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.