Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking.
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.
Barthel
Steven R
SR
Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115, USA.
Wiese
Georg K
GK
Cho
Jaehyung
J
Opperman
Matthew J
MJ
Hays
Danielle L
DL
Siddiqui
Javed
J
Pienta
Kenneth J
KJ
Furie
Bruce
B
Dimitroff
Charles J
CJ
D001853:Bone Marrow / Q000201:enzymology / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000201:enzymology / Q000556:secondary; D051929:CD146 Antigen / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D019040:E-Selectin / Q000378:metabolism; D005647:Fucosyltransferases / Q000096:biosynthesis*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology / Q000556:secondary; D008297:Male; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D012795:Sialoglycoproteins / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen
D051929:CD146 Antigen; D002272:Carcinoembryonic Antigen; D019040:E-Selectin; D018960:Hyaluronan Receptors; C497902:MCAM protein, human; D009844:Oligosaccharides; D012795:Sialoglycoproteins; D000080506:Sialyl Lewis X Antigen; C001643:podocalyxin; D005647:Fucosyltransferases