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Angiogenesis: A small candy for the tumor

Functional Glycomics (08 May 2008) | doi:10.1038/fg.2008.23

The fucosylated histo-blood group glycans H2 and Lewis Y are expressed on subgroups of human endothelial cells and promote migration and tumor angiogenesis.

Impaired sprouting of HBMECs with knocked down FX protein (bottom; top: wildtype HBMECs). From Moehler, T.M. et al. Involvement of alpha1-2-fucosyltransferase I (FUT1) and surface-expressed Lewis(y) (CD174) in first endothelial cell-cell contacts during angiogenesis. Journal of Cellular Physiology, Vol. 215, No.1, 2008, p. 34. Copyright © 2008 Wiley-Liss, Inc.; reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Expression of alpha1,2-fucosyltransferase (FUT1), which adds the terminal fucose to form the histo-blood group antigen glycans Lewis Y and its precursor H2, is restricted in the human body. H2 and Lewis Y are predominantly expressed on red blood cells, vascular endothelium and—in the case of Lewis Y—on some carcinomas, thus both glycans may play a role in tumor angiogenesis. Research by Moehler et al. published in the Journal of Cellular Physiology now sheds more light on the role of Lewis Y and H2 in tumor angiogenesis.

Human bone-marrow endothelial cells (HBMECs) stimulated with tumor-necrosis factor-alpha (TNF-alpha) showed two (Lewis Y) or ten times (H2) higher basal expression of both fucosylated glycans and an concurrent upregulation of FUT1, whereas treatment with vascular endothelial growth factor had no effect. Treatment of human microvascular endothelial cells with TNF-alpha, but not of umbilical cord or aortic endothelilal cells, gave similar effects. Interestingly, HBMECs co-cultivated with the leukemia cell line KG1a showed a doubling of H2 expression. Thus, TNF-alpha, which may be secreted by tumor cells, upregulates FUT1 in HBMECs leading to an increased expression of H2/Lewis Y on the cell surfaces. Looking at the spatial distribution of both glycan structures, the authors found that immunofluorescence indicating H2/Lewis Y presence was found in marginal cell regions and at cellular regions forming inter-endothelial bridges when HBMECs were grown on extracellular matrix components and stimulated by TNF-alpha. These findings point to a role of H2/Lewis Y in endothelial cell adhesion.

Next, Moehler et al. knocked down expression of FUT1 and the FX protein that aids de novo fucose synthesis in HBMECs. Engineered HBMECs did not respond to TNF-alpha stimulation and showed strongly reduced adhesion to extracellular matrix proteins. Blocking fucosylation as well as masking H2/Lewis Y function by antibody incubation decreased migration of the cells towards a TNF-alpha gradient in a transwell system by 40% (anti-H2) and 26% (anti-LewisY antibody). In two- and three-dimensional cell-culture systems, engineered HBMECs showed decreased sprouting and network formation, which indicates a role of H2/Lewis Y in angiogenesis. Furthermore, in samples of colon carcinoma some capillaries showed a strong intracellular Lewis Y immunoreactivity, whereas others showed Lewis Y expression only on one side of the vessel. In zones of where tumor stroma showed strong proliferative activity, Lewis Y was expressed in almost all vascular endothelial cells. These findings reveal a connection between Lewis Y expression in vivo, endothelial vessel formation and tumor growth.

The results of Moehler et al. contribute significantly to the glycobiology of cell migration and angiogenesis. While FUT1 knockout mice develop normally, the FUT1 products H2 and Lewis Y may be required for tumor growth and vascularization. Further research may uncover the signaling mechanism by which H2/Lewis Y presence promotes endothelial migration and vessel formation.

Mirko von Elstermann

Original paper:

  1. Moehler, T.M. et al.
    Involvement of alpha1-2-fucosyltransferase I (FUT1) and surface-expressed Lewis(y) (CD174) in first endothelial cell-cell contacts during angiogenesis.
    Journal of Cellular Physiology 215, 27–36 (2008).
    doi:10.1002/jcp.21285 | Article |