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Aberrant sialylation in ovarian cancers

Lee, Wen-Linga,b,c; Wang, Peng-Huic,d,e,*

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Journal of the Chinese Medical Association: April 2020 - Volume 83 - Issue 4 - p 337-344
doi: 10.1097/JCMA.0000000000000252
  • Open

Abstract

1. INTRODUCTION

Cell surface carbohydrates (oligosaccharides or glycans), known as the glycocalyx, which are major components of the outer surface of cells, build blocks of life and cover a wide spectrum from relatively trivial to crucial for the growth, development, behavior, and survival of cells and organisms. However, glycans have been hugely understudies, partly because of their complexity, the difficulties in study, absence of clear link between glycans and deoxyribonucleic acid (DNA).1–18 Glycan structures cannot be amplified as nucleic acid can, they generally come as a highly heterogeneous mix of different species bound to a single target, they are nonlinear molecules, and there is no universal method to precisely determine the structure of a glycan species without making assumptions regarding the biological system.

Glycans are named as glycoproteins, proteoglycans, and glycolipids, dependent on which targets are connected. Glycans build the basis for a universal language (the glycome or the glycobiology) and are determined not only by the nature of the targets they are bound to but also by the tissues or cells where they are made. Glycans modulate the interaction of targets with their environments, influencing their solubility, activity, and biologic fate.1,2 In terms of glycosylation on target protein, glycans either added sequentially to the hydroxyl oxygen of serine/threonine (Ser/Thr) residues (O-linked glycosylation), contributing to the four common O-glycan core structures in mammalian tissues (core-1 → core-4), or as preassembled blocks of 14 sugars that are transferred cotranslationally via the amide group of an asparagine (Asn) residue (N-linked glycosylation, of which the sequence can be Asn-Xxx-Ser or Asn-Xxx-Thr, where X is any kind of amino acid except proline), may stabilize the conformation of proteins and confer proteolytic resistance and influence protein turnover, and are involved in host-pathogen interactions, immune cell recognition, receptor-ligand interactions, cell-cell signaling, and adhesion.19–21

Glycosylation is often terminated by sialic acids (SAs): a nine-carbon amino sugar neuraminic acid family, which, owing to their negative electric charge, make them the “bridging” molecules between cells, as well as between cells and the extracellular matrix, and is further involved in biological and pathological processes, such as differentiation, oncogenic transformation, tumor metastases, and tumor invasions.7,22–35

2. SIALIC ACIDS

SAs, containing at least 50 species, such as N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), deaminoneuraminic acid (Kdn), and its derivatives with modifications, such as methylation, acetylation and sulfation at the 4,7,8, and 9 positions, are linked to subterminal sugars through an α2,6 bond to N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc); an α2,3 or α2,6 bond to galactose (Gal) or through a α2,8 bond to another SA, forming polysialic acids, by specific enzymes (sialyltransferases [ST] and sialidases), although the overlapping function occurs often, contributing to almost unlimited variations in the structure.6–8,13,19–21,24,25,32–35

3. SIALYLTRANSFERASES

ST are a family of glycosyltransferases, catalyze the addition of SA residue from the β-glycoside donor cytidine-5′-monophosphate-Neu5Ac, CMP-Neu5Ac to the terminal position of growing oligosaccharide chains of glycoconjugate acceptors, to produce α-sialosides.36–41 As shown above, according to the glycosidic linkage formed and their glycoconjugate acceptor, vertebrate STs include four families.33,34,38

Six α2,3-sialyltransferases, including type I-IV (ST3Gal I, ST3GalII, ST3GalIII, ST3GalIV, ST3GalV, and ST3GalVI) catalyze the transfer of SA to an underlying Gal residue in an α2,3 bond.33,34 Two α2,6 sialyltransferases, including type I-II (ST6Gal I and ST6Gal II) add SA in an α2,6 bond to an underlying Gal residue, and the former is normal expressed in all homeostatic tissue and the latter has its own restricted expression pattern.38 Six α2,6-sialyltransferases GalNAc, including type I-VI (ST6GalNAc I, ST6GalNAc II, ST6GalNAc III, ST6GalNAc IV, ST6GalNAc V, and ST6GalNAc VI), catalyze the transfer of SC to an underlying GalNAc residue in an α2,6 bond.33,34,38 The final 6 species of α2,8-sialyltransferases Sia, including type I-VI (ST8Sia I, ST8Sia II, ST8Sia III, ST8Sia IV, ST8Sia V, and ST8Sia VI), catalyze the glycosidic linkage between two SA residues in an α2,8 bond, and in particular, are unique because they are capable of iteratively adding SA to form polysialic acid.38 In general, the α2,3 SA linkage to Gal residues seems to be the most widely expressed.38

4. SIALIDASES (NUERAMINIDASES)

Sialidases (also called as neuraminidases [NEU]) are glycosidases that cleave α-bond linking SA residues from cellular glycoconjugates.6,38,42–50 In mammals, sialidases include four types: NEU1, NEU2, NEU3, and NEU4, which differ from each other by the expression pattern, location, and function.6,44,45

NEU1 is localized in the lysosomes as well as cell membrane, which mainly regulates lipid storage in lysosomes and negatively regulates lysosomal exocytosis, involving immune function (such as the mediation of interaction between SA-biding immunoglobulin type lectins [Siglecs] and toll-like receptors), phagocytosis ability, and elastic fiber assembly (forming a complex with NEU1/cathepsin A at the cell surface).6,47

NEU2 is distributed in the cytosol and plasma membrane, although it is notably expressed in extremely low or undetectable in many human tissues and cells with exceptions like the placenta, testis, skeletal muscle, liver, and thymus, and it also joins in myoblast and neuronal differentiation process.6,47

NEU3 is localized in the plasma membrane, involving ganglioside degradation and preferentially targets GM3 gangliosides and its function involves neuronal differentiation, apoptosis, and adhesion.6,47

NEU4 also involves neuronal differentiation, apoptosis, and adhesion, but is localized in the lysosomes, mitochondria, and endoplasmic reticulum.6 Expression of NEU4 is especially higher in the normal mucosa of the colon but dramatically and markedly decreased in colon cancer.47

Because a better understanding of the role of sialylation (sialoglycans) can be presumed from a recent abundant volume of studies on human diseases and a better treatment algorithm to the aberrant sialylation-related diseases, such as cancers will be developed, in this topic, we focus on the updated information about the altered sialylation on epithelial ovarian cancers (EOCs).

5. EPITHELIAL OVARIAN CANCERS

EOC is the deadliest cancer among women placing it with fourth place of all the fatal disease among women in United States and ranking seventh of most common cancer in women cancer and subsequent women’s cancer-related death in Taiwan and globally in 2018.51–55 Symptoms of patients with EOC are often vague or asymptomatic, of short duration, often misdiagnosed as less deadly gastroenteral tract problems, and absence of an effective screening programs, and in addition, heterogeneous in nature and different clinical development, accounting for late diagnosis in its advanced stages, and resulting in a therapeutic challenge and subsequently low cure rate and high mortality rate.56–70

The standard treatment of EOC includes a complete staging surgery with primary debulking surgery (PDS) followed by platinum-paclitaxel combination chemotherapy, although recent evidence also favors the use of neoadjuvant chemotherapy followed by interval debulking surgery and postoperative adjuvant platinum-paclitaxel combination chemotherapy, based on the dramatic reduction of perioperative complications and mortality without a negative impact on the survival of women with advanced-stage EOC.51,55,71–81

Under the aforementioned standard therapy, the median progression-free survival (PFS) is considered to be only between 16 and 21 months, and the median overall survival (OS) is between 32 and 57 months.54 Therefore, physicians and gynecologic oncologists make many efforts to increase therapeutic effects and subsequently prolong PFS and OS, and these strategies include many new modalities of treatment, such as dose-dense multiagent chemotherapy (triweekly → weekly), altered delivery methods of antineoplastic drugs (intravenous or intraperitoneal routes), hyperthermia therapy, and the application of new agents, such as antiangiogenic drugs, immune checkpoint inhibitors, immune system modulators, and targeted therapy, including poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors.54,82–98

Except the relatively matured results of potential benefits obtained from the study of anti-angiogenic drugs and PARP inhibitors for the maintenance therapy after the standard therapy for EOC, the special high cost of these treatment types is a cause for concern, which is further compounded by the need for long-term maintenance therapy and an increased risk of adverse events in some agents.54,72,74,84,87,89,90,96 Therefore, it is still a long-way to achieve the precise management for these patients with EOC. As shown above, aberrant sialylation is very common in various kinds of cancers, not only involving the tumor-genesis but also contributing to tumor growth, dissemination, and refractory to therapy. The following section focuses on the recent advance addressing the relationship between sialylation and EOC.

To identify the relationship between sialylation and ovarian cancer, we used the following strategy to target this topic. Based on our search of PubMed (from August 1978 to October 2019; search terms: “sialylation,” “ovarian cancer”; https://www.ncbi.nlm.nih.gov/pubmed/?term=sialylation%2C+ovarian+cancer), there are only a limited number of publications available.

The key mechanisms of altered sialylation in ovarian cancers, which is very similar to other cancers, can be further classified into the following: aberrant expression and/or altered activity of STs and NEUs that leads the change of sialylation of glycans and expression of specific tumor-associated carbohydrate antigens in cancer cells; enhancing and changing SA synthesis in cancer cells due to aberrant expression and/or altered activity of other oncogenes or suppressor genes involved in SA biosynthesis; SA and/or SA-modified molecules secretion (eg, exosomes) to interact with the tumor-surrounding cells, such as fibroblasts, as well as immune cells, and further change tumor microenvironment, such as extracellular matrix and angiogenesis.2,5–8,10,13–26,28–50,99–101

6. BIOMARKERS AND CANCER

As early as 1978, Braunstein et al found that hormone secreted from normal tissue and cancer showed a revival difference, even though the function such as biological activity and immune-reactivity was similar or identical.102 The authors found that EOC cell-secreting human chorionic gonadotropin (hCG) has a shorter half of life (a faster clearance rate) than the normal placenta-secreting hCG does, and further identified this difference was secondary to different sialylation of this glycoprotein, contributing to the different biological half of life (t1/2).102

Goodarzi and Turner found serum carbohydrate structure of α-1-proteinase inhibitor is altered in ovarian cancer patients with a decreased branching (more bi-antennary chains), increased α2,6 SA linkage and decreased α2,3 SA linkage compared with healthy women.103 On the contrary, serum haptoglobin in ovarian cancer patients is not only increased but also showed the different sialylation, including an increased branching (more tri-antennary chains), more branches ending in α2,3 SA and less branches ending in α2,6 SA.104–107 Furthermore, Tuner et al found that using serum fucosylated α 1 antitrypsin could reflect the therapy response in women with EOC, since patients had relatively low levels of fucosylated α 1 antitrypsin and this was maintained throughout remission; the levels only becoming elevated with the recurrence of tumor growth.108

Based on the aforementioned pioneers’ studies, the concept of the biomarkers for cancers not only for diagnosis but also for monitoring has been developed. Cancer biomarkers are a wide variety of endogenous molecules, such as DNA, messenger ribonucleic acid (mRNA), micro RNA (miRNA or miR), lipid, and organelles transcription factors, cell surface receptors, metabolites, and secreted proteins produced by the tumor tissue or by other tissues in response to the presence of the cancer and/or cancer-associated conditions (inflammation as an example).109,110

The mechanisms of an elevated biomarker in cancer patients are involved in altered gene expression, resulting in increased levels of the targets, increased secretion and shedding and angiogenesis, invasion and destruction of tissue architectures, and a subsequent release of these molecules into the interstitial fluid and finally into the blood.110

The immense work devoted to the discovery of novel entities and several advanced techniques, including mass spectrometry (MS), matrix-assisted laser desorption/ionization-time-of-flight [MALDI-TOF]-MS, electrospray-MS, liquid chromatography (LC)-MS, lectin affinity chromatography (LAC)-MS, serial LAC-MS, multi-LAC-MS, affinity electrophoresis-MS, two-dimensional gel electrophoresis (2D-GE)-MS, remarkably accelerated the characterization of SA and cancer-specific sialylated glycoproteins.111–113

After validation of specificity and sensitivity of these biomarkers using radioimmunoassay, enzyme-linked immunosorbent assay, fluoroimmunoassay, chemiluminescent immunoassay, electrochemiluminescent immunoassay and miniaturized multiplexed nano-immunoassay, and if they are good enough, clinical application of these cancer biomarkers has been processed. There are several cancer biomarkers approved by Food and Drug Administration (FDA), including prostate-specific antigen for prostate cancer, thyroglobulin for thyroid cancer, α-fetoprotein for hepatocellular cancer, carbohydrate (or cancer) antigen 125 (CA 125 and mucin 16) for ovarian cancer, and mucin for bladder cancer.7,114 There are still a handful tumor biomarkers used in the clinical practice, although approved by FDA, such as carcino-embryonic antigen for colon cancer, ß-hCG for nonseminomatous testicular carcinoma or choriocarcinoma, α-fetoprotein for ovarian yolk sac tumor, carbohydrate antigen 19-9 (CA 199) for pancreatic cancer, and carcinoma antigen 153 (CA 153 and mucin 1 epitope) for breast cancer.7,114–119

The quantification of these glycoprotein biomarkers in biological fluid or serum of the patients’ samples is sometimes challenging. There are three general approaches available.114 The most commonly used approach is the measurement of total levels of a targeted biomarker, which usually involves the production of monoclonal antibodies against this given biomarker. Another approach involves the detection and quantification of a particular glycan structure of cancer, such as the antibody-based measurement of the Lewisa in the CA 199 assay.114 The third, although yields the most information and overcomes the weakness of two aforementioned approaches, is most rarely used and also most difficult in approach, because this method allows detection and quantification of both total proteins levels and associated glycan structure.114

7. SERUM SA CHANGE IN OVARIAN CANCER

The first SA measurement was made in 1958 and subsequent measurements were limited on the overall SA levels as total SA (TSA) content, which included glycoprotein- and glycolipid-bound SA and small amounts of free SA as well as glycolipid-bound SA (LS).120 Increased serum levels of TSA and LSA were found in various kinds of malignancies, including EOC.120 Berbec et al showed serum TSA has been altered in EOC patients, suggesting their clinical usefulness as a potential prognostic tumor marker.121 Dwivedi et al and Vardi’ group showed that plasma LSA could be valuable in the prediction of prognosis in patients with EOC during treatment.122,123 Therefore, Dr. Narayanan concluded a potential value of using serum or plasma SA in monitoring EOC patients during treatment.124

With the availability of clinical use of CA 125, either TSA or LSA has not been used alone in routine clinical practice in patients with EOC.125,126 In fact, CA 125 has been widely used to monitor response to therapy in women with EOC.127–129 The European Group on Tumor Markers (EGTM) statement announced that CA125 remains the most important biomarker for EOC, excluding tumors of mucinous origin and CA125 should be used to monitor response to primary treatment.128 Persistently rising CA 125 is a highly specific indicator of recurrent disease.127,129 Another glycosylation marker for EOC is human epididymis protein 4 (HE4), which showed a combination of CA125 and HE4 can provide slightly but significantly better sensitivity for monitoring treatment and shorter lead time to detect recurrence than either marker alone.127

8. SERUM PROTEIN-SPECIFIC SIALYLATION CHANGE IN OVARIAN CANCER

Study on the utility of serum level of TSA has indicated the importance of identifying cancer-specific markers, contributing to the need to analyze individual sialylated glycoprotein in patients with EOC. As shown above, sialylated protein secreted by tumors may reflect the altered sialylation machinery of cancer cells and can be detected in physiological fluids, including serum or plasma.120 In addition, cancer also affects the protein metabolism; for example, cancer-related acute-phase protein production and/or immune response.

Production of acute-phase proteins is related to the complement, coagulation, fibrinolytic system, antiproteases, transport proteins, responsible to inflammatory response and others.120 Saldova et al found that a decrease in galactosylation of immunoglobulin (IgG) and an increase in sialylation on β-chain of haptoglobin (for iron homeostasis, with three major phenotypes, including Hp 1-1, Hp 2-1, and Hp 2-2), α1-acid glycoprotein (also names as orosomucioid, or AGP, detected by concavalin A reactivity due to specific targets for mannosylated N-glycans, and regulated by cytokines, such as interleukin 1 and 6, and glucocorticoids) and α1-antichymotrypsin (possibly involving the inhibition of chymotrypsin-like proteases, regulation of cathepsin G activity, modulation of the cellular function of neutrophils as well as lymphocytes, and inhibition of platelet-activating-factor synthesis), which often present as tri-anetennary N-glycans and core fucosylated agalactosylation diantennary glycans in EOC patients compared to normal healthy controls.107,130,131

AGP is a member of the immunocalin family, a lipocalin subfamily modulating immune and inflammatory reaction, including tissue damage, repair, infection, surveillance, and immune tolerance.120,132 Changes in sialylation of AGP affect the biological properties. For example, increased sialylation of AGP enhances the inhibition of lymphocyte proliferation, as well as functions as feedback inhibition of granulocyte extravasation into inflamed tissues and desialylated AGP increased inhibition of platelets aggregation.133,134 In addition, a relative increase of sialylation form with biantennary glycans of AGP is present in acute inflammation and a relative decrease of this sialylation in chronic inflammation, pregnancy, the use of estrogen, and liver damage.120,135,136 In summary, the serum N-glycome in patients with EOC has shown the following characteristics such as decreases of high-mannoses and bisecting GlcNAc, increases of branching, sialylation, and antennary fucosylation.137

9. SERUM SIALYLATION-SPECIFIC ANTIGENS IN OVARIAN CANCER

As shown by Saldova’ study,130,131 the increased sialylation on different glycoproteins could be further identified as a special and/or common tumor-associated carbohydrate structures, such as Sialyl Lewis A (SLeA) and sialyl Lewis X (SLeX) antigens, which are examples of type 1 and type 2 terminal carbohydrate structures, respectively, and sialyl Tn antigen (STn), which is an example of an O-glycan core structure, and a single residue of N-acetylgalactosamine linked to the serine or threonine of a protein by a glycosidic bond, and also reported to be increased in patients with EOC, as a marker indicator of poor prognosis.120,138,139 STn-positive mucins secreted by cancer cells can impair the maturation of dendritic cells (DCs) and lead to DC-mediated induction of T cells that express high levels of the Treg cell-associated transcription factor forkhead box protein P3 (FOXP3) and low level of interferon gamma.138 In addition, STn-mucins interact with Siglecs on tumor-infiltrating macrophages and initiate inhibitory immune signaling through the activation of the mitogen-activated protein kinase-extracellular signal-regulated kinase (ERK) pathway, and also direct reduce natural killer cell activity by interacting with SIGLEC7 and SIGLEC9.138 All drive an immune-inhibitory circuit.138

The SLex epitope consists of an α2,3 SA-linked to galactose β1-4 linked to Glc-NAc, to which a fucose is also α1,3 linked.120 The specific sialylated-specific antigens function as ligands for selectins (E-selectin in endothelial cells, P-selectin, and L-selectin), responsible for tumor-cell adhesion, migration and metastases, and their increased sialylation increases the antiapoptotic and anti-inflammatory properties.120 SLe antigen also contributes to shape unique glycol-codes resulting in immune suppression.138 All may enhance the cancer growth and metastasis.120

10. ALTERED SIALYLATION IN OVARIAN CANCER

Dedová et al found an initial increase of relative abundance of total complex fucosylated N-glycans in early FIGO (International Federation of Gynecology and Obstetrics) EOC stages, followed by a decrease in advanced FIGO EOC stages.112 On the evaluation of level of total sialylation in EOC, results showed a statistically significant decrease of mono-antennary afucosylated N-glycans, but a statistically significant increase of tri-antennary fucosylated N-glycans and of both fucosylated and afucosylated tetra-antennary N-glycans, regardless of the linkage type.112 To study the change of sialylation in early-stage EOC, the α2,3/α2,6 ratio for bi-antennary afucosylated and fucosylated N-glycans was statistically significantly increased.112 Finally, Dedová et al concluded that the relative α2,3-linked sialylation increase with increasing antennarity and cancer stage, reaching its maximum in tetra-antennary structures (50%).112

In fact, our previous studies have shown that α2,3-linked sialylation was statistically significantly increased in serous-type EOC cancer part, but absence of α2,3-linked sialylation in normal ovarian tissue, using the lectin Maackia amurensis agglutinin to perform an immunohistochemical staining, and further study found that the increased α2,3-linked sialylation of EOC might be secondary to upregulate ST3GalI expression.29 Based on the aforementioned finding, we further evaluated the relationship between ST3Gal I and various subtypes of EOC and confirmed the overexpression of ST3Gal I is present in both serous-type and clear cell-type EOC.11,12 High expression of ST3GalI was associated with advanced stage EOC, contributing to aggressive behavior of cancer cells, such as increased migration and cell invasion ability.12 In addition, we found the interaction between ST3GalI and epidermal growth factor receptor (EGFR) and sialylated EGFR might be relatively resistant to EGFR inhibitor treatment, suggesting simultaneous use of ST3Gal I inhibitor and EGFR inhibitors could enhance the cytotoxicity of serous-type EOC.12 In 2018, we further identified that inhibition of ST3GalI in clear cell-type EOC can increase the E-cadherin expression with subsequently suppressing migration of clear cell-type EOC cells.11

Besides an increase of α2,3-linked sialylation in EOC, α2,6-linked sialylation might be also increased in EOC.29 Our study has also shown the statistically significantly increased expression of ST6GalI in EOC tissue compared to the normal ovarian tissue.29 Christie et al found forced expression of ST6GalI in EOC cells, resulting in sialylation of β 1 integrins, induced greater cell adhesion to and migration toward collagen I, contributing to more invasive phenotype of EOC cells, which might accelerate dissemination of EOC cells intro the abdominal cavity.26

Similar to an increased α2,3 sialylation of EGFR, an increased α2,6-linked sialylation of certain targets also plays an important role for cancer growth and survival, although the mechanism is much complicated. For example, Holdbrooks et al found the ST6GalI expression is a critical factor to tumor necrosis factor (TNF)-mediated TNF receptor 1 (TNFR1) inducing either cell survival or cell death.140 Although using EOC cells with ST6GalI knockdown or overexpression, α2,6-linked sialylation of TNFR1 had no effect on early TNF-induced signaling events, including the rapid activation of NF-kB, c-Jun N-terminal kinase, ERK, and Akt (occurring within 15 minutes), EOC cell with high ST6GalI levels exhibited resistant to TNF-induced apoptosis with displaying sustained activation of the survival molecules Akt and NF-kB, without cell morphology change and decreased activation of caspases 8 and 3 when extended TNF treatment persisted.140 With further evaluation of TNFR internalization, which is essential for apoptosis induction of TNF, the authors found the TNF-induced TNFR1 internalization was inhibited by α2,6-linked sialylation of TNFR1, suggesting that ST6GalI acts as a functional switch to divert signaling toward survival.140

11. THE PERSPECTIVE

SA sugars function as important modulators for cell-cell interaction and involve the fate and behaviors of these cells.1,2,5–8,11–16,18–25,28,30,141–145 Targeting the SA sugars or their contributing factors, such as ST and NEU, might be an impressive and promising field in promoting health in the future.

ACKNOWLEDGMENTS

This study was supported in part by grants from the Ministry of Science and Technology (MOST 106-2314-B-075-061-MY3) and the Taipei Veterans General Hospital (Grants VGH108C-085 and V109C-108), Taipei, Taiwan.

The authors also appreciate very much the financial support from the Female Cancer Foundation, Taipei, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. No additional external funding was received for this study.

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Keywords:

Cancer; Neuraminidases; Ovarian carcinoma; Sialidases; Sialylation; Sialyltransferases

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