Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape.

Mostafa Jarahian,Mahnaz Ghaebi,Martin R Berger,Marwah Suliman Maashi,Faroogh Marofi,Abdolrahman Khezri

doi:10.3390/cancers13205203

Abstract

Simple SummaryThe immune system consists of various mechanisms contributing to the battle against cancer cells or hazardous pathogens. However, in cancer progression the immune system is often unable to eliminate neoplastic cells, although immune effector cells infiltrate the tumor environment. The current paper reviews the causes for this immune escape. Specifically, we comprehensively discuss various roles of sialic acids in this process. Specific focus is given to adhesion molecules re-expressed on membranes of tumor cells, which carry oligo- and polysialic acid chains. These carrier proteins loaded with sialic acids direct the interaction between immune effector and tumor cells and thus prevent the “kiss of death” between the latter and the former cells. We also discuss strategies suited to reduce the degree of sialic acid presence on the surface of tumor cells, which can be the basis for future therapeutic intervention.Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell–cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell–cell and/or cell–extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.

Highlights

In cancer progression, the immune system is often not capable of eliminating cancer cells, despite the presence of immune effector cells infiltrating the tumor microenvironment [1,2,3]
Even some pathogenic microorganisms contain sialic acids, e.g., bacteria, viruses, and parasites; they utilize cell surface sialic acids as ligands to attach to corresponding cell surface lectins, and to infect respective cells [30,31,32,33]. (Some Gram-negative bacteria synthesize sialic acids via an aldolase enzyme: they use a mannose derivative (Man-NAc) as a substrate and attach the three carbons of pyruvate to it, resulting in a sialic acid structure [34].) Sialic acid is a key component of glycoconjugates in glycoproteins/glycolipids, which commonly occur in cell membranes, cytoplasm, and glandular secretions that mediate cellular communication [24,35]
Sialic acids, which are located at outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids play a central role in immune regulation

Summary

Introduction

The immune system is often not capable of eliminating cancer cells, despite the presence of immune effector cells infiltrating the tumor microenvironment [1,2,3]. The poor prognosis of metastatic cancers has been correlated with overexpression of membrane glycoproteins on cancer cells, which are (poly-) sialylated [7,8,9] In this respect, recent advances in glycobiology and cancer research have described a mechanistic role of sialic acid in tumor development and progression: aberrant sialylation of glycoproteins and glycolipids has been shown to mediate conditions such as increased tumor growth [10,11], inhibition of apoptosis [12,13], metastasis [14,15,16], resistance to therapy [17,18,19], and enhanced invasiveness of tumor cells [11,20]. Sialic acid has been repeatedly proposed as a possible therapeutic target against tumors [11,20,24,25]

Methods

Results

Conclusion