Introducing α(1,2)‐linked fucose into hepatocarcinoma cells inhibits vasculogenesis and tumor growth

Abstract

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 Eselectin exclusively through sLe x oligosaccharides, the synthesis of which could be completely prevented by the a(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 Eselectin-mediated interaction between HCC and endothelial cells, the inhibition of which remarkably retards tumor growth. ' 2007 Wiley-Liss, Inc.Key words: a(1,2)-fucosyltransferase-I; E-selectin; sialyl-Lewis; antitumor; vasculogenesisThe sialyl-Lewis antigens (sLex and sLea) are blood grouprelated antigens naturally expressed on leukocytes to initiate leukocyte-endothelium interaction mediated by the cytokine-inducible endothelial adhesion molecule E-selectin. 1,2 In addition to this physiological role in inflammation, sialyl-Lewis antigens are also considered as tumor markers expressed on many cancer cells and therefore, they are thought to be involved in metastasis by initiating tumor cell-endothelium adhesion. 3 Indeed, the expression of sialyl-Lewis antigens on carcinoma cells is frequently associated with advanced states of cancer and a statistically relevant relationship has been established between the postoperative prognosis of patients and the degree of expression of sialyl-Lewis antigens on cancer tissues. 3 Besides, several lines of evidence from selectin-deficient mice studies pointed out the contribution of selectins in facilitating tumor growth and progression. 4,5 In particular, E-selectin and its sLex-containing glycoconjugate ligands have been shown to be involved in the essential events of tumor angiogenesis, 6-9 including the fact that coinjection of tumor cells expressing high level of sLe x together with endothelial cells constitutively expressing E-selectin, has been found to promote tumor angiogenesis and growth. 10 We have recently succeeded in strongly blocking the expression of sLex on digestive cancer cells...

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“…This is in agreement with Mathieu et al . who showed that fut1-deficient hepatocarcinoma cells had reduced angiogenic responses [43]. …”

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