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Glycobiology Advance Access published online on October 16, 2006
Glycobiology, doi:10.1093/glycob/cwl059
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received June 21, 2006
Revised October 4, 2006
Accepted October 6, 2006

Article

P-selectin mediates metastatic progression through binding to sulfatides on tumor cells

Josep Garcia 1, Nico Callewaert 2, and Lubor Borsig 3 *

1 The Center for Integrative Human Physiology and Institute of Physiology University of Zürich, 8057 Zürich, Switzerland
2 GlycoInit ETH, Swiss Federal Institute of Technology Zurich, Wolfgang Paulistrasse 10, CH-8093 Zürich, Switzerland
3 The Center for Integrative Human Physiology and Institute of Physiology University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

* To whom correspondence should be addressed.
Lubor Borsig, E-mail: ccess.unizh.ch


  Abstract

Hematogenous carcinoma metastasis is associated with tumor cell emboli formation, which is now known to be facilitated by selectins. P-selectin-mediated interactions of platelets with cancer cells are based mostly on mucin- and glycosaminoglycan-type selectin ligands. We previously showed that mouse colon carcinoma cells (MC-38) carry P-selectin ligands of non-mucin origin, which were not identified. Here we show that P-selectin ligands recognized on MC-38 cells are sulfated glycolipids, thereby facilitating experimental metastasis in a syngeneic mouse model. Metabolic inhibition of sulfation by incubation of cells with sodium chlorate almost completely abrogated P-selectin binding. Metabolic labeling of MC-38 cells with 35S sulfate revealed only a single band as detected by HPTLC analysis of a total lipid extract. MALDI-TOF-TOF analysis of the purified sulfate-containing lipid fraction identified the selectin ligand to be a sulfated galactosylceramide (SM4 sulfatide). Modulation of glycolipid biosynthesis in MC-38 cells altered P-selectin binding, thereby confirming sulfoglycolipids to be major P-selectin ligands. In addition, P-selectin was also found to recognize lactosylceramide sulfate (SM3) and gangliotriaosylceramide sulfate (SM2) in human hepatoma cells. Finally, the enzymatic removal of sulfation from the cell surface of MC-38 cells resulted in decreased P-selectin binding and led to attenuation of metastasis. Thus, SM4 sulfatide serves as a native ligand for P-selectin contributing to cell-cell interactions and to facilitation of metastasis.

Keywords: carbohydrate sulfation; glycolipids; MALDI-TOF; metastasis; selectin.
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