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 ␣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. (1). Delineating mediators of PCa metastasis to target organs may lead to identification of prognostic biomarkers and anti-metastatic therapeutics. Recently, our lab has advanced a scenario to account for organ metastasis involving PCa cell adhesion to surface receptors expressed on microvascular endothelial cells of the target organ (2-4). Bone-metastatic PCa cells are known to attach more avidly to bone marrow endothelial cells (BMEC) compared with endothelial linings of nontarget organs (5, 6). For example, human bone-metastatic PCa MDA PCa 2b (MDA) cells roll and adhere on BMEC by binding endothelial (E)-selectin, raising the possibility that PCa metastasis could be conferred through E-selectin Ϫ E-selectin ligand adhesive interactions (2-4). In fact, BM microvessels express E-selectin constitutively, while E-selectin is inducible on endothelial linings of inflamed tissues and of bronchial mucosa, a common PCa target tissue (7-9). Mechanistically, an identical traffic control axis involving selectins is well-known in the extravasation of hematopoietic progenitor cells (HPC) into BM (10, 11). HPC rolling on E-and platelet (P)-selectin is regulated by sLe X -bearing glycoforms of CD44 (HCELL), PSGL-1 and glycolipids (10,12,13). Synthesis of sLe X in HPC is catalyzed in the Golgi compartment by members of the glycosyltransferase gene family (14). The final step involves the transfer of fucose to N-acetylglucosamine at the terminal ␣2,3 sialo-lactosamine unit by ␣1,3 fucosyltransferases (FT) 3, 4, 5, 6, and/or 7, depending on cell type (13, 15). That metastatic PCa cells traverse the vasculature through 'hematopoietic mimicry' is consistent with several observations, including the association of sLe X with PCa grade and progression (2, 16, 17), cancer cell E-selectin ligand activity is a direct correlate with metastatic potential (18,19) and cancer cells can trigger E-selectin expression on liver sinusoidal microvasculature to steer circulating cancer cells to the liver (20,21). Thus, mapping glyco-metabolic pathways regulating E-selectin ligand synthesis may be vital for understanding PCa metastasis.In this report, we identify E-s...

Physiological Contribution of CD44 as a Ligand for E-Selectin during Inflammatory T-Cell Recruitment

“…Recent studies have further demonstrated that expression of Fut7 is sufficient to confer E-selectin binding capacity to CD44. 39,40,54 In line with these findings, our expression analyses indicate that, compared with neutrophils, Th1 cells express very low levels of Fut4, whereas Fut7 expression is similar. This, together with the observation that cell arrest is differentially controlled by CD44 in Th1 cells and by ESL-1 in neutrophils ( 11 and this study), suggests a different repertoire of E-selectin ligands between these leukocyte subsets.…”

Integrated Proteomic and Glycoproteomic Analyses of Prostate Cancer Cells Reveal Glycoprotein Alteration in Protein Abundance and Glycosylation*

“…These fucosidases were down-regulated in PC3 cells, along with the up-regulation of Fut8 and Fut11 as observed in the global analysis, which explains the change in fucosylation observed in PC3 cells. In prostate tissues, three fucosyltransferases (FUT3, FUT6, and FUT7) have been shown to have elevated gene expression, and the overexpression of these fucosyltransferases in PC3 cells showed that they may serve as master regulators of prostate cancer cell trafficking and explain the aggressive nature of PC3 cells (31). In our global proteomic study, only two fucosyltransferases (FUT8 and FUT11) were identified as overexpressed in PC3 cells.…”

Metabolic Inhibition of Sialyl-Lewis X Biosynthesis by 5-Thiofucose Remodels the Cell Surface and Impairs Selectin-Mediated Cell Adhesion

“…Notable in this regard is that genetic deficiencies in FUT activity lead to an inability to mount a robust inflammatory response (22). Furthermore, sLe X overexpressing tumors often exhibit increased transcription of ␣1, , and the increased expression of FUTs is linked to the metastatic ability of cancer cells (26,27). Consistent with ␣1,3-FUTs playing an important role in cancer, antisense-mediated decreases in FUTs, including FUT3, impair tumor growth (28) and limit metastasis (29).…”