title: Effects of adenosine on lymphangiogenesis.
abstract: BACKGROUND
  The lymphatic system controls tissue homeostasis by draining protein-rich lymph to the vascular system. Lymphangiogenesis, the formation of lymphatic vessels, is a normal event in childhood but promotes tumor spread and metastasis during adulthood. Blocking lymphangiogenesis may therefore be of therapeutic interest. Production of adenosine is enhanced in the tumor environment and contributes to tumor progression through stimulation of angiogenesis. In this study, we determined whether adenosine affects lymphangiogenesis.
  
  
  METHODS
  Lymphatic endothelial cells (HMVEC-dLy) were cultured in presence of adenosine and their proliferation, migration and tube formation was assessed. Gelatin sponges embedded with the stable analogue of adenosine 2-chloro adenosine were implanted in mice ear and lymphangiogenesis was quantified. Mice were intravenously injected with adenoviruses containing expression vector for 5'-endonucleotidase, which plays a major role in the formation of adenosine.
  
  
  RESULTS
  In vitro, we observed that adenosine decreased the proliferation of lymphatic endothelial cells, their migration and tube formation. However, in vivo, gelatin sponges containing 2-chloro adenosine and implanted in mice ear displayed an elevated level of lymphangiogenesis (2.5-fold, p<0.001). Adenovirus-mediated over-expression of cytosolic 5'-nucleotidase IA stimulated lymphangiogenesis and the recruitment of macrophages in mouse liver. Proliferation of lymphatic endothelial cells was enhanced (2-fold, p<0.001) when incubated in the presence of conditioned medium from murine macrophages.
  
  
  CONCLUSIONS
  We have shown that adenosine stimulates lymphangiogenesis in vivo, presumably through a macrophage-mediated mechanism. This observation suggests that blockade of adenosine receptors may help in anti-cancer therapies.
authors.affiliation: Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé (CRP - Santé), Luxembourg.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Lenoir
authors.affiliation: Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé (CRP - Santé), Luxembourg; Division of Cardiology, Centre Hospitalier Luxembourg, Luxembourg.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Wagner
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer, University of Liège, Liège, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom.
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Sala-Newby
authors.affiliation: Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Cancer, University of Liège, Liège, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé (CRP - Santé), Luxembourg.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Devaux
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D018047:Receptors, Purinergic P1; D015720:5'-Nucleotidase; D000241:Adenosine