Sulfatides Activate Platelets Through P-Selectin and Enhance Platelet and Platelet–Leukocyte Aggregation

Merten, Michael; Beythien, C.; Gutensohn, K.; Kühnl, P.; Meinertz, Thomas; Thiagarajan, Perumal

doi:10.1161/01.atv.0000149675.83552.83

Cited by 60 publications

(58 citation statements)

References 33 publications

(34 reference statements)

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“…Interestingly, sulfatides were found to facilitate P-selectinmediated platelet adhesion and aggregation (Merten and Thiagarajan 2001). The recent finding that sulfatides could lead to platelet activation and their aggregation with leukocytes suggest this mechanism to play an important role in hemostasis and thrombosis (Merten et al 2005). In this context, our finding that murine colon carcinoma cells carrying sulfatides can effectively induce P-selectin-mediated platelet aggregation raises the possibility for the involvement of these interactions also during hematogenous metastasis.…”

Section: Discussionmentioning

confidence: 75%

P-selectin mediates metastatic progression through binding to sulfatides on tumor cells

Garcia

Callewaert²,

Borsig

2006

Glycobiology

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Hematogenous carcinoma metastasis is associated with tumor cell emboli formation, which is now known to be facilitated by selectins. P-selectin-mediated interactions of platelets with cancer cells are based mostly on mucin-and glycosaminoglycan-type selectin ligands. We previously showed that mouse colon carcinoma cells (MC-38) carry P-selectin ligands of nonmucin origin, which were not identified. Here we show that P-selectin ligands recognized on MC-38 cells are sulfated glycolipids, thereby facilitating experimental metastasis in a syngeneic mouse model. Metabolic inhibition of sulfation by incubation of cells with sodium chlorate almost completely abrogated Pselectin binding. Metabolic labeling of MC-38 cells with 35 S sulfate revealed only a single band as detected by high-performance thin layer chromatography analysis of a total lipid extract. Matrix-assisted laser desorption/ ionization tandem time-of-flight/time-of-flight analysis (MALDI-TOF-TOF) analysis of the purified sulfatecontaining lipid fraction identified the selectin ligand to be a sulfated galactosylceramide SM4 (HSO 3 -3Galb-1Cer). Modulation of glycolipid biosynthesis in MC-38 cells altered P-selectin binding, thereby confirming sulfoglycolipids to be major P-selectin ligands. In addition, P-selectin was also found to recognize lactosylceramide sulfate SM3 and gangliotriaosylceramide sulfate SM2 [GalNAcb-4(HSO 3 -3)Galb-4Glcb-1Cer] in human hepatoma cells. Finally, the enzymatic removal of sulfation from the cell surface of MC-38 cells resulted in decreased P-selectin binding and led to attenuation of metastasis. Thus, SM4 sulfatide serves as a native ligand for P-selectin contributing to cell -cell interactions and to facilitation of metastasis.

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Section: Discussionmentioning

confidence: 75%

P-selectin mediates metastatic progression through binding to sulfatides on tumor cells

Garcia

Callewaert²,

Borsig

2006

Glycobiology

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“…A similar amplification loop exists for sulfatides, which interact with P-selectin on activated platelets to enhance further platelet activation and P-selectin expression. 69 This interaction pathway also recapitulates the cooperativity between P-selectin and ␣ M ␤ 2 in mediating PMN-endothelial cell conjugation; engagement of PSGL-1 on PMNs with P-selectin on endothelial cells results in PMN rolling and ␣ M ␤ 2 activation (reviewed in McEver and Cummings 70 ). However, because blockade of ␣ M ␤ 2 /GPIb␣ results in only approximately 50% reduction of platelet activation, a second independent pathway for MP activation of platelets is also likely to exist and could involve platelet agonists, which are reported to be present in PMN-derived MPs.…”

Section: Discussionmentioning

confidence: 80%

Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles

Pluskota

Woody

Szpak

et al. 2008

Blood

175

148

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IntroductionLeukocyte-platelet cross-talk plays multiple and important roles in inflammatory and thrombotic responses. 1 Activated platelets and platelet-released mediators, such as PDGF and PAF, activate leukocytes enhancing their responses such as adhesion, chemotaxis, phagocytosis, and superoxide generation. [2][3][4][5] Conversely, activated leukocytes induce platelet activation as evidenced by increased platelet P-selectin expression. 6 In vivo studies show that leukocytes and platelets colocalize within atherosclerotic and restenotic lesions, at sites of hemorrhage and ischemia-reperfusion injury. [7][8][9][10] Indeed, increased levels of leukocyte-platelet aggregates are found in patients with diabetes, acute coronary syndromes, trauma, and sepsis. [11][12][13] Numerous studies have analyzed the receptors involved in leukocyte-platelet interactions. P-selectin on activated platelets binds PSGL-1 on leukocytes 14,15 to support their rolling on adherent platelets and to activate leukocyte integrin ␣ M ␤ 2 , which mediates firm leukocyte adhesion. [16][17][18] Several ␣ M ␤ 2 counterreceptors on platelets have been proposed, including Fg-bound ␣ IIb ␤ 3 , 19 GPIb␣,20,21 and JAM-3. 22 Recognition of these counterreceptors requires that ␣ M ␤ 2 be in an activated conformation. ␣ M ␤ 2 can be activated by stimulation of leukocytes by agonists and can be monitored with monoclonal antibodies (mAbs), CBRM1/5 and mAb24, which react selectively with the activated conformation.Microparticles (MPs) are released by membrane blebbing from cells undergoing activation or apoptosis. MPs are usually defined by 2 criteria: size (Ͻ 1 m) and surface expression of negatively charged phosphatidylserine (reviewed in Boulanger et al, 23 Morel et al, 24 Martinez et al, 25 and Distler et al 26 ). MPs are not simply the markers of cell activation or damage but may exert pleiotropic effects on blood and vascular cells. MPs of platelet and endothelial origin have procoagulant and proinflammatory activities (reviewed in Boulanger et al, 23 Morel et al, 24 Martinez et al, 25 and Distler et al 26 ) and are markers of acute coronary syndromes. 27,28 The functions of leukocyte-derived MPs are less clear. MPs shed by PMNs behave as inflammatory mediators and activate endothelial cells 29,30 but also exert antiinflammatory effects on macrophages. 31 One of the most important features of leukocyte-derived MPs is the expression of tissue factor 32 and negatively charged phospholipids, suggesting that they may contribute to blood coagulation. Indeed, in vivo studies have shown that leukocyte MPs are captured by activated platelets within thrombi by a P-selectin/PSGL-1-dependent mechanism that leads to accumulation of tissue factor and ultimately enhanced fibrin deposition. 33,34 Although the interactions of leukocyte-derived MPs with activated platelets have been well documented, additional mechanisms in which leukocyte MPs may activate resting platelets, when platelet P-selectin expression is low, have not been examined. In this study, we show...

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“…Sulfatide was also identifi ed as an interacting partner of P-selectin and promoted a P-selectinmediated metastasis process in colon cancer cells ( 20 ). Sulfatide and P-selectin interactions led to subsequent platelet aggregation ( 21 ) and played an important role in the formation of cancer embolus. Our previous study ( 15,18 ) revealed that hepatoma cells expressed sulfatide after CST transfection.…”

Section: Plasmid Constructionmentioning

confidence: 99%

Regulation of integrin αV subunit expression by sulfatide in hepatocellular carcinoma cells

Dong

Shi

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org linked ␣ -and ␤ -subunit, with each subunit having a large extracellular domain, a single membrane-spanning domain, and a short, noncatalytic cytoplasmic tail. Integrins seem to be the major receptors by which cells attach to components of the extracellular matrix (ECM), such as vitronectin, etc. ( 4 ), and are involved in the metastasis signaling of hepatocellular carcinoma (HCC) ( 5 ).The integrin ␣ V subunit associates with one of fi ve integrin ␤ subunits, ␤ 1, ␤ 3, ␤ 5, ␤ 6, or ␤ 8, to form fi ve distinct ␣ V ␤ heterodimers ( 6 ). The integrin ␣ V ␤ heterodimers on the cell surface interact with cell adhesive proteins, such as collagen, fi brinogen, fi bronectin, and vitronectin. These interactions play an important role in cell adhesion or migration, especially in tumor metastasis. Integrins increase in invasive tumors and distant metastases, characterize the metastatic phenotype, and play a key role in tumor metastasis ( 7,8 ). Many studies have documented marked differences in the surface expression and distribution of integrins between malignant tumors and preneoplastic tissues. For example, the integrin ␣ V ␤ 3 complex is strongly expressed in the invasive front cells of malignant melanoma and angiogenic blood vessels, but it is weakly expressed on preneoplastic melanomas and quiescent blood vessels ( 9 ). Also, it has been demonstrated that ␣ V ␤ 3 integrin is specifi cally required to sustain neovascularization induced in vivo by fibroblast growth factor-2 ( 10 ). Integrin ␣ V ␤ 3 physically associates with phosphorylated and activated insulin-like growth factor receptor, and it may be involved in the HCC cell migration and progression ( 11 ). Furthermore, inducing the expression of the integrin ␣ V ( 7 ) or ␤ 3 ( 12 ) subunit in melanoma cells increases their metastatic potential. Integrins have been implicated as very important adhesion molecules that are involved in multiple physiological processes, such as cell adhesion, proliferation, and survival ( 1-3 ). Each integrin generally consists of a noncovalently Abstract Integrin is important in migration and

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Sulfatides Activate Platelets Through P-Selectin and Enhance Platelet and Platelet–Leukocyte Aggregation

Cited by 60 publications

References 33 publications

P-selectin mediates metastatic progression through binding to sulfatides on tumor cells

P-selectin mediates metastatic progression through binding to sulfatides on tumor cells

Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles

Regulation of integrin αV subunit expression by sulfatide in hepatocellular carcinoma cells

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