Elsevier

Biochimie

Volume 85, Issues 3–4, March–April 2003, Pages 455-463
Biochimie

Original article
Role of tumor-associated gangliosides in cancer progression

https://doi.org/10.1016/S0300-9084(03)00006-3Get rights and content

Abstract

Neuroectodermic tumors can mostly be characterized by the presence of tumor-associated glycosphingolipid antigens, such as gangliosides, defined by monoclonal antibodies. Recently, cumulative evidence indicates that gangliosides modify the biological effects of several trophic factors, in vitro and in vivo, as well as the mitogenic signaling cascade that these factors generate. The functional roles of gangliosides in tumor progression can be revisited: (i) ganglioside antigens on the cell surface, or shed from the cells, act as immunosuppressors, as typically observed for the suppression of cytotoxic T cells and dendritic cells, (ii) certain gangliosides, such as GD3 or GM2, promote tumor-associated angiogenesis, (iii) gangliosides strongly regulate cell adhesion/motility and thus initiate tumor metastasis, (iv) ganglioside antigens are directly connected with transducer molecules in microdomains to initiate adhesion coupled with signaling, and (v) ganglioside antigens and their catabolites are modulators of signal transduction through interaction with tyrosine kinases associated with growth factor receptors or other protein kinases. Given the potential importance of these sialylated gangliosides and their modulating biological behavior in vivo, further studies on the role of gangliosides are warranted.

Introduction

Accumulating evidence indicates that cellular function and phenotype are highly influenced by gangliosides. Gangliosides are acidic glycosphingolipids that are characterized by the presence of at least one sialic acid linked to their oligosaccharide chain. They are present on the outer leaflet of plasma cell membranes of all types of tissues [1], with their hydrophobic ceramide backbone anchored in the membrane and the hydrophilic carbohydrate residue projected into the extracellular environment. Gangliosides have been shown to have crucial regulatory roles in the normal physiological process, such as embryogenesis [2], as well as in pathological conditions, including tumor onset and progression [3]. Many recent studies indicate that tumor-associated gangliosides are a result of initial oncogenic transformation and play a key role in the induction of invasion and metastasis. This role of tumor-associated gangliosides in promoting tumor cell invasion and metastasis is of crucial importance in current cancer research; however, it is more difficult to understand the defined functional concepts of gangliosides in cancer than the functional role of proteins and their genes in defining cancer cell phenotypes. The concept of ganglioside-dependent promotion of tumor progression has been developed in conjunction with clinicopathological studies that have shown that there are some ganglioside species with relatively simple structures that show very restricted expression in normal tissues and markedly enhanced expression in a particular malignant tumor. GD3 (Fig. 1), which has been identified as a melanoma-specific antigen, is an example of such a ganglioside [4]. All primary melanoma tissues as well as established melanoma cell lines contain high amounts of GD3 as a major ganglioside component [5]. In contrast, human melanocytes, the normal counterpart of melanoma cells, expressed no or minimal levels of GD3 [6]. Furthermore, highly metastatic cells show an increase in ganglioside content and express more GD3 or complex gangliosides than poorly metastatic cells [7], [8]. These findings suggest that GD3 might play an important role in the transformation of melanocytes into melanomas and also in the maintenance of malignant characteristics in melanoma cells. Little is known about the mechanisms through which tumor-associated gangliosides induce invasive and metastatic phenotypes of tumor cells.

Glycosphingolipids, including gangliosides, have been shown to be major components in some types of microdomains associated with various functional membrane proteins involved in cell adhesion and cell signaling at the cell–extracellular matrix interface [9]. Studies have shown that microdomains have different physical properties and specialized functions. The potential roles of gangliosides and the structural variety of glycoclusters in microdomains have been recently reviewed [9]. Gangliosides are also actively shed from the tumor to their microenvironment in the form of micelles, monomers, and membrane vesicles [10], [11]. Shed gangliosides are able to bind and interact with a wide variety of proteins, including signaling molecules present in the tumor microenvironment [12]. Furthermore, because shed gangliosides can be incorporated into the membrane of neighboring host cells, it is possible that the shed gangliosides modulate tumor–host cell interactions [13], [14].

The expression mechanism of these gangliosides in terms of the status of their respective glycosyltransferase genes has been extensively studied [15]. They are biosynthesized by the sequential action of a series of specific glycosyltransferases and sialyltransferases (Fig. 2). The first such proposal was given by Yu and Ando [16]. Fig. 2 is derived from this paper. To date, a large number of glycosyltransferase and sialyltransferase genes have been cloned and characterized [17], and studies of these genes have shown that various expression patterns of gangliosides are determined basically by a combination of activated glycosyltransferase genes [15]. Ganglioside biosynthesis takes place in the Golgi apparatus and endoplasmic reticulum [18], [19], where glucosylceramide is glycosylated by sequential addition of galactose, sialic acid, and N-acetylgalactosamine [20].

The availability of these transferase genes and information about their structure and function enable further analysis of the implication of the tumor-associated gangliosides in malignant phenotypes of cancer cells. The development of cell lines with defects in distinct biosynthetic pathways marks a significant advance in understanding the function of tumor-associated gangliosides. This review will focus on recent reports that have revealed a large amount of information about the role of gangliosides in tumorigenesis, tumor progression and tumor metastasis.

Section snippets

Gangliosides are involved in tumorigenesis

Several experimental approaches can be used to study the function of endogenous gangliosides. One is to assess the effect of eliminating molecules. Early studies in this direction included pharmacological inhibition of ganglioside synthesis using an inhibitor of glucosylceramide synthase, the key enzyme for glycosphingolipid synthesis, to block endogenous cellular ganglioside production. The first such molecule was d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) [21], [22].

Gangliosides as adhesion molecules and mediators of metastasis

During the last decade, several studies have established the importance of carbohydrate–carbohydrate interactions as the basis for cell adhesion and cell recognition. Although the greatest interest has been focused on glycoprotein–glycoprotein interactions, glycolipids may also participate in these carbohydrate–carbohydrate relationships and they have attracted increasing attention as possible key modulators. Some ganglioside antigens, which are highly expressed in specific human cancers, have

Gangliosides and angiogenesis

Tumors shed glycosphingolipids, mainly gangliosides, into the microenvironment, in greater quantities than do healthy tissues. This leads to elevated levels, up to 10 μM, of tumor-associated gangliosides in the serum [65]. Changes in the amounts of gangliosides in serum can influence the rate of tumor growth through an undetermined mechanism [3]. The potential importance of gangliosides in tumor cell growth has been suggested by demonstrating the reduction of experimental tumor growth and

Gangliosides as immunomodulators

Interactions between tumor cells and the cells of the immune system appear to be critical for tumor growth. The hypothesis that gangliosides may be active in the suppression of the antitumor immune response is supported by studies demonstrating that tumor cells synthesize and shed gangliosides into their microenvironments [70] and that these shed gangliosides directly bind to target cells in vitro [71]. Coupled with these observations, many studies have shown that exogenous or tumor-derived

Acknowledgements

Work in the laboratory of the authors was supported by National Institute of Health grants NS 11853, American Cancer Society grant IRG-105, and US Public Health Service grant NS11853-24. SB was also supported by a fellowship from the Fondation pour la Recherche Médicale, the Ligue Contre le Cancer, and the Groupement des Entreprises Françaises dans la Lutte contre le Cancer.

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    The ganglioside nomenclature is that of Svennerholm (J. Neurochem. 10 (1963) 613-623) in accordance with the International Union of Pure and Applied Chemistry (www.iupac.org/).

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