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Alpha 1,3 Fucosyltransferases Are Master Regulators of Prostate Cancer Cell Trafficking

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Alpha 1,3 Fucosyltransferases Are Master Regulators of Prostate Cancer Cell Trafficking 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 Edited by Carolyn R. Bertozzi, University of California, Berkeley, CA, and approved September 24, 2009 (received for review June 2, 2009) How cancer cells bind to vascular surfaces and extravasate into target sistent with several observations, including the association of sLeX organs is an underappreciated, yet essential step in metastasis. We with PCa grade and progression (2, 16, 17), cancer cell E-selectin postulate that the metastatic process involves discrete adhesive ligand activity is a direct correlate with metastatic potential (18, 19) interactions between circulating cancer cells and microvascular en- and cancer cells can trigger E-selectin expression on liver sinusoidal dothelial cells. Sialyl Lewis X (sLeX) on prostate cancer (PCa) cells is microvasculature to steer circulating cancer cells to the liver (20, thought to promote metastasis by mediating PCa cell binding to 21). Thus, mapping glyco-metabolic pathways regulating E-selectin microvascular endothelial (E)-selectin. Yet, regulation of sLeX and ligand synthesis may be vital for understanding PCa metastasis. related E-selectin ligand expression in PCa cells is a poorly understood In this report, we identify E-selectin ligand formation through factor in PCa metastasis. Here, we describe a glycobiological mecha- ␣1,3 fucosylation as a critical event in triggering vascular adhesion nism regulating E-selectin-mediated adhesion and metastatic poten- of circulating PCa cells. We show corroborative evidence that native tial of PCa cells. We demonstrate that ␣1,3 fucosyltransferases (FT) 3, PCa lesions derived from bone and liver metastases are enriched in 6, and 7 are markedly elevated in bone- and liver-metastatic PCa and ␣1,3 FT3, FT6. and FT7 mRNA compared with normal or localized dictate synthesis of sLeX and E-selectin ligands on metastatic PCa cells. malignant prostate tissue. PCa metastases also expressed all gly- Upregulated FT3, FT6, or FT7 expression induced robust PCa PC-3 cell cosyltransferases involved in sLeX synthesis. Recapitulating FT adhesion to bone marrow (BM) endothelium and to inflamed post- enrichment through overexpression in sLeX (-) PCa PC-3 cells was capillary venules in an E-selectin-dependent manner. Membrane pro- sufficient for induction of sLeX and E-selectin-binding determi- teins, CD44, carcinoembryonic antigen (CEA), podocalyxin-like pro- nants on CD44, CEA, PCLP, MCAM, and, potentially, glycolipids. tein (PCLP), and melanoma cell adhesion molecule (MCAM) were As a result, PC-3 FT cells rolled on BMEC and inflamed postcap- major scaffolds presenting E-selectin-binding determinants on FT- illary venules via E-selectin; and elevated FT7 expression, in upregulated PC-3 cells. Furthermore, elevated FT7 expression pro- particular, promoted PC-3 cell trafficking to and retention in BM moted PC-3 cell trafficking to and retention in BM through an dependent on E-selectin. These findings demonstrate that ␣1,3 FTs E-selectin dependent event. These results indicate that ␣1,3 FTs could are regulators of sLeX and E-selectin ligand biosynthesis in PCa enhance metastatic efficiency of PCa by triggering an E-selectin- PC-3 cells and may encourage PCa metastasis by inducing intra- dependent trafficking mechanism. vascular cell adhesion. metastasis ͉ selecins ͉ HCELL ͉ homing ͉ CTCs Results Metastatic PCa Cells Overexpress ␣1,3 FT3, FT6, and FT7. sLeX is associated with Gleason score and progression of PCa (2, 16, 17). etastatic prostate cancer (PCa) claimed the lives of 28,660 X MAmerican men in 2008 (1). Delineating mediators of PCa To identify glycosyltransferases involved in sLe expression, we metastasis to target organs may lead to identification of prognostic analyzed relative mRNA amount of glycosyltransferases in normal biomarkers and anti-metastatic therapeutics. Recently, our lab has prostate tissue and in localized and metastatic PCa tissue. Of six advanced a scenario to account for organ metastasis involving PCa metastatic PCa specimens from bone and liver, all were enriched for at least one ␣1,3 FT, FT3, FT6, or FT7 (Fig. 1). In particular, a 2- cell adhesion to surface receptors expressed on microvascular ␣ endothelial cells of the target organ (2–4). Bone-metastatic PCa to 283-fold elevation in 1,3 FT3, FT6, and FT7 was detected in cells are known to attach more avidly to bone marrow endothelial three, four, and five of six metastatic specimens from bone and liver, respectively. In fact, metastatic specimens, 12, 15, and 17 each cells (BMEC) compared with endothelial linings of nontarget ␣ organs (5, 6). For example, human bone-metastatic PCa MDA PCa exhibited concurrent elevation of all three 1,3 FT. In addition, FT7 expression was elevated in one localized high grade sample (spec- 2b (MDA) cells roll and adhere on BMEC by binding endothelial MEDICAL SCIENCES imen 8). Two other ␣1,3 FTs, FT4, and FT9, were expressed in all (E)-selectin, raising the possibility that PCa metastasis could be ␣ conferred through E-selectin Ϫ E-selectin ligand adhesive interac- prostate tissue, whereas 1,3 FT5 was not detected with two tions (2–4). In fact, BM microvessels express E-selectin constitu- different primer pairs. FT4 expression, in general, was 3- to 15-fold lower in metastatic specimens, although was 40- to 2,900-fold lower tively, while E-selectin is inducible on endothelial linings of in- than FT3, FT6, and FT7 in metastatic PCa tissue enriched for ␣1,3 flamed tissues and of bronchial mucosa, a common PCa target FT. Prostate tissue also expressed ␣1,2 FT1 and FT2, as well as ␣1,6 tissue (7–9). Mechanistically, an identical traffic control axis in- FT8. With the exception of FT5, normal prostate tissue, as well as volving selectins is well-known in the extravasation of hematopoi- etic progenitor cells (HPC) into BM (10, 11). HPC rolling on E- and X platelet (P)-selectin is regulated by sLe -bearing glycoforms of Author contributions: C.J.D. designed research; S.R.B., G.K.W., J.C., M.J.O., D.L.H., and J.S. CD44 (HCELL), PSGL-1 and glycolipids (10, 12, 13). Synthesis performed research; J.S., K.J.P., and B.F. contributed new reagents/analytic tools; S.R.B., of sLeX in HPC is catalyzed in the Golgi compartment by members G.K.W., J.C., and M.J.O. analyzed data; and S.R.B. and C.J.D. wrote the manuscript. of the glycosyltransferase gene family (14). The final step involves The authors declare no conflict of interest. the transfer of fucose to N-acetylglucosamine at the terminal ␣2,3 This article is a PNAS Direct Submission. sialo-lactosamine unit by ␣1,3 fucosyltransferases (FT) 3, 4, 5, 6, 1To whom correspondence should be addressed. E-mail: [email protected]. and/or 7, depending on cell type (13, 15). That metastatic PCa cells This article contains supporting information online at www.pnas.org/cgi/content/full/ traverse the vasculature through ‘hematopoietic mimicry’ is con- 0906074106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0906074106 PNAS ͉ November 17, 2009 ͉ vol. 106 ͉ no. 46 ͉ 19491–19496 Downloaded by guest on September 29, 2021 70 70 PC-3 cell transfectants 60 FT1 60 FT2 HPC 50 50 40 40 (KG1a) Empty FT3 FT6 FT7 30 30 HECA-452 20 20 X 10 (sLe ) 10 0 0 -10 mRNA Fold Difference mRNA -10 -20 80H5 -20 5 6 7 9 0 3 6 2 3 4 8 4 7 2 5 -30 X 2 5 7 1 3 4 6 7 9 0 2 3 4 8 1 5 6 (Le ) 70 70 60 60 50 50 Ca19-9 40 FT3 40 FT4 a 30 30 (sLe ) 20 20 10 10 0 0 CSLEX-1 mRNA Fold Difference mRNA X -10 -10 (sLe ) -20 -20 6 2 3 4 5 6 7 9 0 2 3 4 5 7 1 8 1 2 7 1 4 6 1 3 4 5 6 8 0 2 3 5 7 9 360 20 CHO-131 300 16 (sLeX-core 2- 240 FT6 12 FT7 O-glycan) 180 8 FH-6 120 X 4 (sLe -internal 60 ND fucosylated) 0 0 mRNA Fold Difference mRNA -60 -4 2 6 8 0 2 7 1 4 7 9 1 3 4 5 6 3 5 2 8 9 1 2 5 7 1 3 4 7 3 4 6 5 6 0 ␣ X 70 1600 Fig. 2. 1,3 FTs are potent inducers of sLe synthesis in PCa PC-3 cells. KG1a X X 60 1300 (HPC) cells, PC-3 empty, FT3, FT6, and FT7 cells were assayed for sLe variants, Le , a 50 1000 and sLe .(Open histograms) Staining with anti-Lewis carbohydrate mAb or with 40 FT8 700 FT9 isotype control Ab (Shaded histograms); (n ϭ 3). Shown are representative 30 400 20 histograms from three experiments. 100 ND 10 0 -200 n e -10 -500 m mRNA Fold Difference mRNA i c e -20 -800 p # mined by reactivity with mAb CHO-131, a positive correlate of 2 4 7 1 3 5 6 8 9 4 8 1 2 3 6 7 9 5 S 13 10 15 14 16 17 11 12 14 15 16 10 11 12 13 17 Normal Low High Lymph Bone Liver Normal Low High Lymph Bone Liver P-selectin ligand expression (22).
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