Question

Compare and contrast some of the changes that occur in the biosynthesis and diversification of N-Glycan and O-glycan structures in normal and malignant cells. Using examples to illustrate your answer, describe the consequences of these changes in terms of lectin-glycan interactions and tumour progression

Answer 1

Like normal cells during embryogenesis, tumor cells undergo activation and rapid growth, adhere to a variety of other cell types and cell matrices, and invade tissues. Embryonic development and cellular activation in vertebrates are typically accompanied by changes in cellular glycosylation profiles. Thus, it is not surprising that glycosylation changes are also a universal feature of malignant transformation and tumor progression.

Glycosylation can be altered in various ways in malignancy:

Glycan changes in malignant cells takes place in various ways. For Example:

1. Loss of expression or excessive expression of certain structures.
2. The persistence of incomplete or truncated structures.
3. the accumulation of precursors, and, less commonly, the appearance of novel structures.

cancer is a “microevolutionary” process in which only the fittest cells in a genetically heterogeneous population survive, it is reasonable to suggest that these specific glycan changes are selected for during tumor progression.

Changes in Sialic acid expression in malignancy:

The classic observation of increased wheat germ agglutinin binding to animal tumor cells is likely explained by an overall increase in cell-surface sialic acid content, which in turn reduces attachment of metastatic tumor cells to the matrix and may help protect them from recognition by the alternative pathway of complement activation (by recruiting the factor H controlling protein).

The increase in sialylation is often manifested as specific increases in α2–6-linked Sialic acid attached to outer N-acetyllactosamine (Galβ1–4GlcNAc units) or to inner GalNAc-α1-O-Ser/Thr units on O-glycans. There is some evidence that the overexpression of Siaα2–6Galβ1–4GlcNAc units on N-glycans may enhance β1-integrin action.

As discussed above, sialyl-Tn expression may well be a “side effect” of decreased O-glycan extension, and it is currently a target for immunotherapy.

Apart from the amount and linkage of Sialic acid, there can also be significant changes in their modifications. Sialic acid 9-O-acetylation either can be up-regulated (e.g., the ganglioside epitope 9-O-acetylated GD3 is increased in melanoma cells in species ranging from humans to fish) or may be decreased (e.g., on the O-glycans of colon carcinomas). Some tumor cell types have also been reported to express small amounts of de-N-acetyl gangliosides (Figure-1), wherein the N-acetyl group typical of common sialic acids is removed, exposing a free amino group. Again, the pathological significance of these molecules is uncertain. Some studies have suggested that O-acetylated gangliosides may protect cells from apoptosis, and that de-N-acetyl gangliosides act by stimulating tyrosine phosphorylation of the epidermal growth factor (EGF) receptor. It is possible that altered sialylation of tumor cells affects interactions with some Siglecs. Such interactions could be potentially beneficial to the tumor cell by sending an inhibitory signal to innate immune cells.

Figure: -1

Some pathways for expression of gangliosides in human neuroectodermal tumors. The heavy arrows indicate pathways that are up-regulated. The dashed arrows indicate pathways that have not yet been formally proven. O-Acetylation of the terminal sialic acid can occur at the 7- or 9-position, with the former migrating to the latter position under physiological conditions

Symbolic representation of common monosaccharides and linkage: