Cancer intelligence acquired (CIA): tumor glycosylation and sialylation codes dismantling antitumor defense

Abstract

Aberrant glycosylation is a key feature of malignant transformation and reflects epigenetic and genetic anomalies among the multitude of molecules involved in glycan biosynthesis. Although glycan biosynthesis is not template bound, altered tumor glycosylation is not random, but associated with common glycosylation patterns. Evidence suggests that acquisition of distinct glycosylation patterns evolves from a 'microevolutionary' process conferring advantages in terms of tumor growth, tumor dissemination, and immune escape. Such glycosylation modifications also involve xeno- and hypersialylation. Xeno-autoantigens such as Neu5Gc-gangliosides provide potential targets for immunotherapy. Hypersialylation may display 'enhanced self' to escape immunosurveillance and involves several not mutually exclusive inhibitory pathways that all rely on protein-glycan interactions. A better understanding of tumor 'glycan codes' as deciphered by lectins, such as siglecs, selectins, C-type lectins and galectins, may lead to novel treatment strategies, not only in cancer, but also in autoimmune disease or transplantation.

Fig. 1

Characteristic patterns of tumor surface glycosylation as a consequence of epigenetically and genetically modified glycan biosynthesis. Glycan synthesis is not template bound but involves the concerted action of glycosyltransferases, glycosidases and glycan-modifying enzymes (e.g. sulfotransferases). The glycan machinery is frequently modified upon malignant transformation due to epigenetic and genetic changes. Environmental factors and immune pressure may lead to characteristic tumor-associated cell surface glycosylation patterns (see main text), including hypersialylation, truncation, altered branching, and even xenoglycosylation, which may confer a survival advantage to face the diverse challenges imposed by the host

Fig. 2

Incorporation of Neu5Gc-containing xenoglycans in human cancer. Neu5Gc is rare in human tissues due to the deletion of the enzyme that mediates hydroxylation of CMP-Neu5Ac into CMP-Neu5Gc (CMAH), and animal dietary sources may constitute the main supply of Neu5Gc. Under hypoxia, commonly found in human solid tumors, the expression of a lysosomal sialic acid transporter, Sialin, is enhanced. This leads to increased disponibility of free cytosolic Neu5Gc derived from lysosomal digested glycoproteins or -lipids, eventually resulting in overexpression of Neu5Gc-containing xenoglycans on the cancer cell surface

Fig. 3

The multiplicity of putative protein–glycan interactions that determines NK cell tumor immunosurveillance. Overexpression of specific sialic acid (purple diamonds)-containing carbohydrates (sialoglycans) leading to suppressed NK cell reactivity by engagement of their inhibitory Siglec-7 and -9 receptors. Interference of the interaction of activatory NK cell receptor NKG2D with its ligand MICA on the cancer cell, as a result of enhanced MICA sialylation, masking by sialoglycans, or Galectin-3 (Gal3) binding to glycosylated MICA. TGF-β release of P-selectin-sialoglycan bound platelets, as found in tumor emboli, may result in suppressed NK cell activity