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Targeting Selectins and Their Ligands in Cancer.

Natoni A, Macauley MS, O'Dwyer ME - Front Oncol (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences, National University of Ireland Galway , Galway , Ireland.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

The glycans determinants required for selectins binding are generated within the Golgi apparatus. STs, such as ST3GAL6, are responsible for the covalent linkage of sialic acid (♦) to the underline sugar backbone. Once on the cell surface, selectin ligands interact with selectins mediating cell rolling on the vasculature endothelium. Interactions of tumor cells with platelets or the endothelium (represented in the figure) can be blocked at the level of the Golgi apparatus by inhibiting STs or by directly interfering with the binding to selectins using blocker antibodies (Ab) or small molecules, such as GMI-1271, among others.
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Figure 3: The glycans determinants required for selectins binding are generated within the Golgi apparatus. STs, such as ST3GAL6, are responsible for the covalent linkage of sialic acid (♦) to the underline sugar backbone. Once on the cell surface, selectin ligands interact with selectins mediating cell rolling on the vasculature endothelium. Interactions of tumor cells with platelets or the endothelium (represented in the figure) can be blocked at the level of the Golgi apparatus by inhibiting STs or by directly interfering with the binding to selectins using blocker antibodies (Ab) or small molecules, such as GMI-1271, among others.

Mentions: Inhibition of selectin–selectin ligand interactions could impact different aspects of the tumor from metastatic spread to reshaping the metastatic niche. The consequence of this strategy depends certainly on the type of cancer and the stage at diagnosis. Inhibition of selectin/selectin ligand interactions can be achieved by different strategies, including inhibition of key enzymes responsible for generating the selectin ligands, such as STs, or blockage of selectin/selectin ligands interaction (Figure 3); in the latter case, the use of a variety of compounds can be employed spanning from small molecules, glycomimetics, heparin derivatives, and blocking antibodies.


Targeting Selectins and Their Ligands in Cancer.

Natoni A, Macauley MS, O'Dwyer ME - Front Oncol (2016)

The glycans determinants required for selectins binding are generated within the Golgi apparatus. STs, such as ST3GAL6, are responsible for the covalent linkage of sialic acid (♦) to the underline sugar backbone. Once on the cell surface, selectin ligands interact with selectins mediating cell rolling on the vasculature endothelium. Interactions of tumor cells with platelets or the endothelium (represented in the figure) can be blocked at the level of the Golgi apparatus by inhibiting STs or by directly interfering with the binding to selectins using blocker antibodies (Ab) or small molecules, such as GMI-1271, among others.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834419&req=5

Figure 3: The glycans determinants required for selectins binding are generated within the Golgi apparatus. STs, such as ST3GAL6, are responsible for the covalent linkage of sialic acid (♦) to the underline sugar backbone. Once on the cell surface, selectin ligands interact with selectins mediating cell rolling on the vasculature endothelium. Interactions of tumor cells with platelets or the endothelium (represented in the figure) can be blocked at the level of the Golgi apparatus by inhibiting STs or by directly interfering with the binding to selectins using blocker antibodies (Ab) or small molecules, such as GMI-1271, among others.
Mentions: Inhibition of selectin–selectin ligand interactions could impact different aspects of the tumor from metastatic spread to reshaping the metastatic niche. The consequence of this strategy depends certainly on the type of cancer and the stage at diagnosis. Inhibition of selectin/selectin ligand interactions can be achieved by different strategies, including inhibition of key enzymes responsible for generating the selectin ligands, such as STs, or blockage of selectin/selectin ligands interaction (Figure 3); in the latter case, the use of a variety of compounds can be employed spanning from small molecules, glycomimetics, heparin derivatives, and blocking antibodies.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences, National University of Ireland Galway , Galway , Ireland.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus