Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A

Takada, Ayako; Ohmori, Katsuyuki; Takahashi, Naofumi; Tsuyuoka, Kiyotaka; Yago, Akihiro; Zenita, K; Hasegawa, Akira; Kannagi, Reiji

doi:10.1016/0006-291x(91)91875-d

Cited by 342 publications

(163 citation statements)

References 14 publications

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“…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%

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.

623

650

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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.

623

650

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“…O-linked glycoepitopes present in mucin-type structures include (i) ABH and Lewis blood group antigens; (ii) tumorassociated antigens T, Tn (77,78), and sialyl-Tn (79, 80); (iii) E-selectin epitopes sialyl-Le x (32) and sialyl-Le a (81,82) 30). The ''myeloglycan'' epitope (see Table 1 for structure) found originally in GSLs (35,36) may well be present in O-linked form in PSGL-1 and other mucin-type glycoproteins.…”

Section: Type 2 Glycosynapse: O-linked Mucin-type Adhesion Epitopes Omentioning

confidence: 99%

“…SLe x or SLe x -Le x , present as ganglioside or mucin-type glycoprotein in tumor cell glycosynapse, mediates binding of tumor cells to activated endothelial cells (ECs) expressing E-selectin. The tumor-associated epitope SLe a , the positional isomer of SLe x , is equally active in binding to Eselectin (81,82). The same process can be considered for promotion of tumor cell metastasis by this epitope (111).…”

Section: Tumor Cell Malignancy Defined By Glycosynapse Functionmentioning

confidence: 99%

The glycosynapse

Hakomori

2002

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

472

217

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Physically distinguishable microdomains associated with various functional membrane proteins are one of the major current topics in cell biology. Glycosphingolipids present in such microdomains have been used as “markers;” however, the functional role of glycosyl epitopes in microdomains has received little attention. In this review, I have tried to summarize the evidence that glycosyl epitopes in microdomains mediate cell adhesion and signal transduction events that affect cellular phenotypes. Molecular assemblies that perform such functions are hereby termed “glycosynapse” in analogy to “immunological synapse,” the membrane assembly of immunocyte adhesion and signaling. Three types of glycosynapses are so far distinguishable: (i) Glycosphingolipids organized with cytoplasmic signal transducers and proteolipid tetraspanin with or without growth factor receptors; (ii) transmembrane mucin-type glycoproteins with clustered O-linked glycoepitopes for cell adhesion and associated signal transducers at lipid domain; and (iii) N-glycosylated transmembrane adhesion receptors complexed with tetraspanin and gangliosides, as typically seen with the integrin–tetraspanin–ganglioside complex. The possibility is discussed that glycosynapses give rise to a high degree of diversity and complexity of phenotypes

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“…Such findings were not known when we had planned this prospective randomized control study. But now, it is known that sialyl Lewis-X (sL x ) and sialyl Lewis-A (sL a ) antigens are ligands to Eselectin, and sL x and sL a expressed on cancer cells mediate adhesion of the cancer cells to vascular endothelial cells expressing Eselectin (Phillips et al, 1990;Takada et al, 1991Takada et al, , 1993. The adhesion of cancer cells to vascular endothelial cells is a key step in invasion and metastasis of cancer cells (Hoff et al, 1989(Hoff et al, , 1990Nakamori et al, 1993).…”

mentioning

confidence: 99%

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells

et al. 2002

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Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day 71 of cimetidine orally together with 200 mg day 71 of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P50.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL x ) and A (sL a ). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL x and sL a antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL x , of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL x and sL a .

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Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A

Cited by 342 publications

References 14 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

The glycosynapse

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells

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