Sialic acids in cancer biology and immunity

Abstract

During malignant transformation, glycosylation is heavily altered compared with healthy tissue due to differential expression of glycosyltransferases, glycosidases and monosaccharide transporters within the cancer microenvironment. One key change of malignant tissue glycosylation is the alteration of sialic acid processing that leads to a general upregulation of sialylated glycans (hypersialylation) on cell surfaces and an increased introduction of the non-human sialic acid N-glycolyl-neuraminic acid (Neu5Gc) instead of N-acetyl-neuraminic acid into cell surface glycans. These changes have been shown to be the result of altered sialyltransferase and sialidase expression. Functionally, cancer-associated hypersialylation appears to directly impact tumor cell interaction with the microenvironment, in particular the modulation of sialic acid-binding lectins on immune cells. Moreover, Neu5Gc expression in human tissues enhances inflammation due to an anti-Neu5Gc immune response, which can potentially influence inflammation-induced cancer and cancer-associated inflammation. In this review, we summarize the changes of sialic acid biology within the malignant microenvironment and the resulting effect on cancer immunity.

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

“…Receptors that bind to PAMPs and DAMPs have also been implicated in cancer progression and anticancer immunity (6,7). In addition to these well-described pathways, sialoglycans have been shown to serve as a self-associated molecular patterns (SAMPs) by binding to CD33-related sialic acid-binding immunoglobulin-like lectins (CD33rSiglecs) (8,9), a family of receptors on immune cells containing intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIM) (10)(11)(12)(13). Unlike the conserved Siglecs (Siglec-1, Siglec-2, Siglec-4, and Siglec-15), CD33rSiglecs, including Siglec-3 (CD33), Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, Siglec-10, Siglec-11, Siglec-14, and Siglec-16, have evolved rapidly due to multiple selection forces, including evolutionary pressure by pathogens that can mimic sialoglycan-SAMPs (Sia-SAMPs) and bind to inhibitory CD33rSiglecs to escape innate immune control (14)(15)(16)(17)(18).…”

Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer

“…Glycan structures are depending on the cell type, developmental stage and cell differentiation, and are modified in pathologic states including cancers and inflammatory diseases such as cystic fibrosis or bowel diseases. The modifications of cell glycosylation observed in cancers mainly affect the outer part of glycans, leading to the expression of cell surface antigenic sialylated structures that are strongly associated with a poor prognosis in certain tumors [1,2,3]. For example, sialyl-Lewis a (sLe a ) and sialyl-Lewis x (sLe x ) antigens are abnormally found on glycoproteins and glycolipids in several types of solid tumors and sLe x /selectin interactions are clearly involved in metastatic progression of gastric [4], lung [5] and prostate [6] cancers.…”

Sialylation regulates myofibroblast differentiation of human skin fibroblasts

“…Sialic acids, with relatively strong electronegative charges, on glycans contribute to many cellular functions including migration and proliferation; hence, changes in sialylation levels have been considered to be functionally involved in developmental and pathological states [8, 27]. Recent reports using lectin microarrays have demonstrated changes in sialylation of glycoproteins during senescence in human mesenchymal stem cells and human skin fibroblasts [13, 28].…”