Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 46, Pages 19491-19496Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0906074106
Keywords
metastasis; selecins; HCELL; homing; CTCs
Categories
Funding
- American Cancer Society Research Scholar Award [06-024-01-CSM]
- National Institutes of Health (NIH) National Cancer Institute (NCI) [RO1 CA118124]
- NIH National Center for Complementary and Alternative Medicine [RO1 AT004268]
- NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [P30 AR042689]
- NIH NCI Specialized Programs of Research Excellence [P50 CA69568]
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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 alpha 1,3 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 post-capillary 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 alpha 1,3 FTs could enhance metastatic efficiency of PCa by triggering an E-selectin-dependent trafficking mechanism.
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