Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking
- Steven R. Barthela,b,
- Georg K. Wiesea,
- Jaehyung Chob,c,
- Matthew J. Oppermana,
- Danielle L. Haysa,
- Javed Siddiquid,
- Kenneth J. Pientad,
- Bruce Furieb,c and
- Charles J. Dimitroffa,b,1
- aHarvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115;
- bHarvard Medical School, Boston, MA 02115;
- cDivision of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115; and
- dDepartment of Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Edited by Carolyn R. Bertozzi, University of California, Berkeley, CA, and approved September 24, 2009 (received for review June 2, 2009)
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 (sLeX) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Yet, regulation of sLeX 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 α1,3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone- and liver-metastatic PCa and dictate synthesis of sLeX 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 α1,3 FTs could enhance metastatic efficiency of PCa by triggering an E-selectin-dependent trafficking mechanism.
Footnotes
- 1To whom correspondence should be addressed. E-mail: cdimitroff{at}rics.bwh.harvard.edu
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Author contributions: C.J.D. designed research; S.R.B., G.K.W., J.C., M.J.O., D.L.H., and J.S. performed research; J.S., K.J.P., and B.F. contributed new reagents/analytic tools; S.R.B., G.K.W., J.C., and M.J.O. analyzed data; and S.R.B. and C.J.D. wrote the manuscript.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
