title: Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists.
abstract: OBJECTIVE
  Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds. We investigated the fibroblast growth factor-2 (FGF2) antagonist and antiangiogenic activity of a series of LMW N,O-sulfated K5 derivatives.
  
  
  RESULTS
  Surface plasmon resonance analysis showed that LMW-K5 derivatives bind FGF2, thus inhibiting its interaction with heparin immobilized to a BIAcore sensor chip. Interaction of FGF2 with tyrosine-kinase receptors (FGFRs), heparan sulfate proteoglycans (HSPGs), and alpha(v)beta3 integrin is required for biological response in endothelial cells. Similar to LMWH, LMW-K5 derivatives abrogate the formation of HSPG/FGF2/FGFR ternary complexes by preventing FGF2-mediated attachment of FGFR1-overexpressing cells to HSPG-bearing cells and inhibit FGF2-mediated endothelial cell proliferation. However, LMW-K5 derivatives, but not LMWH, also inhibit FGF2/alpha(v)beta3 integrin interaction and consequent FGF2-mediated endothelial cell sprouting in vitro and angiogenesis in vivo in the chick embryo chorioallantoic membrane.
  
  
  CONCLUSIONS
  LMW N,O-sulfated K5 derivatives affect both HSPG/FGF2/FGFR and FGF2/alpha(v)beta3 interactions and are endowed with FGF2 antagonist and antiangiogenic activity. These compounds may provide the basis for the design of novel LMW heparin-like angiostatic compounds.
authors.affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Italy. presta@med.unibs.it
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
authors.forename: Pasqua
authors.initials: P
authors.lastname: Oreste
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zoppetti
authors.forename: Mirella
authors.initials: M
authors.lastname: Belleri
authors.forename: Elena
authors.initials: E
authors.lastname: Tanghetti
authors.forename: Daria
authors.initials: D
authors.lastname: Leali
authors.forename: Chiara
authors.initials: C
authors.lastname: Urbinati
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Ronca
authors.forename: Stefania
authors.initials: S
authors.lastname: Nicoli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Moroni
authors.forename: Helena
authors.initials: H
authors.lastname: Stabile
authors.forename: Maura
authors.initials: M
authors.lastname: Camozzi
authors.forename: German Andrés
authors.initials: GA
authors.lastname: Hernandez
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dell'Era
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016667:Bacterial Capsules; D016466:CHO Cells / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry* / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000031:analogs & derivatives / Q000378:metabolism; D005818:Genetic Engineering / Q000379:methods*; D019812:Heparan Sulfate Proteoglycans / Q000031:analogs & derivatives / Q000172:deficiency / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000096:biosynthesis* / Q000138:chemical synthesis / Q000235:genetics; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011135:Polysaccharides, Bacterial / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D019812:Heparan Sulfate Proteoglycans; D006495:Heparin, Low-Molecular-Weight; D039302:Integrin alphaVbeta3; D011135:Polysaccharides, Bacterial; D016222:Fibroblast Growth Factor 2; C050673:capsular polysaccharide K5; D005346:Fibroblast Growth Factors