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E-selectin ligand formation: Cancer cells dress up for metastasis

Actin stress fibres (green) in endothelial cells after activation of E-selectin (red) during the diapedesis of colon cancer cells. From Tremblay, P. L. et al. Regulation of transendothelial migration of colon cancer cells by E-selectin-mediated activation of p38 and ERK MAP kinases. Oncogene 25, 6563–6573 (2006).

Endothelial (E-) selectin is part of the homing cascade of leukocytes and hematopoietic stem cells, and is also used by cancer cells to metastasize to target organs through endothelial adhesion and transmigration. In contrast to ligands of selectins such as the platelet (P-) selectin, the neutrophil ligand for E-selectin has not been identified yet. The tetrasaccharide sialyl-Lewis X is a component of all selectin ligands, but is not sufficient on its own to serve as an E-selectin ligand. Work by Nimrichter et al. published in Blood now shows that neutrophils interact with E-selectin via a complex fucosylated glycolipid. Their work is complemented by another study by Barthel et al. published in Glycobiology, which underscores the role of E-selectin ligand fucosylation for prostate cancer cells (PCCs) metastasizing to the bone.

Nimrichter et al. extracted glycolipid fractions from human neutrophils and analyzed them by mass spectrometry. The initiation of neutrophil adhesion to the endothelium was found to depend mostly upon a glycolipid fraction high in N-acetyllactosamines (LacNAc) and fucose. N-glycans with a higher number of LacNAc repeats contained more fucose, indicating that such structures are better substrates for the fucosyltransferases. In sum, the authors identified a glycosphingolipid containing 5–6 LacNAc repeats and 2–3 fucose residues as the most potent neutrophil E-selectin ligand.

E-selectin ligand fucosylation is also essential for metastasizing PCCs — however, in these cells it serves to form a different ligand structure. Barthel et al. compared the expression levels of fucosyltransferases in bone-metastasizing PCCs binding to E-selectin (ESL⁺ cells) with PCCs not colonizing the bones or displaying E-selectin binding (ESL^- cells). ESL⁺ cells were found to express fucosyltransferases FT3, FT6 and FT7 much more than normal prostate cells but, surprisingly, ESL^- cells expressed fewer of these transferases than normal prostate cells. Furthermore, ESL⁺ cells used the sialyl-Lewis X glycan on the P-selectin ligand to bind to E-selectin, the same ligand used by hematopoietic cells homing to the bone marrow. These results suggest that bone metastasis of PCCs is largely dependent upon the increased expression of three fucosyltransferases, a feature also found in other types of cancer cells metastasizing to the bones.

E-selectin-glycan interactions orchestrate many aspects of cancer cell migration – this has recently been highlighted by Tremblay et al., reporting to Cancer Research, who used a laminar flow chamber to simulate in vivo conditions of cell migration to analyze the E-selectin-dependent adhesion and transmigration of HT-29 colon cancer cells through the endothelium. Tremblay et al. showed that following adhesion the cancer cells formed a mosaic between endothelium and cancer cells. After mosaic formation, only one fourth of the HT29 cells completed the transmigration (diapedesis) through the endothelium, which eventually can lead to metastasis formation.

Taken together, these studies shed new light on the details of E-selectin binding which may open new avenues for a selective therapeutic modulation of immune and cancer cell migration.

Author: Mirko von Elstermann