The involvement of the sLe-a selectin ligand in the extravasation of human colorectal carcinoma cells

Ben-David, T.; Sagi‐Assif, Orit; Meshel, Tsipi; Lifshitz, Veronica; Yron, Ilana; Witz, Isaac P.

doi:10.1016/j.imlet.2007.11.022

Cited by 19 publications

(12 citation statements)

References 11 publications

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“…The capability of a particular tumor to extravasate and therefore metastasize might correlate with the expression levels of selectin ligands. In colon carcinoma, there was a direct association between the levels of E-selectin ligands and the metastatic phenotype ( 47 ). Colorectal cancer cells expressing high levels of SLe a extravasate more efficiently than cancer cells with low SLe a in vivo .…”

Section: Selectin and Their Ligands In Cancer Metastasismentioning

confidence: 99%

Targeting Selectins and Their Ligands in Cancer

2016

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Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

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Section: Selectin and Their Ligands In Cancer Metastasismentioning

confidence: 99%

Targeting Selectins and Their Ligands in Cancer

2016

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“…For example, sialyl Lewis X (sLe x ) is known to mediate the metastasis of B16 melanoma cancer;15 carbohydrate ligand binding to E-selectin mediates the extravasation of cancer cells and organ selectivity of metastasis;16 sialyl Lewis a (sLe a ) binding to selectin is involved in the extravasation of human colorectal carcinoma cells;17 endothelial cell adhesion, often mediated by carbohydrate-selectin binding, is correlated with cancer progression;18 and sLe a expression on cancer cells is correlated with increased risk of distant hematogenous metastasis,19 presumably a result of carbohydrate-mediated metastasis. In addition, changes in glycosylation patterns often affect the function of a glycoprotein and are biomarkers for pathological or physiological events.…”

Section: Introductionmentioning

confidence: 99%

Carbohydrate recognition by boronolectins, small molecules, and lectins

Jin

Cheng

Reid

et al. 2009

Medicinal Research Reviews

288

214

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Carbohydrates are known to mediate a large number of biological and pathological events. Small and macromolecules capable of carbohydrate recognition have great potentials as research tools, diagnostics, vectors for targeted delivery of therapeutic and imaging agents, and therapeutic agents. However, this potential is far from being realized. One key issue is the difficulty in the development of "binders" capable of specific recognition of carbohydrates of biological relevance. This review discusses systematically the general approaches that are available in developing carbohydrate sensors and "binders/receptors," and their applications. The focus is on discoveries during the last five years.

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“…sLe a is a known ligand for endothelial leukocyte adhesion molecule and expression of sLe a was found to have an impact on metastatic potential (5, 6) and to correlate with increased metastatic potential in human colon cancer (7, 8) and pancreatic adenocarcinoma (9). In a study of 43 breast cancer patients with infiltrating ductal carcinoma it was found in about 79% of samples (10) and there was higher expression in patients with greater node involvement.…”

Section: Introductionmentioning

confidence: 99%

Human Monoclonal Antibodies to Sialyl-Lewisa (CA19.9) with Potent CDC, ADCC, and Antitumor Activity

Sawada

Sun

et al. 2011

Clinical Cancer Research

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Purpose: The carbohydrate antigen sialyl-Lewis a (sLe a ), also known as CA19.9, is widely expressed on epithelial tumors of the gastrointestinal tract and breast and on small-cell lung cancers. Since overexpression of sLe a appears to be a key event in invasion and metastasis of many tumors and results in susceptibility to antibody-mediated lysis, sLe a is an attractive molecular target for tumor therapy. Experimental Design: We generated and characterized fully human monoclonal antibodies (mAb) from blood lymphocytes from individuals immunized with a sLe a -KLH vaccine. Results: Several mAbs were selected based on ELISA and FACS including two mAbs with high affinity for sLe a (5B1 and 7E3, binding affinities 0.14 and 0.04 nmol/L, respectively) and further characterized. Both antibodies were specific for Neu5Aca2-3Galb1-3(Fuca1-4)GlcNAcb as determined by glycan array analysis. Complement-dependent cytotoxicity against DMS-79 cells was higher (EC 50 0.1 mg/mL vs. 1.7 mg/mL) for r7E3 (IgM) than for r5B1 (IgG1). In addition, r5B1 antibodies showed high level of antibodydependent cell-mediated cytotoxicity activity on DMS-79 cells with human NK cells or peripheral blood mononuclear cells. To evaluate in vivo efficacy, the antibodies were tested in a xenograft model with Colo205 tumor cells engrafted into SCID (severe combined immunodeficient mice) mice. Treatment during the first 21 days with four doses of r5B1 (100 mg per dose) doubled the median survival time to 207 days, and three of five animals survived with six doses. Conclusion: On the basis of the potential of sLe a as a target for immune attack and their affinity, specificity, and effector functions, 5B1and 7E3 may have clinical utility.

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The involvement of the sLe-a selectin ligand in the extravasation of human colorectal carcinoma cells

Cited by 19 publications

References 11 publications

Targeting Selectins and Their Ligands in Cancer

Targeting Selectins and Their Ligands in Cancer

Carbohydrate recognition by boronolectins, small molecules, and lectins

Human Monoclonal Antibodies to Sialyl-Lewisa (CA19.9) with Potent CDC, ADCC, and Antitumor Activity

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