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Inhibition of E-selectin expression on the surface of endothelial cells inhibits hepatocellular carcinoma growth by preventing tumor angiogenesis

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Abstract

Purpose

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.

Conclusion

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.

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Funding

This work was supported by institutional funding from INSERM (Paris, France), the Aix-Marseille Université (Marseille, France) and by a Grant INCa-DGSO-INSERM 6038 from Sites de Recherche Intégrée sur le Cancer (SIRIC).

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Authors and Affiliations

  1. 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, Sylvie Carmona, Sylvie Mathieu, Assou El-Battari & René Gérolami

  2. Service d’Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire Timone, 264 rue Saint-Pierre, 13385, Marseille Cedex 05, France

    Patrick Borentain & René Gérolami

  3. Cellule d’Evaluation Médicale, Assistance Publique - Hôpitaux de Marseille, 80, rue Brochier, 13354, Marseille Cedex 05, France

    Elisabeth Jouve

Authors
  1. Patrick Borentain
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  2. Sylvie Carmona
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  3. Sylvie Mathieu
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  4. Elisabeth Jouve
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  5. Assou El-Battari
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  6. René Gérolami
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Correspondence to Patrick Borentain.

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All applicable international, national and/or institutional guidelines for the care and use of animals were followed.

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Borentain, P., Carmona, S., Mathieu, S. et al. Inhibition of E-selectin expression on the surface of endothelial cells inhibits hepatocellular carcinoma growth by preventing tumor angiogenesis. Cancer Chemother Pharmacol 77, 847–856 (2016). https://doi.org/10.1007/s00280-016-3006-x

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  • DOI: https://doi.org/10.1007/s00280-016-3006-x

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