title: Long pentraxin-3 inhibits FGF8b-dependent angiogenesis and growth of steroid hormone-regulated tumors.
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.
authors.affiliation: Unit of General Pathology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Leali
authors.forename: Patrizia
authors.initials: P
authors.lastname: Alessi
authors.forename: Daniela
authors.initials: D
authors.lastname: Coltrini
authors.forename: Roberto
authors.initials: R
authors.lastname: Ronca
authors.forename: Michela
authors.initials: M
authors.lastname: Corsini
authors.forename: Giorgia
authors.initials: G
authors.lastname: Nardo
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
mesh_terms: D000728:Androgens / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D006224:Cricetinae; D051524:Fibroblast Growth Factor 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000099153:Pentraxins
chemical_list: D000728:Androgens; D020533:Angiogenesis Inhibitors; D002097:C-Reactive Protein; D051524:Fibroblast Growth Factor 8; D000683:Serum Amyloid P-Component; D000099153:Pentraxins