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Kim, Young J; Varki, Ajit

doi:10.1023/a:1018580324971

Cited by 499 publications

(183 citation statements)

References 96 publications

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“…In an apparently unrelated area of research, many reports showed that carcinoma progression is associated with alterations of cell-surface glycosylation (30)(31)(32)(33)(34). Of note, carcinomas expressing highly sialylated or branched sugar chains and͞or large amounts of mucins have a poor prognosis, because of a high rate of metastasis.…”

Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

“…Of note, carcinomas expressing highly sialylated or branched sugar chains and͞or large amounts of mucins have a poor prognosis, because of a high rate of metastasis. In particular, the expression of sialylated fucosylated glycans like sialyl Lewis x and sialyl Lewis a correlates with a poor prognosis because of tumor progression and metastatic spread (30,31,(33)(34)(35)(36)(37). It was subsequently noted that carcinoma cell-surface mucins carrying sialyl Lewis x/a can be ligands for all three members of the selectin family of cell adhesion molecules (38,39).…”

Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

“…E-, P-, and L-selectins are vascular receptors for certain normal sialyl Lewis x/a containing mucin-type glycoproteins found on leukocytes and endothelium (40)(41)(42)(43). Because selectins can mediate tumor cell interactions with platelets, leukocytes, and endothelium in vitro (39,44,45), an in vivo role for selectins in the metastatic spread of tumors has been suggested (31,33,34). P-selectin expressed on activated endothelium contributes to the rolling of leukocytes that can result in their arrest and extravasation.…”

Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

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Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Borsig

Wong

Feramisco

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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623

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Independent studies indicate that expression of sialylated fucosylated mucins by human carcinomas portends a poor prognosis because of enhanced metastatic spread of tumor cells, that carcinoma metastasis in mice is facilitated by formation of tumor cell complexes with blood platelets, and that metastasis can be attenuated by a background of P-selectin deficiency or by treatment with heparin. The effects of heparin are not primarily due to its anticoagulant action. Other explanations have been suggested but not proven. Here, we bring together all these unexplained and seemingly disparate observations, showing that heparin treatment attenuates tumor metastasis in mice by inhibiting P-selectin-mediated interactions of platelets with carcinoma cell-surface mucin ligands. Selective removal of tumor mucin P-selectin ligands, a single heparin dose, or a background of P-selectin deficiency each reduces tumor cell-platelet interactions in vitro and in vivo . Although each of these maneuvers reduced the in vivo interactions for only a few hours, all markedly reduce long-term organ colonization by tumor cells. Three-dimensional reconstructions by using volume-rendering software show that each situation interferes with formation of the platelet “cloak” around tumor cells while permitting an increased interaction of monocytes (macrophage precursors) with the malignant cells. Finally, we show that human P-selectin is even more sensitive to heparin than mouse P-selectin, giving significant inhibition at concentrations that are in the clinically acceptable range. We suggest that heparin therapy for metastasis prevention in humans be revisited, with these mechanistic paradigms in mind.

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Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

Section: Biochemistry For the Article ''Functional Transitions In Mymentioning

confidence: 99%

See 1 more Smart Citation

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Borsig

Wong

Feramisco

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

623

650

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“…Whether sufficient P-selectin on unactivated platelets supports binding to tumor cells is unclear. Nevertheless, increased expression by tumor cells of P-selectin ligands, such as sialyl Lewis x or glycosaminoglycans, correlate with a poor prognosis owing to increased metastatic spread (41,42). This suggests a mechanism whereby P-selectin expressed on platelets mediates an interaction with tumor cells (4).…”

Section: Discussionmentioning

confidence: 99%

Platelet glycoprotein Ibα supports experimental lung metastasis

Jain

Zuka

Liu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

176

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The platelet paradigm in hemostasis and thrombosis involves an initiation step that depends on platelet membrane receptors binding to ligands on a damaged or inflamed vascular surface. Once bound to the surface, platelets provide a unique microenvironment supporting the accumulation of more platelets and the elaboration of a fibrin-rich network produced by coagulation factors. The platelet-specific receptor glycoprotein (GP) Ib-IX, is critical in this process and initiates the formation of a platelet-rich thrombus by tethering the platelet to a thrombogenic surface. A role for platelets beyond the hemostasis/thrombosis paradigm is emerging with significant platelet contributions in both tumorigenesis and inflammation. We have established congenic (N10) mouse colonies (C57BL/6J) with dysfunctional GP Ib-IX receptors in our laboratory that allow us an opportunity to examine the relevance of platelet GP Ib-IX in syngeneic mouse models of experimental metastasis. Our results demonstrate platelet GP Ib-IX contributes to experimental metastasis because a functional absence of GP Ib-IX correlates with a 15-fold reduction in the number of lung metastatic foci using B16F10.1 melanoma cells. The results demonstrate that the extracellular domain of the ␣-subunit of GP Ib is the structurally relevant component of the GP Ib-IX complex contributing to metastasis. Our results support the hypothesis that platelet GP Ib-IX functions that support normal hemostasis or pathologic thrombosis also contribute to tumor malignancy.adhesion ͉ tumor ͉ hemostasis ͉ knockout ͉ melanoma C irculating blood platelets have an inherent adhesive potential long recognized as essential for hemostasis and thrombosis. Beyond the platelet paradigm for blood clotting and thrombosis, it is becoming apparent that the platelet's adhesive potential influences pathological events outside its role in hemostasis. Indeed, emerging hypotheses suggest the platelet paradigm in hemostasis and thrombosis, an accumulation of platelets and the elaboration of a fibrin matrix, may provide a mechanism for circulating tumor cells to metastasize. Experimental proof that platelets effect tumor metastasis was provided in models where an experimental lowering of circulating platelet counts reduced metastasis (1-3).Evidence suggests that carcinoma cells entering the circulation interact with both platelets and leukocytes to form tumor cell aggregates (1, 4). Data have suggested one mechanism linking the platelet to metastasis is a platelet ''cloak'' surrounding the tumor cell and protecting the tumor cell from immune surveillance (5, 6). Tumorigenesis has been linked to several molecules essential for blood coagulation and normal platelet function. These include thrombin, tissue factor, platelet P-selectin, fibrinogen, and lysophosphatidic acid (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Together, these results suggest that platelets and their procoagulant activity support tumor metastasis, possibly by aiding tumor cells to lodge in the microvasculature and either extravasate...

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“…Manual analysis of the mass difference between the largest glycoform at m/z 7532.8 and the smallest at m/z 5691.5 in Figure 4 suggested that the structural difference between these two glycoforms corresponds to a sugar composition of (Hex) 4 (HexNAc) 3 (NeuAc) 1 (Fuc) 2 . When analyzing the m/z 7532.8 glycoform using GlycoMod, six possible sugar compositions were suggested.…”

Section: Glycopeptide Analysis Residue N 504mentioning

confidence: 99%

Characterization of Glycosylation Sites of the Epidermal Growth Factor Receptor

2003

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The epidermal growth factor receptor is a transmembrane glycoprotein that mediates the cellular responses to epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). In this study of the human EGF receptor naturally expressed in A431 cells, the glycosylation sites of the fulllength, membrane-bound receptor and of a secreted form of the receptor were characterized by mass spectrometry. Our data show that the naturally expressed human EGF receptor is fully glycosylated on eight of the 11 canonical sites; two of the sites are not glycosylated, and one is partially glycosylated, a pattern of site-usage similar but not identical to those reported for the recombinant human EGF receptor heterologously expressed in Chinese hamster ovary cells. We also confirm the partial glycosylation of an atypical NNC site first identified in the receptor expressed in Chinese hamster ovary cells. We show that an additional canonical site in the secreted form of the receptor is fully glycosylated. While the pattern of glycosylation is the same for the sites shared by the fulllength and the secreted forms of the receptor, the oligosaccharides of the full-length receptor are more extensively processed. Finally, we provide evidence that in addition to the known secreted form of the receptor, a proteolytic cleavage product of the receptor corresponding to the full extracytoplasmic, ligand-binding domain is present in the conditioned medium.Glycosylation is a ubiquitous feature of multicellular eukaryotic cells, with diversified oligosaccharides present in both the membrane-bound and the secreted proteins that are synthesized in endoplasmic reticulum (ER) and processed in Golgi complex. Oligosaccharides have been shown to play pivotal roles in protein folding and degradation during ER processing (for a review, see ref 1). They are also implicated in maintaining protein stability, modulating protein-protein interactions, etc. (2). Alteration of the structures of oligosaccharides has been observed in a number of diseases, including autoimmune diseases and cancers (3,4). † This work was supported by grants from the National Institutes of Health: R01 GM58008 (R.M.C.), R01 GM55056 (J.V.S.), and R01 DK25489 (J.V.S.).

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Untitled

Cited by 499 publications

References 96 publications

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

Platelet glycoprotein Ibα supports experimental lung metastasis

Characterization of Glycosylation Sites of the Epidermal Growth Factor Receptor

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