The Ying and Yang of Ganglioside Function in Cancer

Abstract

The plethora of information about the expression of cancer cell-associated gangliosides, their role(s) in signal transduction, and their potential usefulness in the development of cancer treatments makes this an appropriate time to review these enigmatic glycosphingolipids. Evidence, reflecting the work of many, indicates that (1) expression of specific gangliosides, not generally found in high concentrations in most normal human cells, can be linked to certain types of cancer. (2) Gangliosides can affect the ability of cells to interact either directly or indirectly with growth factor receptors, thereby changing such things as a cell's mobility, rate of proliferation, and metastatic ability. (3) Anti-ganglioside antibodies have been tested, with some success, as potential treatments for certain cancers. (4) Cancer-associated gangliosides shed into the circulation can (a) affect immune cell responsiveness either positively or negatively, (b) be considered as diagnostic markers, and (c) be used to look for recurrence. (5) Cancer registries enable investigators to evaluate data from sufficient numbers of patients to obtain information about potential therapies. Despite advances that have been made, a discussion of possible approaches to identifying additional treatment strategies to inhibit metastasis, responsible for the majority of deaths of cancer patients, as well as for treating therapy-resistant tumors, is included.

Keywords: ganglioside; glycocalyx; growth factors; lipid rafts; multivalent oligosaccharide ligands.

Figure 1

Outline of ganglioside synthesis. Ganglioside nomenclature used was initially developed by Svennerholm [29]. The steps involved in the endoplasmic reticulum (ER) are shown in the red circle, and those in the Golgi are in the green square. ER-associated enzymes are SPT, serine-palmitoyl transferase; KSpR, 3-ketodihydrosphingosine reductase; CERS, ceramide synthase; DES, dihydroceramide desaturase; and GalT-1, UDP-galactose:ceramide galactosyl-transferase. Golgi-associated enzymes are UGCG, UDP-glucose:ceramide β1-1′glucosyltransferase; ST3Gal5, ST3 β-galactoside α-2,3-sialyltransferase 5; B4GalT5/6, UDP-galactose:glucosyl-ceramide β1-4 galactosyl transferase (lactosylceramide synthase) [30]; B4GalNT1, UDP-GalNAc:LacCer/GM3/GD3/GT3 β1-4 N-acetylgalactoseaminyl transferase (ganglioside GA2, GM2, D2, and T2 synthase); B3GalT4, UDP-galactose: GA2/GM2/GD2/GT2 β1–3 galactosyl transferase (ganglioside GA1, GM1a, GD1b, and GT1c synthase); ST3Gal5, CMP-sialic acid:lactosyl-ceramide α2-3 sialyltransferase (GM3 synthase); ST8SIA1, CMP-sialic acid:GM3 α-2,8-sialyltransferase (GD3 synthase); ST8SIA3/5, CMP-sialic acid:GD3 α-2,8-sialyltransferase (GT3 synthase); ST8Sia5, similar specificity to ST8SIA3/5 [31]; and ST6GalNT5, ST6 N-acetylgalactosaminide α-2,6-sialyltransferase 5.