FGF8b and to inhibit the vascularization and growth of steroid hormone-regulated tumors. Surface plasmon resonance analysis shows that PTX3 binds FGF8b with high affinity (K(d) = 30-90 nmol/L). 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 dihydrotestosterone (DHT)- and FGF8b-driven proliferation of androgen-regulated Shionogi 115 (S115) mouse breast tumor cells. Furthermore, DHT-treated, PTX3 overexpressing hPTX3_S115 cell transfectants show a reduced proliferation rate in vitro and a limited angiogenic activity in the chick embryo chorioallantoic membrane and murine s.c. Matrigel plug assays. Accordingly, hPTX3_S115 cells show a dramatic decrease of their tumorigenic activity when grafted in immunodeficient male mice. These results identify PTX3 as a novel FGF8b antagonist endowed with antiangiogenic and antineoplastic activity with possible implications for the therapy of hormonal tumors.
Highlights
Fibroblast growth factor-8 (FGF8), originally cloned from an androgen-dependent mouse mammary carcinoma cell line, belongs to the angiogenic FGF family [1]
Fibroblast growth factor-8b (FGF8b) leads to the formation of heparan sulphate proteoglycans (HSPG)/FGF8b/ FGF receptor (FGFR) ternary complexes in a FGF-dependent cell–cell adhesion assay [23] in which FGF8b mediates the adhesion of FGFR1(III)c-overexpressing HSPG-deficient Chinese hamster ovary (CHO) cells to a HSPG-bearing CHO cell monolayer (Supplementary Fig. S1)
FGF8b deeply affects epithelial/stromal compartments of steroid hormone–regulated tumors by exerting a potent autocrine activity on cancer cells and a paracrine proangiogenic function that may contribute to tumor progression [2,3,4,5]
Summary
Fibroblast growth factor-8 (FGF8), originally cloned from an androgen-dependent mouse mammary carcinoma cell line, belongs to the angiogenic FGF family [1]. When assessed for the capacity to interact with a variety of extracellular signaling polypeptides, PTX3 was found to bind FGF2 via its N-terminal extension [8, 9], inhibiting FGF2-dependent endothelial cell proliferation in vitro and angiogenesis in vivo [7,8,9,10]. Under the same experimental conditions, PTX3 did not bind to a wide panel of cytokines, chemokines, and growth factors representative of different classes of soluble polypeptide mediators [8]. PTX3 did not show any interaction with FGF1 and FGF4 [8],
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