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Front Cover 1
Glycosylation and Cancer 4
Copyright 5
Contents 6
Contributors 10
Preface 14
Chapter 1: Glycosylation and Cancer: Moving Glycomics to the Forefront 16
1. Introduction 16
2. Contributions to the Volume 17
3. Opportunities and Challenges 19
4. Emerging Areas 21
References 23
Chapter 2: Glycans and Cancer: Role of N-Glycans in Cancer Biomarker, Progression and Metastasis, and Therapeutics 26
1. Introduction 27
2. Metabolic Pathway of Branched N-Glycans and Their Corresponding Glycosyltransferases 28
2.1. Fut8 (FUT8, Fut8) 30
2.1.1. Enzymatic properties and gene regulation 30
2.1.2. Biological significance and implication in cancer 31
2.2. GnT-III (MGAT3, Mgat3) 33
2.2.1. Enzymatic properties and gene regulation 33
2.2.2. Biological aspects and implication in cancer 35
2.3. GnT-V (MGAT5, Mgat5) 36
2.3.1. Enzymatic properties and gene regulation 36
2.3.2. Biological aspects and implications in cancer 38
2.4. GnT-IVa and GnT-IVb (MGAT4A and MGAT4B, Mgat4a and Mgat4b) 43
2.4.1. Enzymatic properties and gene regulation 43
2.4.2. Biological aspects and implication in cancer 44
2.5. GnT-IX (GnT-Vb or MGAT5B, Mgat5b) 47
2.5.1. Enzymatic properties and gene regulation 47
2.5.2. Biological aspects and implications in cancer 49
3. Future Perspectives 51
3.1. Disease mechanism 51
3.2. Biomarker discovery 52
3.3. Glycan-based therapeutics 52
Acknowledgments 54
References 54
Chapter 3: Simple Sugars to Complex Disease-Mucin-Type O-Glycans in Cancer 68
1. Introduction 69
2. O-glycan Biosynthesis 74
2.1. Core structures 1-4 76
2.2. Extended O-glycans 79
2.3. Extended core 1 80
2.4. Extended core 2 80
2.5. Extended core 3, 4 81
2.6. ABO blood group antigens 81
2.7. Lewis antigens 83
2.8. Sialic acids 84
2.9. Monosaccharide modifications 85
3. Altered O-Glycan Structures Observed in Cancer 85
3.1. Methods to identify altered O-glycosylation in cancer 86
3.2. Truncated O-glycans 87
3.2.1. Tn antigen 101
3.2.1.1. Background 101
3.2.1.2. Histology 101
3.2.1.3. Mechanisms for expression 102
3.2.2. Sialyl-Tn 103
3.2.2.1. Background 103
3.2.2.2. Histology 103
3.2.2.3. Mechanisms for expression 104
3.2.3. T antigen 104
3.2.3.1. Background 104
3.2.3.2. Histology 105
3.2.3.3. Mechanisms for expression 105
3.2.4. Comparing Tn, STn, and T expression and function in tumor biology 106
3.2.4.1. Expression 106
3.2.4.2. Function 106
3.3. Altered terminal and extended structures 107
3.3.1. Terminal a-GlcNAc on core 2 107
3.3.2. Lewis antigens 115
3.3.2.1. Background 115
3.3.2.2. SLea 116
3.3.2.3. SLex 116
3.3.2.4. Functions of SLex and SLea in tumor biology 116
3.3.2.5. Mechanisms for overexpression 117
3.3.3. ABH structures 117
3.3.3.1. Background 117
3.3.3.2. Histology 117
3.3.3.3. Mechanisms for altered expression 118
3.3.3.4. Function of blood group structures in tumor biology 118
3.4. Genetic associations with glycogenes and cancer 119
3.5. Mucins 119
4. Clinical Applications 120
4.1. Cancer detection 121
4.1.1. Serum biomarkers 121
4.1.2. Imaging 122
4.1.3. Assessing anti-O-glycan immune responses 126
4.2. Cancer therapeutics 127
4.2.1. Passive immunotherapies 127
4.2.2. Therapeutic vaccines 128
4.2.3. Selectin-Lewis interactions 129
5. Conclusions 130
Acknowledgments 131
References 131
Chapter 4: Intracellular Protein O-GlcNAc Modification Integrates Nutrient Status with Transcriptional and Metabolic Regu... 152
1. O-GlcNAc Modification: An Overview 153
2. Hyper O-GlcNAc Modification Observed in Human Tumors 154
3. O-GlcNAc Transferase: Structure, Activity, and Regulation 155
4. O-GlcNAcase: Structure and Function 159
5. The Hexosamine Biosynthetic Pathway 161
6. Effects of O-GlcNAc Modification on Epigenetic Regulation 165
7. Anticancer Effects of Reducing Hyper-O-GlcNAcylation in Cancer Cells 166
8. Effects of O-GlcNAc Cycling Enzymes on Glucose Homeostasis and Metabolism 167
9. Detection of O-GlcNAcylated Proteins 169
10. Conclusions 170
References 170
Chapter 5: The Detection and Discovery of Glycan Motifs in Biological Samples Using Lectins and Antibodies: New Methods a... 182
1. Introduction 183
2. Ways to Use GBPs for Probing Glycan Motifs 184
2.1. The detection of glycan motifs 184
2.2. Histochemistry 185
2.3. Imaging 186
2.4. Lectin affinity capture 187
2.5. Antibody-lectin sandwich assays 187
2.6. Lectin arrays 189
3. Defining the Fine Specificities of GBPs from Glycan Array Data 191
3.1. Need for the expansion of glycan arrays 194
4. Higher Order Influences on GBP Binding: Density, Location, and Accessibility 196
4.1. Density 196
4.2. Location of a motif within a glycan 197
5. Quantitative Interpretation of GBP Measurements 198
5.1. Linking with MS data 202
6. Finding the Right Reagent: Mining Glycan Array Data, Engineering GBPs, and Creating Antibodies 202
6.1. Mining glycan array data 202
6.2. Engineering GBPs 205
6.3. Raising antibodies to specific glycans 206
7. Discovering Glycan Motifs Using GBPs: Application to Cancer Biomarkers 207
7.1. Discovery by antibody generation 207
7.2. Screening candidates 208
8. Conclusions and Prospects 209
References 210
Chapter 6: Glycosylation Characteristics of Colorectal Cancer 218
1. Introduction 219
2. Changes of Cellular and Tissue Glycosylation in CRC 221
2.1. N-glycans 221
2.2. O-glycans 225
2.3. GSL-glycans 227
2.4. Fucosylation 229
2.5. Sialylation 229
2.6. (Sialyl) Lewis antigens 232
2.7. Sulfation 233
2.8. Conclusion 234
3. Serum-Related Glycosylation Changes in CRC 235
4. Biological Relevance of Glycan in CRC 236
4.1. Tumorigenesis 236
4.2. Metastasis 238
4.3. Modulation of immunity 241
4.4. Resistance to therapy 244
5. Analysis of Glycans: Useful Techniques for Glycomics 244
5.1. Binding assays 245
5.2. Mass spectrometry 246
6. Conclusion and Future Perspectives 250
Acknowledgment 252
References 252
Chapter 7: Glycosylation and Liver Cancer 272
1. Hepatocellular Carcinoma 273
2. Hepatitis: A Major Risk Factor for HCC 274
3. Proteomic Identification of Biomarkers of Liver Cancer 275
4. Glycomic Methodologies for the Identification of Biomarkers of Liver Cancer 276
5. Fucosylation is Not Universally Increased in HCC Tissue as Compared to Adjacent or Control Tissue 280
6. Increased Branching is Observed in HCC Tissue 282
7. Effect of Glycosylation on Hepatocyte Growth 283
8. Conclusion 283
References 284
Chapter 8: Functional Impact of Tumor-Specific N-Linked Glycan Changes in Breast and Ovarian Cancers 296
1. Introduction 297
1.1. Introduction to the synthesis of glycan structures 297
1.2. History of research to identify glycan changes in cancer 298
1.3. Introduction to breast and ovarian cancer 298
2. N-Linked Glycans 300
2.1. GnT-V 302
2.2. GnT-III 304
2.3. GnT-IV 305
2.4. FUT8 306
2.5. High mannose 307
2.6. Terminal glycan structures 307
3. Concluding Remarks 311
Acknowledgments 311
References 311
Chapter 9: Glycosylation Alterations in Lung and Brain Cancer 320
1. Introduction 321
1.1. Altered glycosylation in cancer 321
1.2. Lung cancer 322
1.3. Brain cancer 323
2. N-Linked Glycans 324
3. O-Linked Glycans 326
4. Mucins 328
5. Sialic Acid 330
6. Fucosylation 332
7. Heparan Sulfate Proteoglycans and Their Modifying Enzymes 335
8. Clinical Significance 340
8.1. Biomarkers 341
8.1.1. HSPGs and their modifying enzymes 341
8.1.2. Mucins 342
8.1.3. Fucosylation 343
8.1.4. Glycosylation of serum proteins 343
8.2. Therapeutics 344
References 346
Chapter 10: Altered Glycosylation in Prostate Cancer 360
1. Introduction 361
2. Current Glycoprotein Biomarkers of Prostate Cancer 363
2.1. Properties of PSA 363
2.2. Glycosylation of PSA 364
2.3. Properties and glycosylation of prostatic acid phosphatase 369
3. N-Linked Glycosylation in Prostate Tissues 370
3.1. Background and historical studies 370
3.2. Glycoproteomic approaches 371
3.3. Cryptic N-glycans 372
3.4. Glycopathology-MALDI mass spectrometry tissue imaging of glycans 375
4. N-Linked Glycosylation in Prostate Cancer Proximal Biofluids and Exosomes 378
4.1. Seminal plasma and prostatic fluids 378
4.2. Serum and plasma 380
4.3. Exosomes 382
5. Glycosylation in Prostate Cancer Cell Lines 383
5.1. Representative examples 383
5.2. Metabolic labeling with azide sugars and glycoproteomics 385
6. O-Linked Glycosylation in Prostate Cancer 386
6.1. Mucins 386
7. Glycolipids in Prostate Cancer 387
7.1. Gangliosides and other glycosphingolipids 387
7.2. F77 antigen and prostate tumor glycolipid antigen 388
8. Summary 388
References 390
Index 398
Color Plate 409
Glycans and Cancer
Role of N-Glycans in Cancer Biomarker, Progression and Metastasis, and Therapeutics
Naoyuki Taniguchi1; Yasuhiko Kizuka Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, RIKEN, Wako, Saitama, Japan
1 Corresponding author: email address: dglycotani@riken.jp
Abstract
Glycosylation is catalyzed by various glycosyltransferase enzymes which are mostly located in the Golgi apparatus in cells. These enzymes glycosylate various complex carbohydrates such as glycoproteins, glycolipids, and proteoglycans. The enzyme activity of glycosyltransferases and their gene expression are altered in various pathophysiological situations including cancer. Furthermore, the activity of glycosyltransferases is controlled by various factors such as the levels of nucleotide sugars, acceptor substrates, nucleotide sugar transporters, chaperons, and endogenous lectin in cancer cells. The glycosylation results in various functional changes of glycoproteins including cell surface receptors and adhesion molecules such as E-cadherin and integrins. These changes confer the unique characteristic phenotypes associated with cancer cells. Therefore, glycans play key roles in cancer progression and treatment. This review focuses on glycan structures, their biosynthetic glycosyltransferases, and their genes in relation to their biological significance and involvement in cancer, especially cancer biomarkers, epithelial–mesenchymal transition, cancer progression and metastasis, and therapeutics.
Major N-glycan branching structures which are directly related to cancer are β1,6-GlcNAc branching, bisecting GlcNAc, and core fucose. These structures are enzymatic products of glycosyltransferases, GnT-V, GnT-III, and Fut8, respectively. The genes encoding these enzymes are designated as MGAT5 (Mgat5), MGAT3 (Mgat3), and FUT8 (Fut8) in humans (mice in parenthesis), respectively. GnT-V is highly associated with cancer metastasis, whereas GnT-III is associated with cancer suppression. Fut8 is involved in expression of cancer biomarker as well as in the treatment of cancer. In addition to these enzymes, GnT-IV and GnT-IX (GnT-Vb) will be also discussed in relation to cancer.
Keywords
Glycosyltransferases
Cancer biomarker
E-cadherin
Integrins
Epithelial–mesenchymal transition
Cancer progression and metastasis
GnT-III
GnT-IV
GnT-V
GnT-Vb (GnT-IX)
Fut8
1 Introduction
Glycans are present as free forms or conjugated forms in mammalian tissues and most are components of various glycoconjugates such as glycoproteins, glycolipids, and proteoglycans. In addition to those glycoconjugates, free glycans such as monosaccharides, oligosaccharides, and polysaccharides are also present in eukaryotic cells.
Glycosylation is the most frequent and well-known posttranslational modification reaction and probably is much more frequent than phosphorylation. For instance, O-GlcNAcylation, which is cytosolic and nuclear glycosylation, is one of the most frequent modification reactions in various proteins including metabolic enzymes and transcription factors.
Glycosylation is catalyzed by the enzymatic reaction of glycosyltransferases whose encoding genes are nearly equivalent to 1–2% of human genome. Over 200 glycosyltransferase genes have been identified to date, and some of them form a glycosyltransferase gene family. Donor substrates for glycosyltransferases are nucleotide sugars including UDP-Gal, UDP-GlcNAc, GDP-fucose, and CMP-NANA, and acceptor substrates are mostly glycoconjugates. Because glycans are so heterogeneous, these glycosyltransferases can produce different kinds of glycans with strict substrate specificity.
Aberrant glycosylation occurs frequently in cancer, and these modifications are characteristics of cancer cells or cancer tissues (Hakomori, 1996, 2001, 2002; Taniguchi, Miyoshi, Gu, Honke, & Matsumoto, 2006; Taniguchi, Miyoshi, Ko, Ikeda, & Ihara, 1999). Moreover, glycosylation plays a pivotal role in cancer progression and metastasis, cell–cell contact, and epithelial–mesenchymal transition (EMT) in cancer cells (Chen et al., 2013; Kalluri & Weinberg, 2009; Li et al., 2014; Pinho et al., 2012; Tan et al., 2014; Terao et al., 2011; Xu et al., 2012). In recent years, EMT has become the important issue for understanding the development and metastasis of cancer (Kalluri & Weinberg, 2009), and in fact, changes in N-glycan structures are considered to be important for understanding the significance of EMT and the resultant change of adhesive properties of cancer cells (Chen et al., 2013; Li et al., 2014; Pinho et al., 2012; Tan et al., 2014; Terao et al., 2011; Xu et al., 2012).
Most of the cancer biomarkers that are in use today are glycoproteins or glycolipids, and they are measured immunochemically using monoclonal antibodies (Packer et al., 2008). The epitope for these monoclonal antibodies against glycoproteins are mostly toward the protein moiety and not toward the glycan structures. Currently, however, it is difficult to detect the early stage of cancer by using these antibodies. Several attempts have been conducted to detect specific glycosylation changes in glycoproteins for the early diagnosis of cancer patients. So far, only one antibody has been approved by FDA for the early detection of a cancer biomarker (Srivastava, 2013).
Application of glycan changes for therapeutics is one of the current strategies for cancer treatment. Deletion of a specific glycan or the modification of glycan chains with fucose or sialic acid enhances antibody-dependent cellular cytotoxity (ADCC) which is a key player in killing the cancer tissues (Satoh, Iida, & Shitara, 2006; Shields et al., 2002; Shinkawa et al., 2003).
This review focuses on the biological significance of branched N-glycans and their implication in cancer biomarkers, progression and metastasis of cancer, and therapeutics. The major N-glycan branching enzymes discussed in this review, GnT-III, GnT-IV, GnT-V, and GnT-IX (Vb), and Fut8, and their product glycans, are shown in Fig. 1.
2 Metabolic Pathway of Branched N-Glycans and Their Corresponding Glycosyltransferases
It is well known that the N-glycosylation machinery begins with a common precursor containing a glycan consisting of 14 monosaccharide units (3 d-glucose, 9 d-mannose, and 2 N-acetyl-d-glucosamine residues) which is incorporated in the protein back bone in the rough endoplasmic reticulum (ER). They are processed in ER and Golgi apparatus by specific glycosidases and glycosyltransferases (Ohtsubo & Marth, 2006). Most of the branching structures are formed by various glycosyltransferases such as GnTs (N-acetylglucosaminyltransferases), Futs (fucosyltransferases), GalTs (galactosyltransferases), and STs (sialyltransferases) in the Golgi apparatus. Among them, GnT-I to GnT-VI act on a common core structure of Manα1–6 (Manα1–3) Manβ1–4GlcNAcβ1–4GlcNAcβ1-Asn (Stanley, Schachter, & Taniguchi, 2009; Taniguchi, Gu, Takahashi, & Miyoshi, 2004) (Fig. 1).
Glycosylation is regulated by various factors including the availability of nucleotide sugars as donor substrates, acceptor substrates, cofactors, nucleotide sugar transporters, endogenous lectins, chaperons, localization within the cell, etc. (Brockhausen, Narasimhan, & Schachter, 1988; Taniguchi, 2009). Therefore in relation to the role of glycans in cancer, the above regulation mechanism should be also kept in mind.
Our group previously developed the method for the simultaneous analysis of nucleotide sugars by ion-paired high-performance liquid chromatography (HPLC). This method enabled us to carry out a quantitative analysis using 1 × 106 cells. By using this technique, we found marked changes in nucleotide sugars in beast and pancreatic cell lines (Nakajima et al., 2010). We also developed an isotopomer analysis method for evaluating the metabolic flow of glycans by using C6-labeled glucose and C2-labeled glucosamine followed by the mass topomer analysis (Nakajima et al., 2013). These metabolic analyses of mass isotopomers using LC-MS also provide us with useful information for understanding the glycan metabolism in cancer cells.
2.1 Fut8 (FUT8, Fut8)
2.1.1 Enzymatic properties and gene regulation
α1,6-Fucose (core fucose) plays various roles in terms of cancer. α1,6-Fucosylation of N-glycans occurs ubiquitously in eukaryote except plant and fungi. This type of fucosylation is catalyzed by the α1,6-fucosyltransferase (Fut8) in mammalian tissues. Fut8 transfers a fucose moiety from...
| Erscheint lt. Verlag | 26.2.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie |
| Naturwissenschaften ► Biologie ► Biochemie | |
| Naturwissenschaften ► Biologie ► Zellbiologie | |
| Technik | |
| ISBN-10 | 0-12-801614-0 / 0128016140 |
| ISBN-13 | 978-0-12-801614-5 / 9780128016145 |
| Haben Sie eine Frage zum Produkt? |
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