Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking.

Abstract

How cancer cells bind to vascular surfaces and extravasate into target organs is an underappreciated, yet essential step in metastasis. We postulate that the metastatic process involves discrete adhesive interactions between circulating cancer cells and microvascular endothelial cells. Sialyl Lewis X (sLe(X)) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Yet, regulation of sLe(X) and related E-selectin ligand expression in PCa cells is a poorly understood factor in PCa metastasis. Here, we describe a glycobiological mechanism regulating E-selectin-mediated adhesion and metastatic potential of PCa cells. We demonstrate that alpha1,3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone- and liver-metastatic PCa and dictate synthesis of sLe(X) and E-selectin ligands on metastatic PCa cells. Upregulated FT3, FT6, or FT7 expression induced robust PCa PC-3 cell adhesion to bone marrow (BM) endothelium and to inflamed postcapillary venules in an E-selectin-dependent manner. Membrane proteins, CD44, carcinoembryonic antigen (CEA), podocalyxin-like protein (PCLP), and melanoma cell adhesion molecule (MCAM) were major scaffolds presenting E-selectin-binding determinants on FT-upregulated PC-3 cells. Furthermore, elevated FT7 expression promoted PC-3 cell trafficking to and retention in BM through an E-selectin dependent event. These results indicate that alpha1,3 FTs could enhance metastatic efficiency of PCa by triggering an E-selectin-dependent trafficking mechanism.

• Authors: Steven R Barthel, Georg K Wiese, Jaehyung Cho, Matthew J Opperman, Danielle L Hays, Javed Siddiqui, Kenneth J Pienta, Bruce Furie, Charles J Dimitroff
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 46 Pg. 19491-6 (Nov 17 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19889975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD146 Antigen
• Carcinoembryonic Antigen
• E-Selectin
• Hyaluronan Receptors
• MCAM protein, human
• Oligosaccharides
• Sialoglycoproteins
• Sialyl Lewis X Antigen
• podocalyxin
• Fucosyltransferases

Topics

• Bone Marrow (enzymology, pathology)
• Bone Marrow Neoplasms (enzymology, secondary)
• CD146 Antigen (metabolism)
• Carcinoembryonic Antigen (metabolism)
• Cell Adhesion
• Cell Movement
• E-Selectin (metabolism)
• Fucosyltransferases (biosynthesis)
• Humans
• Hyaluronan Receptors (metabolism)
• Liver (enzymology, pathology)
• Liver Neoplasms (enzymology, secondary)
• Male
• Neoplasm Metastasis
• Oligosaccharides (biosynthesis)
• Prostatic Neoplasms (enzymology, pathology)
• Sialoglycoproteins (metabolism)
• Sialyl Lewis X Antigen