Introducing alpha(1,2)-linked fucose into hepatocarcinoma cells inhibits vasculogenesis and tumor growth.
The glycoantigen sialyl-Lewis x (sLex) and its isomer sialy-Lewis a (sLea) are frequently associated with advanced states of cancer and metastasis. In a previous work, we have shown that hepatocarcinoma cells (HCC) HepG2 interact with the endothelial E-selectin exclusively through sLe(x) oligosaccharides, the synthesis of which could be completely prevented by the alpha(1,2)-fucosyltransferase-I (FUT1), thus resulting in a strong inhibition of adhesion and rolling on activated endothelial cells. The purpose of the present study was to evaluate the impact of inhibiting sLex synthesis and the subsequent E-selectin adhesion, on HCC tumor growth in nude mice. Four weeks after subcutaneous transplantation of cells, no FUT1-derived tumor could be detected, whereas 75% of control animals developed large size tumor nodules. Between the 4th and the 8th week postinoculation, 33% tumors arose from FUT1-transduced cells but showed a slow growth (nodule volumes less than 500 mm(3)), while more than 50% of control tumors reached volumes between 1,500 and 3,000 mm(3). Several parameters were examined, including cell division and proliferation, apoptosis, adhesion to extracellular matrix components and angiogenesis/vasculogenesis. We provide evidence that among all, vasculogenesis was the most clearly affected by FUT1 expression, suggesting that tumor angiomorphogenesis may, at least partly, depend on E-selectin-mediated interaction between HCC and endothelial cells, the inhibition of which remarkably retards tumor growth.
Mathieu
Sylvie
S
Laboratories of INSERM UMR-777, Faculté de Médecine, 27 Bd. J. Moulin 13385 Marseille, France.
Gerolami
René
R
Luis
José
J
Carmona
Sylvie
S
Kol
Ossarath
O
Crescence
Lydie
L
Garcia
Stéphane
S
Borentain
Patrick
P
El-Battari
Assou
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019040:E-Selectin / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects; D005643:Fucose / Q000494:pharmacology*; D005647:Fucosyltransferases / Q000378:metabolism*; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D009844:Oligosaccharides / Q000096:biosynthesis / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D013997:Time Factors; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D019040:E-Selectin; D005643:Fucose; D005647:Fucosyltransferases; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D000097631:Galactoside 2-alpha-L-fucosyltransferase