title: Sunitinib inhibits inflammatory corneal lymphangiogenesis.
abstract: OBJECTIVE
  To evaluate the antilymphangiogenic potential of multi-target tyrosine kinase inhibitor sunitinib in corneal neovascularization (NV).
  
  
  METHODS
  Inflammatory corneal NV was induced by thermal cauterization applied in the central cornea of mice, to which sunitinib malate was daily administered by gavage or not. At days 6, 11, or 17 post cauterization, lymphatic and blood vessels, as well as inflammatory cells were immunostained and quantified in whole-mounted corneas. RT-PCRs were performed to evidence VEGF-A, VEGF-C, VEGF-D, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor (VEGFR)-1 and -2 (sVEGFR-1, sVEGFR-2) expressions. Macrophages were isolated from mice peritoneal cavity following thioglycollate injection to produce conditioned medium. The effects of sunitinib were evaluated in vitro in the aortic and lymphatic ring assays in the presence or not of macrophage conditioned medium.
  
  
  RESULTS
  Sunitinib treatment drastically reduced pathologic corneal lymphangiogenesis and angiogenesis. Reduced F4/80+ cell infiltration was evidenced in sunitinib-treated mice and was associated to decreased VEGF-A (by 50%, P < 0.01) and VEGF-C (by 35%, P < 0.01) expressions, while VEGF-D and sVEGFR-2 expressions were not affected. In vitro, sunitinib dose-dependently inhibited aortic ring outgrowth, but failed to affect lymphangiogenesis in the lymphatic ring assay. However, macrophage conditioned medium-enhanced angiogenesis and lymphangiogenesis were both strongly counteracted by sunitinib treatment. Mechanistically, sunitinib blocked VEGFR-2 phosphorylation induced by VEGF-A released by macrophages.
  
  
  CONCLUSIONS
  Sunitinib exerts antihemangiogenic and antilymphangiogenic effects in vivo by reducing F4/80+ cell recruitment and interacting with their released factors.
authors.affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Recherche (GIGACancer), University of Liège, Liège, Belgium.
authors.forename: Benoît
authors.initials: B
authors.lastname: Detry
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Charlotte
authors.initials: C
authors.lastname: Erpicum
authors.forename: Jenny
authors.initials: J
authors.lastname: Paupert
authors.forename: Ludovic
authors.initials: L
authors.lastname: Maertens
authors.forename: Catherine
authors.initials: C
authors.lastname: Maillard
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
authors.forename: Vincent
authors.initials: V
authors.lastname: Lambert
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Rakic
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D019084:Fluorescent Antibody Technique, Indirect; D006023:Glycoproteins / Q000378:metabolism; D007211:Indoles / Q000627:therapeutic use*; D042583:Lymphangiogenesis / Q000187:drug effects*; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D000072483:Placenta Growth Factor; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011257:Pregnancy Proteins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007211:Indoles; D026901:Membrane Transport Proteins; D000072483:Placenta Growth Factor; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011257:Pregnancy Proteins; D011505:Protein-Tyrosine Kinases; D011758:Pyrroles; D012333:RNA, Messenger; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C000608037:Pgf protein, mouse; C000608038:Pgf protein, rat; C492273:LYVE1 protein, mouse
keywords: corneal neovascularization; lymphangiogenesis; sunitinib