title: Inhibition of E-selectin expression on the surface of endothelial cells inhibits hepatocellular carcinoma growth by preventing tumor angiogenesis.
abstract: OBJECTIVE
  Interactions between endothelial and tumor cells via E-selectin and sialyl Lewis x (sLex) have been suggested to play a significant role in the development of metastasis and tumor growth. In this work, we tested whether inhibition of E-selectin expression on the surface of endothelial cells might impair endothelial/tumor cells interactions and tumor growth of hepatocarcinoma cells in vitro and in vivo.
  
  
  METHODS
  We used HepG2 cells that highly express sLex antigens and HuH7 cells that do not express sLex. Inhibition of E-selectin expression on the surface of endothelial cells was obtained by using cimetidine and amiloride treatment.
  
  
  RESULTS
  Cimetidine and amiloride inhibited, respectively, by 20 and 64 % E-selectin expression by activated endothelial cells and significantly subsequent adhesion of HepG2 cells to activated endothelial cells. Subcutaneous injection of cimetidine or amiloride resulted in a significant inhibition of HepG2 cells tumor growth in nu/nu mice but not of HuH7 cells. Thus, cimetidine and amiloride administration led to an inhibition of 57 and 75 % of HepG2 tumor growth in vivo, respectively. This effect was associated with an inhibition of vasculogenesis as demonstrated by anti-CD31 immunostaining.
  
  
  CONCLUSIONS
  Inhibition of E-selectin expression allows an anti-tumoral effect on sLex-expressing HCC tumors in vivo. This suggests that interactions between HCC cells and endothelial cells through sLex antigens and E-selectin might be a target for treatment of HCC. Further studies might evaluate the clinical impact of cimetidine and amiloride in the treatment of HCC patients alone or in combination with other anti-tumoral agents.
authors.affiliation: Centre de Recherche en Oncologie biologique et oncopharmacologie, Faculté de Médecine et de Pharmacie, INSERM UMR-911, 27 Bd J. Moulin, 13385, Marseille Cedex 05, France. patrick.borentain@ap-hm.fr.|Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire Timone, 264 rue Saint-Pierre, 13385, Marseille Cedex 05, France. patrick.borentain@ap-hm.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Borentain
authors.affiliation: Centre de Recherche en Oncologie biologique et oncopharmacologie, Faculté de Médecine et de Pharmacie, INSERM UMR-911, 27 Bd J. Moulin, 13385, Marseille Cedex 05, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Carmona
authors.affiliation: Centre de Recherche en Oncologie biologique et oncopharmacologie, Faculté de Médecine et de Pharmacie, INSERM UMR-911, 27 Bd J. Moulin, 13385, Marseille Cedex 05, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Cellule d'Evaluation Médicale, Assistance Publique - Hôpitaux de Marseille, 80, rue Brochier, 13354, Marseille Cedex 05, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jouve
authors.affiliation: Centre de Recherche en Oncologie biologique et oncopharmacologie, Faculté de Médecine et de Pharmacie, INSERM UMR-911, 27 Bd J. Moulin, 13385, Marseille Cedex 05, France.
authors.forename: Assou
authors.initials: A
authors.lastname: El-Battari
authors.affiliation: Centre de Recherche en Oncologie biologique et oncopharmacologie, Faculté de Médecine et de Pharmacie, INSERM UMR-911, 27 Bd J. Moulin, 13385, Marseille Cedex 05, France.|Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire Timone, 264 rue Saint-Pierre, 13385, Marseille Cedex 05, France.
authors.forename: René
authors.initials: R
authors.lastname: Gérolami
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation; D002927:Cimetidine / Q000494:pharmacology; D019040:E-Selectin / Q000032:analysis / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D016256:Lewis X Antigen / Q000032:analysis; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000080506:Sialyl Lewis X Antigen
chemical_list: D019040:E-Selectin; D016256:Lewis X Antigen; C546936:SELE protein, human; D000080506:Sialyl Lewis X Antigen; D000584:Amiloride; D002927:Cimetidine
keywords: Amiloride; Cimetidine; E-selectin; Hepatocarcinoma; Sialyl Lewis x; Tumor angiogenesis