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

• DOI: 10.1007/s00280-016-3006-x
• Publication Date: 2016-03-18T19:32:01Z
• Authors: Patrick Borentain; Sylvie Carmona; Sylvie Mathieu; Elisabeth Jouve; Assou El-Battari; René Gérolami
• Keywords: 0303 health sciences; Carcinoma, Hepatocellular; Neovascularization, Pathologic; [CHIM.THER] Chemical Sciences/Medicinal Chemistry; Liver Neoplasms; Endothelial Cells; Lewis X Antigen; [SDV.CAN]Life Sciences [q-bio]/Cancer; [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology; [CHIM.THER]Chemical Sciences/Medicinal Chemistry; Hep G2 Cells; [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology; 3. Good health; Amiloride; Mice; 03 medical and health sciences; [SDV.CAN] Life Sciences [q-bio]/Cancer; Animals; Humans; Female; Cimetidine; E-Selectin; Sialyl Lewis X Antigen; Cell Proliferation

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.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.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.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.