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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

Structure of SLex (A) and its structural isomer SLea (B).
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Figure 2: Structure of SLex (A) and its structural isomer SLea (B).

Mentions: Sialic acids are incorporated within many different carbohydrate structures, including sialyl Lewis X (SLex) and its isomer sialyl Lewis A (SLea; Figure 2). These tetrasaccharide structures are composed of α2-3-linked sialic acid on the GlcNAc backbone. SLex and SLea represent the minimal recognition motif for ligands of selectins, a family of lectins whose functions are well characterized as mediators of leukocytes trafficking (40, 41). Three types of selectins have been described so far, the L-, E-, and P-selectins. Selectins are type I membrane proteins composed of a N-terminus C-type lectin domain followed by an epidermal growth factor (EGF)-like motif, a series of consensus repeats, a transmembrane domain, and a short cytoplasmatic tail. By interacting with SLex and SLea containing glycoproteins and glycolipids, selectins are responsible for the slow tethering and rolling of leukocytes on the vascular endothelium that is the first step of leukocytes extravasation during inflammation or lymphocytes homing. As is often seen during oncogenic transformation, cancer cells take advantage of this physiological process to spread and colonize to distant organs during the metastatic cascade (3, 42). Indeed, extravasation of tumor cells during metastasis is the best documented function of selectins and their ligands in cancer (43–45). However, recent evidence suggests a role of selectins/selectin ligands interactions beyond the extravasation process, such as emboli formation, formation of a permissive microenvironment for metastasis, and retention of tumor cells in protective niches.


Targeting Selectins and Their Ligands in Cancer.

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

Structure of SLex (A) and its structural isomer SLea (B).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Structure of SLex (A) and its structural isomer SLea (B).
Mentions: Sialic acids are incorporated within many different carbohydrate structures, including sialyl Lewis X (SLex) and its isomer sialyl Lewis A (SLea; Figure 2). These tetrasaccharide structures are composed of α2-3-linked sialic acid on the GlcNAc backbone. SLex and SLea represent the minimal recognition motif for ligands of selectins, a family of lectins whose functions are well characterized as mediators of leukocytes trafficking (40, 41). Three types of selectins have been described so far, the L-, E-, and P-selectins. Selectins are type I membrane proteins composed of a N-terminus C-type lectin domain followed by an epidermal growth factor (EGF)-like motif, a series of consensus repeats, a transmembrane domain, and a short cytoplasmatic tail. By interacting with SLex and SLea containing glycoproteins and glycolipids, selectins are responsible for the slow tethering and rolling of leukocytes on the vascular endothelium that is the first step of leukocytes extravasation during inflammation or lymphocytes homing. As is often seen during oncogenic transformation, cancer cells take advantage of this physiological process to spread and colonize to distant organs during the metastatic cascade (3, 42). Indeed, extravasation of tumor cells during metastasis is the best documented function of selectins and their ligands in cancer (43–45). However, recent evidence suggests a role of selectins/selectin ligands interactions beyond the extravasation process, such as emboli formation, formation of a permissive microenvironment for metastasis, and retention of tumor cells in protective niches.

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