Distinct Selectin Ligands on Colon Carcinoma Mucins Can Mediate Pathological Interactions among Platelets, Leukocytes, and Endothelium

Kim, Young Jin; Borsig, Lubor; Han, Huiling; Varki, Nissi; Varki, Ajit

doi:10.1016/s0002-9440(10)65142-5

Cited by 175 publications

(138 citation statements)

References 53 publications

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“…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%

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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627

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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%

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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627

650

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“…Platelets have been reported to bind to small cell lung and colon carcinoma via P-selectin (11,12,31,39). Alternatively, platelets may attach to certain melanoma, breast, and colon cancer cells through the integrin receptor ␣ IIb ␤ 3 on the platelet surface (4, 40 -43).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that platelets interact with a number of tumor cell lines, but the cell adhesion experiments were conducted exclusively under static conditions (11,12,31). To determine whether COLO320 cells also adhere to platelets under flow conditions and to determine the role of P-selectin on platelets in the process of cell adhesion, tumor cells were perfused through a parallel plate flow chamber whose lower plate was coated with a layer of platelets.…”

Section: Modified Heparins Inhibit Colo320 Cells Adhering To Surface-mentioning

confidence: 99%

Modified Heparin Inhibits P-selectin-mediated Cell Adhesion of Human Colon Carcinoma Cells to Immobilized Platelets under Dynamic Flow Conditions

Wei

Tai

Gao

et al. 2004

Journal of Biological Chemistry

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Accumulating evidence indicates that the formation of tumor cell platelet emboli complexes in the blood stream is a very important step during metastases and that the anti-metastasis effects of heparin are partially due to a blockade of P-selectin on platelets. In this study, heparin and chemically modified heparins were tested as inhibitors of three human colon carcinoma cell lines (COLO320, LS174T, and CW-2) binding to P-selectin, adhering to CHO cells expressing a transfected human P-selectin cDNA, and adhering to surface-anchored platelets expressing P-selectin under static and flow conditions. The aim was to screen for heparin derivatives with high anti-adhesion activity but negligible anticoagulant activity. In this study, four modified heparins with high anti-adhesion activity were identified including RO-heparin, CR-heparin, 2/3ODS-heparin, and N/2/3DS-heparin. NMR analysis proved the reliability of structure of the four modified heparins. Our findings suggested that the 6-O-sulfate group of glucosamine units in heparin is critical for the inhibition of P-selectin-mediated tumor cell adhesion. Heparan sulfate-like proteoglycans on these tumor cell surfaces are implicated in adhesion of the tumor cells to P-selectin. Some chemically modified heparins with low anticoagulant activities, such as 2/3ODS-heparin, may have potential value as therapeutic agents that block P-selectin-mediated cell adhesion and prevent tumor metastasis.Hematogenous metastasis is a highly regulated and dynamic process in which the cancerous cells separate from the primary tumor, migrate across blood vessel walls into the bloodstream, and disperse throughout the body to generate new colonies. Several lines of experiments have demonstrated that platelets can facilitate hematogenous dissemination of tumor cells (1). In this process, platelets act mainly through emboli complexes formed by the interaction of tumor cells and platelets. The formation of tumor cell-platelet emboli complexes in the blood stream not only provides a protective shield that masks them from the cytotoxic activity of natural killer cells, but also favors tumor cell adhesion to vascular endothelial cells (2-4).The interaction between tumor cells and platelets may involve several kinds of adhesion molecules. Selectins are a family of intercellular adhesion molecules that mediate the initial adhesion of leukocytes to the endothelia of blood vessels during inflammation (5-9). The family includes E-, P-, and L-selectin, and all three selectins can bind to sialylated, fucosylated, or, in some cases, sulfated glycans on glycoproteins, glycolipids, or proteoglycans (10). The tetrasaccharides [Neu5Ac␣2,3Gal␤1,4-(Fuc␣1,3)GlcNAc] (sLe x ) 1 and [Neu5Ac␣2,3Gal␤1,3(Fuc␣1,4)-GlcNAc] (sLe a ) have been identified as the minimal ligands for all three types of selectins. Recently, accumulating evidence indicates that P-selectin plays a crucial role during hematogenous metastasis, and P-selectin has been shown to bind to several human cancers and human cancer-derived cell lines, s...

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“…Selectins are vascular cell adhesion molecules that recognize certain sialyl Lewis x/a carrying mucin-type glycoproteins found on normal leukocytes and endothelium (11,(19)(20)(21)(22)(23). Carcinoma cell surface molecules carrying sialyl Lewis x/a also can be recognized by all three selectins (11-15, 17, 24-27), mediating tumor cell interactions with platelets, leukocytes, and endothelium in vitro (10,25,27,28). Based on such data, an in vivo role for E-and P-selectins in metastatic spread has been suggested.…”

mentioning

confidence: 99%

Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis

Borsig

Wong

Hynes

et al. 2002

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

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Here we show similar findings with a murine adenocarcinoma in syngeneic immunocompetent mice but involving a different P-selectin ligand, possibly a sulfated glycolipid. Thus, metastatic spread can be facilitated by tumor cell selectin ligands other than mucins. Surprisingly, L-selectin expressed on endogenous leukocytes also facilitates metastasis in both the syngeneic and xenogeneic (T and B lymphocyte deficient) systems. PL-selectin double deficient mice show that the two selectins work synergistically. Although heparin can block both P-and L-selectin in vitro, the in vivo effect of a single heparin dose given before tumor cells seems to be completely accounted for by blockade of P-selectin function. Thus, L-selectin on neutrophils, monocytes, and͞or NK cells has a role in facilitating metastasis, acting beyond the early time points wherein P-selectin mediates interactions of platelet with tumor cells.cancer ͉ heparin ͉ glycolipids ͉ platelets H ematogeneous metastasis occurs when tumor cells enter the bloodstream, interact with host blood cells, and eventually colonize a distant tissue. Much evidence indicates that hematogenously disseminating tumor cells interact with platelets and leukocytes, forming microemboli that facilitate their arrest in the vasculature (1-4). Although the contribution of platelets to metastasis has been confirmed in several experimental settings (1, 2, 5-10), the mechanisms and significance of leukocyte participation in tumor microemboli remain largely unknown.Altered cell surface glycosylation is a prominent feature of tumor cells (11)(12)(13)(14)(15). In particular, the expression of sialylated fucosylated glycans like sialyl Lewis x/a correlate with a poor prognosis because of tumor progression and a high rate of metastasis (for examples, see refs. 16-18). Selectins are vascular cell adhesion molecules that recognize certain sialyl Lewis x/a carrying mucin-type glycoproteins found on normal leukocytes and endothelium (11,(19)(20)(21)(22)(23). Carcinoma cell surface molecules carrying sialyl Lewis x/a also can be recognized by all three selectins (11-15, 17, 24-27), mediating tumor cell interactions with platelets, leukocytes, and endothelium in vitro (10,25,27,28). Based on such data, an in vivo role for E-and P-selectins in metastatic spread has been suggested. The hypothesis that E-selectin on activated endothelium might facilitate cancer cell seeding (14, 29) is supported by transgenic over-expression of E-selectin in the mouse liver, which redirected metastases to this organ (30), and a system where tumor cell expression of sialylated fucosylated glycans was increased by transfecting a fucosyltransferase (31). Carcinoma lines expressing E-selectin ligands also displayed an increased metastatic capacity in cytokine-pretreated mice (32). However, E-selectin is not constitutively expressed in vivo but must be transcriptionally activated by certain stimuli. We have previously shown that platelets adhere to some human carcinoma cells mostly via P-selectin and that inhibition of th...

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Distinct Selectin Ligands on Colon Carcinoma Mucins Can Mediate Pathological Interactions among Platelets, Leukocytes, and Endothelium

Abstract: Many interactions that occur among leukocytes, platelets, and endothelial cells in the vasculature have been shown to be mediated by the selectin family of cell adhesion molecules.

Cited by 175 publications

References 53 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

Modified Heparin Inhibits P-selectin-mediated Cell Adhesion of Human Colon Carcinoma Cells to Immobilized Platelets under Dynamic Flow Conditions

Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis

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