Altered Glycosylation in Cancer: Sialic Acids and Sialyltransferases

Altered Glycosylation in Cancer: Sialic Acids and 

Sialyltransferases 

Peng-Hui Wang 1 

Review Article 

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, and Institute of Emergency Medicine 

and Critical Care, National Yang-Ming University School of Medicine, Taipei, Taiwan 

Abnormal protein glycosylation, resulting in expression of altered carbohydrate deter- 

minants, is well associated with malignant transformation of the cell. One family of im- 

portant molecules related to aberrant glycosylation is sialic acids (SAs) and their de- 

rivatives, which are ubiquitous at the terminal positions of the oligosaccharides of gly- 

coproteins. Sialylation affects the half-lives of many circulating glycoproteins and 

plays roles in a variety of biologic processes such as cell-cell communication, cell- 

matrix interaction, adhesion, and protein targeting. The transfer of sialic acids from 

CMP-sialic acids to the acceptor carbohydrates is catalyzed by the sialyltransferase 

(ST) family, which includes 20 glycoprotein- and glycolipid-specific α2,3-, α2,6- and 

α2,8-linkage transferring enzymes described up to date. Cell surface SA levels are 

mainly correlated with the mRNA levels of ST genes. In human, STs are expressed in 

many tissues at different levels. Moreover, the level of ST expression is dramatically 

changed during cancer transformation and this alteration can be achieved transcrip- 

tionally through tissue-specific or cell type-specific promoters that lead to the produc- 

tion of mRNA species which diverge in the 5’-untranslated region. Evidence shows that 

altered ST expression have a significant correlation with oncogenesis, tumor progres- 

sion, and lymph node metastases. Therefore, the functional roles of ST in cancer 

pathogenesis should be elucidated with the assistance of advanced molecular technol- 

ogy. In this paper, an overview of sialylation changes in cancer is highlighted. Getting 

insights and understandings of altered glycosylation in cancers will offer a brand-new 

vision in modifying cancer behavior and treating these highly lethal diseases in the near 

future. 

Journal of Cancer Molecules 1(2): 73-81, 2005. 

Introduction 

Glycosylation is one of the most frequently occurring coor 

post-translational modifications made to proteins and 

lipids in the secretion machinery of the cell, with resultant 

carbohydrate side chains to have very complex oligosaccharide 

sequences and concomitant structural diversity [1-3]. 

More than half of known protein sequences can potentially 

be glycosylated [2,3]. Glycosylation can be mainly divided 

into two major types, including O-glycosylation, where the 

sugar is bound to the hydroxyl of a serine (Ser 2 ) or a 

threonine (Thr) residue, and N-glycosylation, where the sugar 

is attached to the amide group of an asparagine (Asn) in 

the consensus sequence Asn-X-Ser/Thr, where X is any residue 

but a proline (Figure 1)[4]. There is a database of Oglycosylated 

proteins [5] and statistical analysis has been 

Received 8/19/05; Revised 11/28/05; Accepted 12/8/05. 

1 Correspondence: Dr. Peng-Hui Wang, Department of Obstetrics and 

Gynecology, Taipei Veterans General Hospital, No. 201, Shih-Pai Road 

Sec. 2, Taipei 112, Taiwan. E-mail: phwang@vghtpe.gov.tw 

2 Abbreviations: Ser, serine; Thr, threonine; Asn, asparagine; SA, sialic 

acid; Neu5Ac, N-acetylneuraminic acid; Gal, galactose; GalNAc, Nacetylgalactosamine; 

ST, sialyltransferase; GlcNAc, N-acetylglucosamine. 

Keywords: 

neoplasms 

sialic acid 

sialylation 

sialyltransferase 

performed on the sequences around such sites to identify 

preferential motifs for O-glycosylation [6]. Potential Nglycosylation 

sites can be identified by the presence of the 

Asn-X-Ser/Thr sequence in peptide sequence databases [2]. 

The protein sequence is completely encoded by the genome; 

however, the diversity of protein can be achieved by different 

sequence and structure of the sugar moiety, or glycan 

attachment. The appropriate and accurate modification of 

sugar or glycan depends on the action of highly specific and 

precisely located enzymes known as glycosyltransferases 

and glycosidases in different tissue or cells. Thus, the glycan 

structure is determined not only by the nature of the 

protein it is bound to, but also by the tissue or cell where it 

is made [3]. These carbohydrate side chains modulate the 

interaction of a protein with its environment, influencing its 

solubility, activity, and biologic fate. The function of the 

glycans covers a wide spectrum, from relatively trivial to 

crucial for the growth, development, and survival of cells 

and organisms. However, sugars are often overlooked, 

compared to the extent of research on genes and proteins 

[3]. This is mainly due to their complexity, which makes 

them difficult to sequence and study. Glycan structures 

cannot be readily obtained because they cannot be amplified 

© 2005 MedUnion Press 73

Wang J. Cancer Mol. 1(2): 73-81, 2005 

Figure 1: Examples of the attachment forms of glycans on a protein 

as nucleic acids can, they generally come as a highly heterogeneous 

mix of different species bound to a single protein, 

they are non-linear molecules, and there is no universal 

method to precisely determine the structure of a glycan species 

without making assumptions regarding the biologic 

system [7]. There is increasing evidence that glycosylation 

also depends on the precise location of the N-glycosylation 

sites because the quality control mechanism appears to be 

regional and so not all glycans are equally important in the 

folding process [4]. Considerable work has been done to 

characterize the sequences of oligosaccharides attached to 

proteins [8,9] and to determine their 3D structures [10]. Databases 

are available for glycan primary structures [11]. 

Among the glycans, one of the particular important 

molecules is the sialic acid (SA) [12]. 

Sialic acids and sialyltransferases 

Sialic acids (SAs) are a group of neuraminic acid (5-amido- 

3,5-dideoxy-D-glycero-D-galacto-nonulosonic acid) and 

widely distributed in nature as terminal sugars on oligosaccharides 

attached to protein or lipid moieties. The members 

include the nine-carbon amino acid, N-acetylneuraminic acid 

(Neu5Ac, Figure 2), and its derivatives. Neu5Ac is the most 

ubiquitous SA and is the biosynthetic precursor for all other 

SAs. All SAs have a carboxylate at the C1 position that is 

typically ionized at physiological pH [13]. SA derivatives are 

ubiquitous at the terminal positions of the oligosaccharides 

of glycoproteins [14-16], which determine the half-lives of 

many circulating glycoproteins. It has been documented 

that the terminal SA of glycans is an important residue in 

affecting cell behavior [17]. Usually, sialyl residues are 

linked to the inner sugar residue galactose (Gal) via α2,6 or 

α2,3-linkage or linked to galactosamine or Nacetylgalactosamine 

(GalNAc) via α2,6-linkage (Figure 3). 

Moreover, SA can also be linked to the C8 position of another 

SA residue. The biosynthesis of these molecules may act 

as a coding system, since they are able to interact with high 

specificity and selectivity with carbohydrate-binding proteins 

including lectins, antibodies, receptors, and enzymes 

[18]. These molecules are also involved in cell communication 

such as cell-cell and cell-matrix interactions and 

molecular recognition during tumor development, differentiation 

and progression [1,19,20], which is catalyzed by enzymes 

of the sialyltransferase (ST) family [19], including 

glycoprotein and glycolipid-specific α2,3-, α2,6- and α2,8linkage 

transferring enzymes [21-36]. 

Sialyltransferases (STs) can be further classified into four 

families according to the carbohydrate linkage they synthesize: 

the ST3Gal (α2,3-ST), ST6Gal (α2,6-ST), ST6GalNAc, 

and ST8Sia (α2,8-ST) families (Figure 3)[37]. Every family 

can be further classified into many subtypes (Table 1). All 

enzymes of the ST3Gal family transfer Neu5Ac residues in 

α2,3-linkage to terminal Gal residues found in glycoproteins 

or glycolipids (Figure 3). In the ST3Gal family, the ST3Gal-I 

and -II subfamilies use exclusively the type 3 oligosaccharide 

structure Galß1→3GalNAc-R, whereas the ST3Gal-III, -IV, 

-V, and -VI use the oligosaccharide isomers Galß1→ 

3/4GlcNAc-R. Moreover, the ST3Gal-V subfamily uses exclusively 

the lactosyl-ceramide (i.e. Galß1→4GlcNAc-Cer) as an 

acceptor substrate, giving rise to the synthesis of the ganglioside 

G M3 [38]. The enzymes of the ST6Gal family comprise 

only two subfamilies, ST6Gal-I and -II, that both use the 

Galß1→4GlcNAc-R as the acceptor substrate. The enzymes 

of the ST6GalNAc family catalyze the transfer of Neu5Ac 

residues in α2,6 linkage to the GalNAc residues found in Oglycosylproteins 

(ST6GalNAc-I, -II and -IV) or found in glycolipids 

(ST6GalNAc-III, -V and -VI). ST6GalNAc-I and -II 

(ST6GalNAc subfamily I) catalyze the transfer of Neu5Ac 

onto Galß1→3GalNAc peptides (sialylated or not), and their 

activity greatly depends on the peptide moiety. Whereas, 

ST6GalNAc-III, -IV, -V, and -VI (ST6GalNAc subfamily II) exhibit 

a more restricted substrate specificity, only utilizing 

sialylated acceptor substrates (Neu5Acα2→3Galß1→ 

3GalNAc-R), found either in glycoproteins or glycolipids 

such as G M1b. Each of these subfamilies has characteristic 

sequence motifs not present in the other subfamily [41]. 

Enzymes of the ST8Sia family mediate the transfer of 

Neu5Ac residues in α2,8-linkage to other Neu5Ac residues 

found in glycoproteins and glycolipids. The two main 

branches of this family tree contain three subfamilies each: 

ST8Sia-I, -V and -VI in the first branch and ST8Sia-II, -III and - 

IV in the second branch. 

All vertebrate STs have a similar architecture. They are 

type II transmembrane glycoproteins that predominantly 

reside in the trans-Golgi compartment [38]. They have a 

short N-terminal cytoplasmic tail, a unique transmembrane 

domain, and a stem region with a variable length from 20 to 

200 amino acids followed by a large C-terminal catalytic domain. 

The members of ST8Sia family appear to have higher 

sequence conservation whereas the ST6GalNAc family has 

the lowest sequence conservation. The members of ST3Gal 

and ST8Sia families share significant sequence similarities; 

in contrast, the ST6Gal family is distinct from the ST6GalNAc 

family. 

The vertebrate ST amino acid sequences described up to 

date show overall limited sequence identity (from 15 to 57% 

for human STs), but share four peptide conserved motifs 

called the sialylmotifs: L (large), S (small), motif III [39], and 

motif VS (very small) [40,41]. These four motifs are common 

in all the STs, irrespective of the linkage- and acceptor saccharide-specificities 

and are involved in the formation of 

essential disulfide bonds and are implicated in the recognition 

of both donor and acceptor substrates [42] and in the 

Figure 2: Structure of sialic acid: N-acetyl-neuraminic acid (Neu5Ac) 

as an example. 

74 Print ISSN 1816-0735; Online ISSN 1817-4256

Figure 3: Types of sialyltransferases and their main substrates and linkage patterns. CMP, cytosine 5’-monophosphate. 

catalytic activity [39]. The well-documented L-, S-, and VSmotifs 

and motif III represent residue conservation patterns 

at the superfamily level. As has been mentioned, these residues 

will either have a structural role or a functional role that 

is common to all the STs. The linkage-specific motifs identified 

by Patel and Balaji [41] represent the second level of 

residue conservation pattern. The residues conserved at 

this level are expected to be important for linkage specificity 

and for recognizing the monosaccharide moiety that accepts 

sialic acid. The third level of residue conservation pattern, 

as has been analyzed by Harduin-Lepers et al. [38], delineates 

residues that are conserved in each of the twenty subfamilies. 

These residues are expected to contribute to the 

overall acceptor substrate specificity, which is not the same 

for the various subfamilies. These conserved residues are 

hallmarks for the identification of eukaryotic ST genes [38]. 

Cell surface SA levels are dependent on the mRNA levels 

of ST genes [43,44]. In humans, ST is expressed in many 

tissues at different levels [45-47]. In addition, the level of ST 

expression is dramatically changed during cancer transformation 

and this alteration of ST expression can be achieved 

transcriptionally through tissue-specific or cell type-specific 

promoters that lead to the production of mRNA species 

which diverge in the 5’-untranslated region [48-56]. For example, 

transcriptional regulation of human ST6Gal-I has 

been studied most thoroughly, including three major mRNA 

species [57]. The first, from a placenta cDNA library, contains 

the 5’-untranslated exons Y and Z (placental or Y + Z 

form: 250 bp) and is thought to represent the basal or 

housekeeping expression of the gene [51-54]. A second 

species lacks exons Y and Z but contains a specific sequence 

in front of exon I and represents the major liver transcript 

(hepatic or H form: 446 bp) [49,51,54]. The third form, 

specific to B-lymphocytes, lacks exons Y and Z but contains 

the 5’-untranslated exon X (X form or X transcript: 128 

bp)[48,50,56]. This tissue or cell type-selective expression of 

different ST6Gal-I transcripts suggests that gene expression 

of ST6Gal-I can be controlled by utilization of specific pro- 

Sialic Acids and Sialyltransferases in Cancer 

moter and corresponding transcriptional factors, which allows 

quantitative regulation of ST6Gal-I expression [55]. In 

addition, the product of ras oncogene might contribute the 

regulation of ST6Gal-I transcription [58-60]. The liverenriched 

factor hepatocyte nuclear factor-1 (HNF1) is also 

thought to participate in the hepatocyte-specific P1 promoter 

activity [61]. Xu et al. have characterized the P1 promoter 

region, which regulates Form 1 mRNA expression. They 

used luciferase assays to show that -156 to -1 region, which 

contains the HNF1 recognition element, was important for 

the transcriptional activity of the ST6Gal-I gene in colon 

adenocarcinoma cell lines, because mutation of the HNF1 

site reduced luciferase activity by ~80% compared with the 

wild-type construct [61]. Similar to ST6Gal-I, multiple promoters 

are found in the ST3Gal-IV, ST3Gal-V (G M3 synthase), 

and ST3Gal-VI genes, which result in multiple isoforms of 

each given ST. These promoters may respond to different 

physiologic signals and stimuli in different cell types. 

Other examples showing complexity in studying STs are 

ST3Gal-IV and ST3Gal-III. The original structures and chromosomal 

locations of ST3Gal-IV genes have been determined 

[62,63]. The mRNA of ST3Gal-IV in human is consisted 

of many isoforms, A1, A2, B1, B2, B3, and BX [63,64]. 

These transcripts are produced by a combination of alternative 

promoter utilization and RNA splicing [65]. The ST3Gal- 

IV mRNA can be transcribed from different promoters, pA, 

pB1, pB2, pB3, and pBX, respectively [66]. The type B mRNA 

is expressed in several cells, whereas the type A mRNA is 

specifically expressed in testis, ovary, and placenta [43]. 

Taniguchi and Matsumoto suggest that epithelial cellspecific 

regulation of ST3Gal-IV gene expression is mediated 

by specific interaction of AP2 with the DNA region -520 to - 

420 [64]. AP2 belongs to the group of transcription factors 

involved in epithelium cell-specific gene expression [67,68]. 

About ST3Gal-III, Grahn et al. have cloned and sequenced 

human ST3Gal-III gene transcripts from peripheral blood 

leukocytes, and isolated 19 different transcripts with a wide 

variety of deletions in nt 45 to 896 region and insertions in nt 



Table 1: Summary of the human sialyltransferase family 

(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=gene) 

Symbol Enzyme Name 

Chromosome 

Location 

ST3Gal (α2,3-ST) 

ST3GAL1 

ST3 β-galactoside α-2,3-sialyltransferase 1 

HGNC: 10862, Gal-NAc6S, MGC9183, SIAT4A, SIATFL, ST3Gal A.1, 

ST3Gal IA, ST3O 

8q24.22 6482 

ST3GAL2 


HGNC: 10863, Gal-NAc6S, SIAT4B, ST3Gal II, ST3GalA.2 

16q22.1 6483 

ST3GAL3 


HGNC: 10866, SIAT6, ST3Gal II, ST3Gal III, ST3N 


1p34.1 6487 

ST3GAL4 HGNC: 10864, CGS23, FLJ11867, NANTA3, SAT3, SIAT4, SIAT4C, 

ST3Gal IV, STZ 

11q23-q24 6484 

ST3GAL5 


HGNC: 10872, SIAT9, SIATGM3S, ST3Gal V 

2p11.2 8869 

ST3GAL6 


HGNC: 18080, SIAT10, ST3Gal VI 

3q12.1 10402 

LOC343705 

ST6Gal (α2,6-ST) 

similar to β-galactoside α-2,3-sialyltransferase 20q11.22 343705 

ST6GAL1 

ST6 β-galactosamide α-2,6-sialyltranferase 1 

HGNC: 10860, CD75, MGC48859, SIAT1, ST6Gal I 

3q27-q28 6480 

ST6GAL2 

ST6GalNAc 

β-galactosamide α-2,6-sialyltranferase 2 

HGNC: 10861, KIAA1877, SIAT2, ST6Gal II 

ST6 (α-N-acetyl-neuraminyl-2,3-β-galactosyl-1,3)-N-acetylgalactosaminide 

2q11.2-q12.1 84620 

ST6GALNAC1 α-2,6-sialyltransferase 1 

HGNC: 23614, HSY11339, SIAT7A, ST6GalNAc I 


17q25.1 55808 


HGNC: 10867, SIAT7, SIAT7B, SIATL1, ST6GalNAc II, STHM 


17q25.1 10610 


HGNC: 19343, PRO7177, SIAT7C, ST6GalNAc III 

1p31.1 256435 

ST6GALNAC4 


α-2,6-sialyltransferase 4 

HGNC:17846, SIAT3C, SIAT7D, ST6GalNAc IV 

similar to α-N-acetyl-neuraminyl-2,3-β-galactosyl- 

9q34 27090 

LOC390377 

1,3-N-acetyl-galactosaminide α-2,6-sialyltransferase (NeuAc-α-2,3-Gal-β- 

1,3-GalNAc-α-2,6-sialyltransferase) 

ST6GalNAc IV, Sialyltransferase 7D, Sialyltransferase 3C 

13q12.11 390377 

ST6GALNAC5 



HGNC: 19342, MGC3184, SIAT7E, ST6GalNAc V 

1p31.1 81849 

ST6GALNAC6 

ST8Sia (α2,8-ST) 



9q34.11 30815 

ST8SIA1 

ST8 α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 

HGNC: 10869, GD3S, SIAT8, SIAT8A, ST8Sia I 

12p12.1-p11.2 6489 

ST8SIA2 


HGNC: 10870, HsT19690, MGC116854, SIAT8B, ST8SIA-II, STX 

15q26 8128 

ST8SIA3 


HGNC: 14269, SIAT8C, ST8Sia III 

18q21.31 51046 

ST8SIA4 


HGNC: 10871, MGC34450, MGC61459, PST, PST1, SIAT8D, ST8SIA-IV 

5q21 7903 

ST8SIA5 


HGNC: 17827, SIAT8E, ST8Sia V 

18q21.1 29906 

ST8SIA6 


HGNC: 23317, SIAT8F, ST8SIA-VI, ST8Sia VI 

10p12.33 338596 

76 Print ISSN 1816-0735; Online ISSN 1817-4256 

Gene 

ID

Figure 4: A schematic model 

for granulocyte binding to 

activated endothelial cells. 

Unstimulated endothelial cells 

express low amounts of ICAM-1 

and ICAM-2. After stimulation 

by cytokines, the amounts of 

ICAM-1 and ICAM-2 are upregulated 

and the levels of E 

and P-selectin are induced. 

Binding of E or P-selectin with 

the sialyl Lewis X of CD11/CD18 

on granulocytes can trigger 

activation of CD11/ CD18 and 

lead granulocytes to firm attachment 

onto endothelial cells 

via association with ICAM-1 and 

ICAM-2. This model is generally 

thought to be applicable to the 

mode of tumor cell adhesion 

and metastasis. 

26 to 173 [69]. In the aspect of transcriptional regulation, 

Taniguchi et al. found that the transcription initiation site of 

ST3Gal-III gene have been mapped to -181 bp from the 

translation starting codon in four cell lines (K-562, HT-29, 

PC-3, and HepG2) and that the ST3Gal-III gene does not have 

multiple mRNAs as have been identified for ST3Gal-IV to -VI 

genes [70]. They also noted that the 5’-untranslated region 

was divided into two exons E1 and E2, indicating that the 

transcriptional regulation of ST3Gal-III could be dependent 

on the pIII promoter locating upstream of exon E1, and that 

ubiquitous transcription factors such as Sp1 may be important 

for ST3Gal-III gene expression [70]. 

Together all, the study of STs is relatively complicated 

[38,71], because all involve tumor-associated changes in the 

expression of cell-surface sialyl-glycoconjugates [72]. In 

addition, the specificity studies and cloning of STs from 

different cell types reveal significant differences between 

enzymes with similar activities. In fact, the six exhibited 

activities towards more than one substrate and could overlap 

in their specificity, except for ST3Gal-V [35]. Therefore, 

the critical specificity of the enzymes is dependent on when 

and in which cells the enzyme meets with an acceptor substrate 

[73]. The established theory of “one enzyme-one linkage” 

has been revised to “one enzyme family-usually one 

linkage” [74]. Moreover, many splicing forms of the individual 

STs have also been detected. It is quite difficult to 

study all STs or all splicing forms of the individual STs at the 

same time. 

Glycosylation contributes to the tumor behavior 

The metastasis of the tumor is of the most important 

process for tumor spreading, which involves the multistep 

series of adhesive events and signaling events [75]. The 

process is very similar to the leukocyte response to infection 

or injury (Figure 4), which can be found in the normal physiological 

and/or pathological process [76]. To initiate these 

responses, circulating leukocytes must adhere to the vascular 

wall under shear forces. Selectins mediate the first 

adhesive step, which is characterized by tethering and rolling 

of leukocytes on endothelial cells, platelets or other leukocytes 

[77,78]. L-selectin, expressed on most leukocytes, 

binds to ligands on some endothelial cells and on other leukocytes. 

E-selectin, expressed on cytokine-activated endothelial 

cells, binds to ligands on most leukocytes. P-selectin, 


expressed on activated platelets and endothelial cells, also 

binds to ligands on most leukocytes. The regulated expression 

of the selectins and their ligands helps initiate and terminate 

the inflammatory response. However, inappropriate 

expression of these molecules contributes to leukocytemediated 

tissue damage in a variety of inflammatory and 

thrombotic disorders [79]. The interactions between tumor 

cells and endothelial cells, the attachment and invasion of 

tumor cells through the endothelium via binding of selectins 

to their ligands, may be an important step in the metastatic 

process [80]. 

Overexpression of sialylated antigens, including sialyl-Tn, 

sialyl-T, sialyl-Le a , and sialyl-Le x , at the surface of cancer 

cells has been widely reported [81]. Tumor cells with mucin 

type O-glycans and sialyl-Le x ligands readily bind to Eselectins 

on activated endothelium [82-84]. In several experimental 

models, O-glycans are critical for metastases 

[80,85,86]. Inhibition of O-glycan extension by GalNAcbenzyl 

prevents this binding of human colon cancer cells to 

E-selectin, and thus reduces liver metastases of LS174T 

human cancer cells in nude mice [87]. Because expression 

of Lewis antigens can be inhibited with GalNAc-benzyl, these 

appear to be mainly attached to O-glycans [88,89]. While 

sialyl-Le x attached to O-glycans may promote cell adhesion 

and invasiveness, other O-glycan structures may also play 

important roles on cancer cell surfaces [90]. Compared to 

primary tumors, expression of Tn and T antigens is decreased 

in metastatic colon cancer cells, with a corresponding 

increase in sialyl-Tn, sialyl-T, sialyl-Le a , and sialyl- 

Le x [91]. The tissue distribution of sialyl-Tn and Le y antigens 

differs significantly between primary tumors and metastases 

of cervical cancer [90]. 

Sialyl-Tn is an important carbohydrate antigen overexpressed 

in several epithelial cancers (i.e. gastric, pancreatic, 

colorectal, ovarian and breast cancers), and is usually associated 

with poor prognosis [92]. Sialyl-Tn is synthesized by 

ST6GalNAc-I, which transfers a sialic acid residue in α2,6linkage 

to the GalNAcα1-O-Ser/Thr moiety [93-95]. 

GalNAc-benzyl treatment of B16 L6 melanoma cells increases 

peanut agglutinin (PNA) binding, probably due to 

the exposure of the T antigen on its cell surface, which results 

in enhanced adhesion of tumor cells to activated endothelial 

cells or platelets mediated by endothelial leukocyte 

adhesion molecule-1 (ELAM-1, i.e. E-selectin) or granule 

membrane protein 140 (GMP-140, i.e. P-selectin), and re- 



duces sialylation of CD44 while enhancing the metastatic 

capacity [84]. 

In variants of human KM12 colon cancer cells, the expression 

of sialyl-dimeric Le x attached to mucin-type chains corresponds 

to high invasiveness [96]. Sialyl-dimeric Le x is 

frequently increased in metastatic colon cancer [97,98]. 

These sialylated Lewis structures may play roles in cancer 

metastasis other than through their selectin-binding properties. 

SA has repeatedly been implicated in the metastatic 

process [99]. Inhibition of sialylation and O-glycan extension 

and sialylation reduces the metastatic potential of cancer 

cells [87,100]. Metastatic colon cancer cells produce 

hypersialylated mucins, which appear to play an important 

role in cell adhesion [101,102]. It is possible that chains 

carrying SA may regulate the interaction of cancer cells with 

other cells and with the cell matrix. These chains may therefore 

be responsible for adhesion as well as anti-adhesion, 

and for extending the survival time of cancer cells in the 

blood stream. Sialic acid may also be involved in growth 

regulation [103]. Because sialyl-glycoconjugates regulate 

adhesion and promote motility, they may be important for 

the colonization and metastatic potential of cancer cells 

[104-106]. 

The β 1 integrin heterodimerizes with one of 12 possible α 

subunits and mediates cell adhesion, spreading, and migration 

on multiple ligands including collagen, laminin, and fibronectin 

[107-109]. Accordingly, this integrin is ideally 

suited to influence tumor cell behavior in diverse extracellular 

matrix milieus. As evidence of the central role of β 1 integrin 

in the colon adenocarcinoma phenotype, blocking 

antibodies against β 1 integrins were shown to reduce metastasis 

of human colon carcinoma cells in an in vivo nude 

mouse model [110]. The elevated α2,6-sialylation of β 1 integrins 

has been observed in colon adenocarcinoma tissues, 

which likely alters interactions of colon tumor cells with their 

local matrix environment [111]. As verification of the role of 

sialylation in β 1 integrin function, Seales et al. found that 

forced ST6Gal-I expression in SW48 cells led to increased β 1 

integrin-mediated attachment and migration on collagen I 

and increased coupling of the β 1 subunit to the cytoskeletalassociated 

protein talin [111]. In addition to directly modulating 

β 1 integrin-ligand interactions, ST6Gal-I-mediated sialylation 

could influence other, more indirect mechanisms of 

integrin activation. For example, up-regulated α2,6sialylation 

might alter the lateral association of β 1-containing 

integrins with other membrane-associated proteins, such as 

tetraspanins [112] and urokinase-type plasminogen activator 

receptor [113], to coordinately regulate integrin-dependent 

processes. In particular, the interaction of α 3β 1 and α 5β 1 heterodimers 

with tetraspanin CD 82 seems to be dependent on 

the glycosylation state of both the respective integrin and CD 

82 [114]. In addition to ST6Gal-I, ST3Gal-IV might be also 

important for tumor cell adhesion and migration. For example, 

Soyasaponin I was able to inhibit cellular ST3Gal-IV activity, 

resulting in significantly decreased expression of cell 

surface α2,3-sialic acids on MCF-7 breast cancer cells and 

thus significantly increased adhesion of MCF-7 cells onto 

the extracellular matrix [115]. Likewise, Soyasaponin I significantly 

impaired metastatic ability of MDA-MB-231 breast 

cancer cells [115]. 

The antigenicity of one mucin glycoprotein, episialin 

(MUC1), is altered in many kinds of cancers [116-118]. The 

changes in expression level and post-translational modification 

of MUC1, especially glycosylation and/or sialylation, 

have been found to affect the behavior of cancer cells, particularly 

in relation to interactions with other cells and with 

the extracellular matrix [119]. In the normal glandular epithelial 

cell, MUC1 expression is limited to the apical surface 

bordering a lumen. In cancer cells however, which have lost 

polarity, the MUC1 is expressed all over the surface. Because 

of its rod-like structure, the molecule extends more than 

100-200 nm above the surface, which is 5-10-fold the length 

of most membrane molecules. By virtue of the high abundance 

of sialic acid, MUC1 exhibits negatively charged and 

cells expressing high levels of MUC1 may repel each other. 

Such repulsive effects have been demonstrated by showing 

that MUC1 transfectants show reduced aggregation as compared 

to the non-expressing parental cells [119] and interactions 

with the extracellular matrix are also inhibited [120]. 

With E-cadherin-mediated cell interactions, MUC1 has been 

reported to be the inhibitory molecule for cell adhesion [121]. 

In contrast, MUC1 could enhance adhesion by interacting 

with β-catenin [122]. In considering the effects of MUC1 on 

cell-cell interactions, it is clear that without specific interactions, 

for example with a lectin molecule, the long highly 

charged molecule can easily result in repulsion between 

cells. This inhibitory effect on cell interactions appears to 

depend on the large size and the negative charge of the 

molecule [120,121]. However, where a specific interaction is 

possible, for example a particular carbohydrate epitope 

binding to a lectin, then cell interactions may be enhanced. 

Therefore, MUC1 has been reported to be a ligand for ICAM1 

expressed by endothelial cells [123] and to enhance antigen 

presentation to T-cells, possibly operating through interaction 

with lectin [124]. Furthermore, MUC1 has been shown to 

be a ligand for sialoadhesin, a macrophage restricted adhesion 

molecule, which specifically binds Neu5Acα2→3Gal and 

so may be involved in recruiting macrophages into the tumour 

site [125]. When the glycosylation pattern of the mucin 

is changed in carcinomas, resulting in the production of 

different glycoforms, such carbohydrate-dependent interactions 

will be affected. The O-glycans on cancer mucins vary 

with cancer types, so that while selectin ligands may appear 

on MUC1 produced by colon carcinoma cells but may not be 

present in breast cancer cells. How the MUC1 on cancer cell 

surface may influence metastatic progression is not clear, 

although in MUC1-null mice, mammary tumour progression 

has been reported to be delayed [126]. In null mutant mice 

of β1,6-N-acetylglucosaminyltransferase V, a rate-limiting 

enzyme in the N-glycan pathway, tumor growth and metastasis 

are remarkably suppressed [127]. 

Conclusion 

Altered sialylation is very common and important in cancers, 

including cancer transformation and cancer metastasis. 

More understandings of the role in glycosylation, especially 

sialylation, for cancers will offer a new vision in managing 

cancers in the near future. 

Acknowledgment 

This work was supported by grants from the National 

Science Council (NSC-93-2314-B-075-047 and NSC-94-2314- 

B-075-013) and Taipei Veterans General Hospital (94VGH- 

195). 

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Altered Glycosylation in Cancer: Sialic Acids and Sialyltransferases

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