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Glycoproteins and glycoproteomics in pancreatic cancer

Glycoproteins and glycoproteomics in pancreatic cancer org/10.3748/wjg.v22.i42.9288 Aberrations in protein glycosylation and polysaccha- rides play a pivotal role in pancreatic tumorigenesis, influencing cancer progression, metastasis, immuno- response and chemoresistance. Abnormal expression INTRODUCTION in sugar moieties can impact the function of various Pancreatic cancer is one of the most deadly cancers, in glycoproteins, including mucins, surface receptors, adhesive proteins, proteoglycans, as well as their part because detection of pancreatic cancer is difc fi ult WJG|www.wjgnet.com 9288 November 14, 2016|Volume 22|Issue 42| 65 65 65 65 NS NS 25 NS Pan S et al . Glycoproteomics study in pancreatic cancer Hyaluronan Heparan sulphate Chondroitin sulphate GalNAc Glycosylphosphatidy- N-glycan GlcNAc linositol anchored Gal glycoproteins Gal Man Protein Fuc Etn O-glycan Xyl Sialic acid Ser GlcA Asn ldoA Ser Inositol P Ser/Thr Ser/Thr O-GlcNAc glycoproteins Protein Figure 1 Illustration of protein glycosylation and polysaccharides. [13] at its early stages when surgical and other treatments residues . One unique subclass of O-glycosylation is [1,2] [14] are most effective . In addition, innate or adapted the phosphorylation-like, reversible O-GlcNAcylation . drug-resistance has been a major hurdle in pancreatic Less common forms of glycosylation include glycosyl- [3,4] cancer chemotherapy . Malignance induced changes phosphatidylinositol anchors attached to protein in protein glycosylation, such N-glycosylation and carboxyl terminus, C-glycosylation that occurs on [15] O-glycosylation, can profoundly impact the function tryptophan residues and S-linked glycosylation [16] of a protein in multiple ways, including protein ma- through a sulfur atom on cysteine or methionine . turation, expression, localization, as well as post- In addition to protein glycosylation, proteoglycans and translational modifications, influencing a wide hyaluronan are major components of the extracellular spectrum of glycoproteins and their binding ligands. matrix (ECM), which are implicated in cell proliferation One approach for developing better diagnostic and and migration. therapeutic strategies in pancreatic cancer involves Most secretory and membrane-bound proteins targeting cancer-associated aberrant glycosylation. produced by mammalian cells contain covalently Recent developments of technology in proteomics linked sugar chains with diverse structures. The and chemical biology have thus stimulated growing glycosylation form and density of glycans on a interest in elucidating the complex glycosylation events protein can be altered signic fi antly in association with involved in pancreatic adenocarcinoma. changes in cellular pathways and processes resulted from diseases, such as malignancy. In fact, altered glycosylation patterns have long been recognized as PROTEIN GLYCOSYLATION AND ITS [17-22] hallmarks in epithelial cancer , including pancreatic IMPLICATION IN CANCER ductal adenocarcinoma (PDAC), which accounts for about 90% of pancreatic cancer. Glycosylation Glycosylation is one of the most complex and common [5,6] abnormalities can be characterized by one or both of forms of protein post-translational modifications . the following changes: (1) composition and structural It plays a pivotal role in many biological processes, alterations of glycan; and (2) change in the density such as protein folding, cell adhesion and trafc fi king, of glycosylation at protein sites (hyper, hypo or neo- cell signaling, pathogen recognition and immune [7-11] glycosylation). Ultimately, malignant transforma- response . Protein glycosylation occurs in the tion is usually associated with one or both of these endoplasmic reticulum and Golgi apparatus in multiple types of glycosylation alterations, leading to the enzymatic steps. As illustrated in Figure 1, the most expressional and functional changes of tumor-specic fi common protein glycosylations are N-linked and glycoproteins. Malignancy associated glycosylation O-linked glycosylation. N-linked glycans are attached abnormalities can influence cancer cell proliferation, to the amide group of asparagine residues in a consensus Asn-X-Ser/Thr sequence (X can be any invasion and viability, as well as interactions with [12] amino acid except proline) . O-linked glycans are tumor micro environment. Disruption or inhibition of linked to the hydroxyl group on serine or threonine glycosylation and carbohydrate-dependent cellular WJG|www.wjgnet.com 9289 November 14, 2016|Volume 22|Issue 42| Proteoglycans Pan S et al . Glycoproteomics study in pancreatic cancer Intact glycopeptides Glycans Glycoprotein MS analysis Database search and bioinformatics Deglycosylated peptides Figure 2 Mass spectrometry based glycoproteomics analysis. [15,44-52] pathways may represent potential modalities for glycosites) . Figure 2 illustrates the overall [23,24] cancer therapies . Receptor tyrosine kinases approaches for MS analysis of glycoproteins. Prior (RTKs), which are transmembrane glycoproteins to MS acquisition, glyco-enrichment strategies, [53-56] [57-60] that play important roles in malignancy and drug including lectin afn fi ity , hydrazide chemistry , [61] [62] resistance, have been targets of anti-cancer drug boronic acid , size-exclusion chromatography , [63] development for various malignancies, including and hydrophilic interaction , may be applied to [25,26] pancreatic adenocarcinoma . In addition, many enrich glycoproteins from complex biological samples, of the current blood-based tumor markers are gly- and thus, enhance analytical sensitivity. The direct coproteins, including CA 19-9 for pancreatic cancer, analysis of intact glycopeptides with carbohydrate CA 125 for ovarian cancer, CA 15-3 for breast cancer, attachments is analytically challenging, but allows and CA 242 for gastrointestinal cancer. CA 19-9, which complementary identic fi ation of the peptide backbone detects the epitope of sialyl Lewis (a) on mucins and and the glycan structure in a single measurement, other adhesive molecules such as carcinoembryonic providing site-specific glycosylation characterization [27-29] antigen , is widely used for monitoring the clinical directly. However, this approach is complicated by the [30] course of pancreatic cancer patients . To date, mixed information obtained from the MS signals from while implication of aberrant protein glycosylation in the peptide backbone, the carbohydrate group and the [21,31] malignancy has been well recognized , limited combinations of both, and therefore, is largely limited information is available describing the site specific for analyzing purie fi d glycoproteins or simple systems. glycoproteome changes associated with pancreatic Alternatively, glycans, especially N-linked glycans, cancer. can be enzymatically or chemically cleaved from proteins or peptides and analyzed separately by MS. Using glycan databases and bioinformatics tools, MS GLYCOPROTEOMICS METHODS analysis enables global identic fi ation of glycan species A number of proteomics studies in pancreatic cancer in a complex biological sample. On the other hand, [32-39] have been reported . As a sube fi ld of proteomics, de-glycosylated glycopeptides can also be profiled in glycoproteomics uniquely focuses on analyzing glycosy- a global fashion using shotgun proteomics approach lated proteins to reveal glycoproteome alterations to identify the amino acid sequence of the backbone associated with pancreatic cancer. The major challenge peptides. The N-glycosylation sites can be precisely for a comprehensive glycoproteomics analysis in a mapped using the consensus sequence of Asn-X-Ser/ clinical sample arises from the biological intricacy Thr, in which asparagine is converted to aspartic acid within the molecule of a glycoprotein, including the after PNGase F enzymatic cleavage, which introduces a variety in glycan composition and structure, as well mass difference of 0.9840 Dalton for MS identic fi ation. as the complex linkage to the corresponding protein. By defining the glycan structures and profiling the Mass spectrometry has been the most effective and glycoproteins in complex clinical samples, disease versatile instrument platform for both glycan and associated aberrant glycan forms and site-specific protein analysis. Although various sample preparation occupancy on proteins can be revealed. For quantitative strategies may be applied to collect glycoproteins analysis, additional steps, such as differential stable or glycans from different biological specimens, isotope labeling of the sample and controls, may be a glycoproteomics pipeline typically consists of required. Ultimately, to comprehensively address glyco-enrichment, MS analysis and bioinformatics disease associated aberrant glycosylation, all the data interpretation. The technical details of global analysis obtained from different aspects of the worko fl w need of glycoprotein can be found in a number of reviews [40-43] on the subject of glycomics (analysis of glycans) to be integrated, so that the full extent of glycosylation and glycoproteomics (analysis of glycoproteins and changes with site-specific information can be better WJG|www.wjgnet.com 9290 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer [71] revealed. cancer associated signal . Although the detection of increase level of fucosylated HP alone does not provide sufficient accuracy for pancreatic cancer diagnosis, DISCOVERY OF ABERRANT it is possible that fucosylated HP might be used as an indication of liver metastasis if the biomarker GLYCOSYLATION IN BODILY FLUIDS [72,73] undergoes further validation . The changes in Identification and detection of abnormal protein protein fucosylation and sialylation in pancreatic glycosylation associated with pancreatic cancer in cancer were also investigated by analyzing intact bodily u fl ids may present meaningful targets for cancer glycopeptides. Using immunoprecipitation, partial detection. A variety of carbohydrates and glycoproteins deglycosylation and LC MS/MS, one study suggested have been investigated for pancreatic cancer detection. that the core-fucosylation levels at site N396 and Currently, CA19-9 is the only clinical biomarker test for N1424 in alpha-2-macroglobulin (A2M) were decreased [64] management of pancreatic cancer . While CA19-9 in serum of both pancreatic cancer and chronic is widely used for monitoring the clinical course of [74] pancreatitis compared to non-diseased controls . cancer patients, it does not provide adequate accuracy The investigation of sialylated N-glycopeptide levels for pancreatic cancer diagnosis and early detection, in sera from pancreatic cancer patients in comparison underscoring the importance of obtaining molecular to non-diseased controls and acute pancreatitis details on specific glycosylation events involved in patients identified 13 glycoforms, mainly from high- neoplastic progression. Mucin (MUC) proteins, including abundant serum proteins, with changes associated MUC1, MUC5AC, and MUC16 are major protein carriers [75] with pancreatic cancer group . Mucinous cystic of CA 19-9, and play important roles in pancreatic neoplasms (MCN) and intraductal papillary mucinous cancer tumorigenesis, invasiveness and metastasis, neoplasms (IPMN) are pancreatic cysts that are subject [28,65-67] in part through their characteristic glycoforms . to high risk of malignant transformation. Proteomic Changes of MUC1 and MUC5AC in pancreatic cancer and glycomic investigation of cyst u fl ids collected from serum involved distinct glycan alterations, including patients with MCN and IPMN led to the identification Thomsen-Friedenreich antigen and fucose and Lewis [28] of 80 N-linked glycans, and several hyper-fucosylated antigens . The measurement of CA 19-9 antigen glycoproteins, including triacylglycerol lipase and on MUC1, MUC5AC and MUC16 individually did not [76] pancreatic α-amylase . improve the performance of cancer detection, owing to the biological heterogeneity of the patients in their [68] CA 19-9 protein carriers . However, the combined GLYCOPROTEOMICS OF PANCREATIC measurement of standard CA 19-9 assay and the CANCER CELLS AND TISSUES detection of the CA 19-9 antigen on MUC5AC and MUC16 did improve the performance of pancreatic Known tumor-specific glycoproteins, such as mucins [68] cancer detection . and carcinoembryonic antigen-related cell adhesion In addition to CA19-9, other aberrant protein molecules, have been extensively studied for their glycosylations associated with pancreatic cancer have roles in neoplastic progression and metastasis of [77-81] also been investigated in bodily u fl ids. The glycosylation pancreatic cancer . The emerging technology of serum ribonuclease 1 (RNASE1) - another well- of glycoproteomics has been recently applied to studied pancreas associated protein, showed a 40% interrogate broader changes of glycoproteome in [69] increase in core fucosylation in pancreatic cancer . pancreatic cancer cells and tissue. A large number of Using Concanavalin A lectin afn fi ity chromatography for cell surface proteins are transmembrane glycoproteins, N-glycopeptide enrichment and LC MS/MS, one study including many of cell-surface receptors such as RTKs, identified 92 individual glycosylation sites and 105 which play pivotal roles in signaling, trafficking and unique carbohydrate structures in serum, and observed cell-cell interactions. These cell-surface receptors, such increased branching of N-linked oligosaccharides, as as epithelial growth factor receptor (EGFR), integrins, well as increased protein fucosylation and sialylation in and TGF β receptor (TGFβR) have been important [70] the sera from pancreatic cancer patients . Increased targets for anti-cancer therapy, and their glycosylation [82-85] level of sialyl Lewis X of major serum acute-phase forms impact their functionality . Using a biocytin [86] proteins, including alpha-1-acid glycoprotein (AGP1 hydrazide cell surface capturing technique , or or ORM1), haptoglobin (HP), fetuin (AHSG), alpha- azido sugar based bioorthogonal chemical reporter [87] 1-antitrypsin (SERPINA1) and transferrin (TF) were for metabolic glycan labeling for glycopeptide observed in the sera from patients with advanced enrichment, studies were carried out to prolfi e N-linked pancreatic cancer and chronic pancreatitis - an glycopeptides derived from surface glycoproteins of [88,89] alteration possibly associated with inflammatory pancreatic cancer cells using LC MS/MS . The [71] [88] response . In addition, the observation of an increase studies indicated the overexpression of CD109 and [89] in core fucosylation on AGP1 and HP in the serum of ecto-50-nucleotidase in pancreatic cancer cells and advanced pancreatic cancer may represent a potential tissues. Using multi-lectin affinity chromatography WJG|www.wjgnet.com 9291 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer and LC-MS/MS, another study investigated the the orchestrated glycosylation mechanism underlying differential glycoproteins associated with pancreatic pancreatic tumorigenesis, immune response and + + cancer CD24 CD44 stem-like cells in comparison pancreatic functional changes, remains poorly - + [90] with CD24 CD44 cells . The study indicated understood and warrant further investigation. that the high expression and high positive rate of CD24 was significantly associated with late-stage MUCIN GLYCOSYLATION pancreatic adenocarcinomas, while CD13 expression and positive rate were negatively associated with Mucins are high molecular weight glycoproteins tumor progression. By manipulating exogenous produced by various epithelial cells, and have 21 substrate supply, a study reported that increases in family members. The mucins are heavily glycosylated metabolic flux through the sialic acid pathway could in O- and N-linked glycosylation and implicated dramatically enhance the sialylation of certain N-linked in PDAC through their characteristic glycoforms glycoproteins to influence cancer cell adhesive and influencing tumorigenicity, invasiveness, metastasis mobility properties of SW1990 pancreatic cancer and drug resistance. Mucins have been extensively [91] cells . studied in PDAC, and showed various expressional Glycoproteomic techniques were also applied to and glycosylation changes not only in pancreatic investigate the glycoproteome of pancreatic cancer carcinoma, but also in pancreatic intraepithelial [66,67,99] tissues. In our study, we observed an overall increase neoplasia (PanIN), IPMN and MCN . Several in N-glycosylation level on many glycoproteins in mucins, including MUC1, MUC4, MUC5AC and MUC16, [92] PDAC tissue in comparison with normal pancreas . are frequently upregulated in PDAC. Mucin core protein Supplemental Table 1 summarizes some of the expression and the differential localization in PDAC and glycoproteins with at least one N-glycopeptide its precursor lesions have been well documented in the [66,67,100-103] overexpressed (≥ 2 fold) in pancreatic cancer, literature . In addition, mucin glycoforms also including many pancreatic cancer associated proteins, play an important role in modulating their functionality such as MUC5AC, carcinoembryonic antigen-related in tumorigenesis as well as cancer cell interaction cell adhesion molecule 5, insulin-like growth factor with the tumor microenvironment. In fact, the glycan binding protein (IGFBP3), cathepsin D (CTSD), as component can make up more than 50% of the well as a number of CD antigens (including CD44 - molecular weight of a mucin glycoprotein. a marker of pancreatic cancer stem-like cells) and The glycosylation of cancer associated mucins integrins. Pathway analysis suggested that increased is largely associated with Tn antigen, sialyl Tn and N-glycosylation activities of these proteins were fucosylated core 1 structures, forming the so-called [104] implicated in several pancreatic cancer pathways, tumor-associated antigens . Altered glycoforms of [92] including TGF-β, TNF, and NF-kappa-B . Other MUC1, MUC4 and MUC5AC were observed early in glycoproteins, such as Thy-1 membrane glycoprotein pancreatic cancer progression (PanINs) to late stage [105] (THY1), which was recently developed into an metastatic disease . The elevation of fucosylated ultrasound molecular imaging marker for pancreatic core structures, fucose and Lewis antigen have [93] cancer detection , was found heavily N-glycosylated frequently been detected on MUC1 and MUC5AC in [28] in pancreatic cancer tissues. Further mapping of the blood from patients with pancreatic cancer . N-glycosylation sites revealed that the change of Additionally, MUC16 and its sialofucosylated N-glycosylation level in pancreatic cancer was not structures were reported overexpressed in pancreatic only protein specific, but also glycosylation site cancer cell and acted as a functional ligand for E- specific. Specific N-glycosylation sites within certain and L-selectin to enhance cancer cell metastatic [106] individual proteins can have significantly altered spread . By stimulating pancreatic cancer cells glycosylation occupancy (e.g., a change in glycan with pro-inflammatory conditions, such as oxidative density) in pancreatic cancer, reflecting the complex stress and cytokines, mucin glycosylation can be nature of glycosylation events underlying pancreatic significantly altered in specific pancreatic cancer cell tumorigenesis. Notably, the increase of N-glycosylation lines, suggesting a possible molecular link between of many of these proteins was also found in chro- inflammation, glycosylation alteration and adaptive nic pancreatitis tissue, supporting the notion that [107] responses of those pancreatic cancer cells . Efforts pancreatic cancer and chronic pancreatitis share have also been made to use proteomic approaches [94-98] many common clinical and molecular features . to prolife mucins in cyst u fl ids to enhance the discri - It is also noteworthy to mention that in contrast to mination of malignant pancreatic cyst lesions from many glycoproteins with increased N-glycosylation, [108] those that are benign . pancreatic secretory granule membrane major glycoprotein (GP2) - a pancreas specic fi glycoprotein, showed a reduced N-glycosylated level in both cancer ECM GLYCOPROTEINS, and chronic pancreatitis tissues. While the global data PROTEOGLYCANS AND HYALURONAN have revealed the aberrant N-glycosylation changes of many relevant proteins in pancreatic cancer tissues, In our proteomic study, we observed a large group of WJG|www.wjgnet.com 9292 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer [92,94] ECM associated proteins overexpressed in pancreatic pancreatic tumorigenesis . [97] cancer and chronic pancreatitis tissues . Many of Proteoglycans are heavily glycosylated proteins these proteins are glycoproteins and are involved in with serine attached glycosaminoglycans (GAGs), stellate cell activation and ECM organizational and such as heparan sulphate and chondroitin sulphate (Figure 1). Proteoglycans are an important component structural changes, which regulate pancreatic b fi rosis of ECM and affect multiple biological processes, - one of the fundamental histological abnormalities including cell differentiation and proliferation, binding observed in pancreatic adenocarcinoma and chronic pancreatitis. ECM components, including matrix to cytokines, growth factors and morphogens. proteins, proteoglycan proteins, galectins and hya- During tumorigenesis, the expression and glycosylation patterns of proteoglycans change in the stroma luronan, which interact with each other and form surrounding cancer, influencing tumor growth and supramolecular complexes, are subjected to alterations [125] neoplastic progression . In proteomics and other during cancer progression, leading to cancer asso- [109-115] studies, the increased expression of proteoglycan ciated ECM . Abnormal protein glycosylation proteins, including lumican, decorin, versican, and can significantly affect the mechanical properties of [110,116] biglycan, has been observed in pancreatic cancer ECM, enhancing tumor cell migration . Studies [97,121,126-130] tissues or cells . Since GAGs are large, have shown that ECM components associated with linear polysaccharides, to a certain extent, the integrin-ECM axis are highly up-regulated in pancreatic [117] biological function of proteoglycans can be governed cancer . The glycoforms of integrins, such as the by the interaction of the attached GAGs with other presence of N-linked oligosaccharides, can regulate proteins. Most of proteoglycans also contain N- and integrin function, affecting the cell-ECM interactions. In O-linked glycans. In a quantitative glycoproteomics pancreatic cancer tissues, we observed increased levels study, N-glycosylation levels of several major ECM of N-glycosylation, not only on several integrins (both proteoglycans, including decorin (DCN), biglycan α and β subunits), but also on ECM adhesion proteins, (BGN), lumican (LUM), versican (VCAN), and aggrecan including collagens, b fi ronectin, vitronectin, and laminin [92] (ACAN), were found elevated in pancreatic cancer (Supplemental Table 1) . These observations warrant [92] tissues (Supplemental Table 1) . mechanistic study to better understand how aberrant Hyaluronan is a non sulfated glycosaminoglycan glycosylation of integrins and ECM adhesion ligands that is not covalently attached to proteoglycans and influence pancreatic cancer migration and malignant [131] can have a very high molecule weight . CD44 and phenotypes. Galectins and fibulins play a role in receptor for HA-mediated motility are the two main organization of ECM supramolecular structure, such receptors for the anchorage of hyaluronan-rich ECM to as basement membranes, by forming intramolecular [132,133] the cell surface . Although it has relatively simple bridges, binding to complex carbohydrates and ECM [118-120] chemical composition, as one of the major components adhesive proteins . The core protein expression of ECM, hyaluronan is involved in promoting pancreatic and N-glycosylation level of b fi ulin 1 were both found [132-134] [92,97] cancer progression and chemoresistance . Aberrant up-regulated in pancreatic cancer tissues . Galectin production and deposition of hyaluronan provide a 1 (LGALS1) is a human extracellular lectin that spe- favorable microenvironment to enhance cancer cell cifically binds to β-galactoside sugars, including N- proliferation, migration, invasion, angiogenesis, and limit and O-linked glycans. Galectin 1 was overexpressed [134-137] the delivery of anti-cancer agents . Studies have in the stroma of both pancreatic cancer and PanINs [121] also shown that the interaction between hyaluronan lesions , and its expression was related to pancreatic [122,123] and its CD44 receptor is involved in the stemness and cancer survival . Concurrently, the N-glycosylation [138] survival of cancer stem cells , and may be relevant level of endogenous ligands of galectin-1 in the ECM, + + to pancreatic cancer CD24 CD44 stem-like cells. including fibronectin (FN1), laminins and galectin-3- binding protein (LGALS3BP), were all up-regulated in pancreatic cancer tissue (Supplemental Table 1), IMPLICATIONS IN ANTI-CANCER DRUG implying an intensified interaction of galectins and [92] DEVELOPMENT their major binding partners in pancreatic cancer . Periostin (POSTN), an ECM protein involved in cell Protein glycosylation has become a prominent target [124] mobility and neovascularization , has both up- for drug development. One strategy involves dis- regulated core protein expression and N-glycosylation ruption of the protein glycosylation process, such as [92,97] levels in pancreatic cancer tissue . Cathepsins are inhibition of glycosylation enzymes and hexosamine proteases that are implicated in cancer invasion by biosynthetic pathway, to reduce pancreatic cancer [23,24] degrading ECM, including proteoglycans and collagens. progression and tumor growth . Silencing O-GlcNAc We observed up-regulation of both core protein transferase has shown to inhibit pancreatic cancer [139] expression and N-glycosylation level of cathepsins growth . Inhibition of N-glycosylation can inu fl ence (CTSD, CTSL) (Supplemental Table 1) in pancreatic the maturation and surface expression of RTKs cancer tissue, suggesting its possible functional role in (e.g., EGFR, IGF1R), and enhance chemosensitivity WJG|www.wjgnet.com 9293 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer [82] of drug-resistant pancreatic cancer cells . Lewis-Y technical obstacles may be transient. Nonetheless, carbohydrate antigen is expressed by many epithelial many strategies have been demonstrated to target [24,140] cancers, including pancreatic cancer , and has been protein glycosylation and polysaccharides for diagnostic a target for cancer vaccines and immunoconjugated and therapeutic gains in pancreatic cancer. These studies [141,142] chemotherapy . have laid foundation and will provide experimental Mucins (especially MUC1, MUC4, MUC5AC, MUC16) guidance for future investigations. are an important group of glycoproteins in pancreatic cancer and have been targeted for therapeutic REFERENCES treatment. Multiple efforts have been made to develop 1 Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA MUC peptide based vaccination for pancreatic cancer, [99] Cancer J Clin 2013; 63: 11-30 [PMID: 23335087 DOI: 10.3322/ unfortunately with no signic fi ant clinical effects . New caac.20138] data suggests that it may be important to incorporate 2 Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. cancer associated glycoforms in the vaccine design Pancreatic cancer. Lancet 2011; 378: 607-620 [PMID: 21620466 so that the specic fi immunogenic epitopes expressed DOI: 10.1016/S0140-6736(10)62307-0] [143-145] 3 Páez D, Labonte MJ, Lenz HJ. 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Proteomics 2011; 11: 3665-3674 Glycoconj J 2013; 30: 119-136 [PMID: 22886069 DOI: 10.1007/ [PMID: 21751362 DOI: 10.1002/pmic.201000827] s10719-012-9438-6] 30 Goon etillek e KS , S iriw ardena A K . S ys tematic review of 50 Pan S, Chen R, Aebersold R, Brentnall TA. Mass spectrometry carbohydrate antigen (CA 19-9) as a biochemical marker in based glycoproteomics--from a proteomics perspective. Mol the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007; 33: Cell Proteomics 2011; 10: R110.003251 [PMID: 20736408 DOI: 266-270 [PMID: 17097848 DOI: 10.1016/j.ejso.2006.10.004] 10.1074/mcp.R110.003251] 31 Stowell SR, Ju T, Cummings RD. Protein glycosylation in cancer. 51 Wuhrer M, Catalina MI, Deelder AM, Hokke CH. Glycoproteomics Annu Rev Pathol 2015; 10: 473-510 [PMID: 25621663 DOI: based on tandem mass spectrometry of glycopeptides. J Chromatogr 10.1146/annurev-pathol-012414-040438] B Analyt Technol Biomed Life Sci 2007; 849: 115-128 [PMID: 32 Cecconi D, Palmieri M, Donadelli M. 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Pancreas 2008; 36: 329-336 54 Kaji H, Saito H, Yamauchi Y, Shinkawa T, Taoka M, Hirabayashi [PMID: 18437077 DOI: 10.1097/MPA.0b013e31815cc452] J, Kasai K, Takahashi N, Isobe T. Lectin affinity capture, isotope- 35 Omenn GS, Yocum AK, Menon R. Alternative splice variants, coded tagging and mass spectrometry to identify N-linked a new class of protein cancer biomarker candidates: findings glycoproteins. Nat Biotechnol 2003; 21: 667-672 [PMID: in pancreatic cancer and breast cancer with systems biology 12754521 DOI: 10.1038/nbt829] implications. Dis Markers 2010; 28: 241-251 [PMID: 20534909 55 Wang Y, Wu SL, Hancock WS. Approaches to the study of DOI: 10.1155/2010/705847] N-linked glycoproteins in human plasma using lectin affinity WJG|www.wjgnet.com 9295 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer chromatography and nano-HPLC coupled to electrospray linear ion 71 Sarrats A, Saldova R, Pla E, Fort E, Harvey DJ, Struwe WB, de trap--Fourier transform mass spectrometry. Glycobiology 2006; 16: Llorens R, Rudd PM, Peracaula R. Glycosylation of liver acute- 514-523 [PMID: 16497783 DOI: 10.1093/glycob/cwj091] phase proteins in pancreatic cancer and chronic pancreatitis. 56 Yang Z, Hancock WS. Monitoring glycosylation pattern changes Proteomics Clin Appl 2010; 4: 432-448 [PMID: 21137062 DOI: of glycoproteins using multi-lectin affinity chromatography. 10.1002/prca.200900150] J Chromatogr A 2005; 1070: 57-64 [PMID: 15861788 DOI: 72 Miyoshi E, Nakano M. Fucosylated haptoglobin is a novel 10.1016/j.chroma.2005.02.034] marker for pancreatic cancer: detailed analyses of oligosaccharide 57 Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore structures. Proteomics 2008; 8: 3257-3262 [PMID: 18646007 DOI: RJ, Smith RD. Human plasma N-glycoproteome analysis by 10.1002/pmic.200800046] immunoaffinity subtraction, hydrazide chemistry, and mass 73 Miyoshi E, Shinzaki S, Moriwaki K, Matsumoto H. Identification spectrometry. J Proteome Res 2005; 4: 2070-2080 [PMID: of fucosylated haptoglobin as a novel tumor marker for pancreatic 16335952 DOI: 10.1021/pr0502065] cancer and its possible application for a clinical diagnostic test. 58 Pan S, Wang Y, Quinn JF, Peskind ER, Waichunas D, Wimberger Methods Enzymol 2010; 478: 153-164 [PMID: 20816478 DOI: JT, Jin J, Li JG, Zhu D, Pan C, Zhang J. Identification of 10.1016/S0076-6879(10)78006-X] glycoproteins in human cerebrospinal fluid with a complementary 74 Lin Z, Yin H, Lo A, Ruffin MT, Anderson MA, Simeone DM, proteomic approach. J Proteome Res 2006; 5: 2769-2779 [PMID: Lubman DM. Label-free relative quantification of alpha-2- 17022648 DOI: 10.1021/pr060251s] macroglobulin site-specific core-fucosylation in pancreatic cancer 59 Zhang H, Li XJ, Martin DB, Aebersold R. Identification and by LC-MS/MS. Electrophoresis 2014; 35: 2108-2115 [PMID: quantification of N-linked glycoproteins using hydrazide chemistry, 24285556] stable isotope labeling and mass spectrometry. Nat Biotechnol 75 Kontro H, Joenväärä S, Haglund C, Renkonen R. Comparison 2003; 21: 660-666 [PMID: 12754519 DOI: 10.1038/nbt827] of sialylated N-glycopeptide levels in serum of pancreatic 60 Zhang H, Aebersold R. Isolation of glycoproteins and identification cancer patients, acute pancreatitis patients, and healthy controls. of their N-linked glycosylation sites. Methods Mol Biol 2006; 328: Proteomics 2014; 14: 1713-1723 [PMID: 24841998 DOI: 10.1002/ 177-185 [PMID: 16785649 DOI: 10.1385/1-59745-026-X:177] pmic.201300270] 61 Sparbier K, Koch S, Kessler I, Wenzel T, Kostrzewa M. Selective 76 Mann BF, Goetz JA, House MG, Schmidt CM, Novotny MV. isolation of glycoproteins and glycopeptides for MALDI-TOF MS Glycomic and proteomic profiling of pancreatic cyst fluids detection supported by magnetic particles. J Biomol Tech 2005; 16: identifies hyperfucosylated lactosamines on the N-linked glycans 407-413 [PMID: 16522863] of overexpressed glycoproteins. Mol Cell Proteomics 2012; 11: 62 Alvarez-Manilla G, Warren NL, Abney T, Atwood J, Azadi P, M111.015792 [PMID: 22393262 DOI: 10.1074/mcp.M111.015792] York WS, Pierce M, Orlando R. Tools for glycomics: relative 77 Chaturvedi P, Singh AP, Chakraborty S, Chauhan SC, Bafna S, quantitation of glycans by isotopic permethylation using 13CH3I. Meza JL, Singh PK, Hollingsworth MA, Mehta PP, Batra SK. Glycobiology 2007; 17: 677-687 [PMID: 17384119 DOI: 10.1021/ MUC4 mucin interacts with and stabilizes the HER2 oncoprotein pr050275j] in human pancreatic cancer cells. Cancer Res 2008; 68: 2065-2070 63 Hägglund P, Bunkenborg J, Elortza F, Jensen ON, Roepstorff P. [PMID: 18381409 DOI: 10.1158/0008-5472.CAN-07-6041] A new strategy for identification of N-glycosylated proteins and 78 Remmers N, Bailey JM, Mohr AM, Hollingsworth MA. Molecular unambiguous assignment of their glycosylation sites using HILIC pathology of early pancreatic cancer. Cancer Biomark 2010; 9: enrichment and partial deglycosylation. J Proteome Res 2004; 3: 421-440 [PMID: 22112488] 556-566 [PMID: 15253437 DOI: 10.1021/pr034112b] 79 Simeone DM, Ji B, Banerjee M, Arumugam T, Li D, Anderson 64 Szajda SD, Waszkiewicz N, Chojnowska S, Zwierz K. Carbohydrate MA, Bamberger AM, Greenson J, Brand RE, Ramachandran V, markers of pancreatic cancer. Biochem Soc Trans 2011; 39: 340-343 Logsdon CD. CEACAM1, a novel serum biomarker for pancreatic [PMID: 21265800 DOI: 10.1042/BST0390340] cancer. Pancreas 2007; 34: 436-443 [PMID: 17446843 DOI: 65 Hollingsworth MA, Swanson BJ. 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J Hepatobiliary Pancreat Surg 2007; 14: 2007; 67: 10222-10229 [PMID: 17974963 DOI: 10.1158/0008-5472. 243-254 [PMID: 17520199 DOI: 10.1007/s00534-006-1169-2] CAN-06-2483] 68 Yue T, Maupin KA, Fallon B, Li L, Partyka K, Anderson MA, 82 Contessa JN, Bhojani MS, Freeze HH, Rehemtulla A, Lawrence Brenner DE, Kaul K, Zeh H, Moser AJ, Simeone DM, Feng Z, TS. Inhibition of N-linked glycosylation disrupts receptor tyrosine Brand RE, Haab BB. Enhanced discrimination of malignant from kinase signaling in tumor cells. Cancer Res 2008; 68: 3803-3809 benign pancreatic disease by measuring the CA 19-9 antigen [PMID: 18483264 DOI: 10.1158/0008-5472.CAN-07-6389] on specific protein carriers. PLoS One 2011; 6: e29180 [PMID: 83 Purchio AF, Cooper JA, Brunner AM, Lioubin MN, Gentry LE, 22220206 DOI: 10.1371/journal.pone.0029180] Kovacina KS, Roth RA, Marquardt H. 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Mass-spectrometric 101 Higashi M, Yokoyama S, Yamamoto T, Goto Y, Kitazono I, Hiraki identification and relative quantification of N-linked cell surface T, Taguchi H, Hashimoto S, Fukukura Y, Koriyama C, Mataki Y, glycoproteins. Nat Biotechnol 2009; 27: 378-386 [PMID: 19349973 Maemura K, Shinchi H, Jain M, Batra SK, Yonezawa S. Mucin DOI: 10.1038/nbt.1532] expression in endoscopic ultrasound-guided fine-needle aspiration 87 Agard NJ, Bertozzi CR. Chemical approaches to perturb, profile, specimens is a useful prognostic factor in pancreatic ductal and perceive glycans. Acc Chem Res 2009; 42: 788-797 [PMID: adenocarcinoma. Pancreas 2015; 44: 728-734 [PMID: 25906442 19361192 DOI: 10.1021/ar800267j] DOI: 10.1097/MPA.0000000000000362] 88 Haun RS, Fan CY, Mackintosh SG, Zhao H, Tackett AJ. CD109 102 Matsuyama M, Kondo F, Ishihara T, Yamaguchi T, Ito R, Overexpression in Pancreatic Cancer Identified by Cell-Surface Tsuyuguchi T, Tawada K, Yokosuka O. Evaluation of pancreatic Glycoprotein Capture. J Proteomics Bioinform 2014; Suppl 10: intraepithelial neoplasia and mucin expression in normal pancreata. S10003 [PMID: 25635161] J Hepatobiliary Pancreat Sci 2012; 19: 242-248 [PMID: 21644061 89 Haun RS, Quick CM, Siegel ER, Raju I, Mackintosh SG, Tackett DOI: 10.1007/s00534-011-0401-x] AJ. Bioorthogonal labeling cell-surface proteins expressed in 103 Yonezawa S, Higashi M, Yamada N, Yokoyama S, Goto M. pancreatic cancer cells to identify potential diagnostic/therapeutic Significance of mucin expression in pancreatobiliary neoplasms. J biomarkers. Cancer Biol Ther 2015; 16: 1557-1565 [PMID: Hepatobiliary Pancreat Sci 2010; 17: 108-124 [PMID: 19787286 26176765 DOI: 10.1080/15384047.2015.1071740] DOI: 10.1007/s00534-009-0174-7] 90 Zhu J, He J, Liu Y, Simeone DM, Lubman DM. Identification 104 Park HU, Kim JW, Kim GE, Bae HI, Crawley SC, Yang SC, Gum of glycoprotein markers for pancreatic cancer CD24+CD44+ JR, Batra SK, Rousseau K, Swallow DM, Sleisenger MH, Kim YS. stem-like cells using nano-LC-MS/MS and tissue microarray. Aberrant expression of MUC3 and MUC4 membrane-associated J Proteome Res 2012; 11: 2272-2281 [PMID: 22335271 DOI: mucins and sialyl Le(x) antigen in pancreatic intraepithelial 10.1021/pr201059g] neoplasia. Pancreas 2003; 26: e48-e54 [PMID: 12657964 DOI: 91 Almaraz RT, Tian Y, Bhattarcharya R, Tan E, Chen SH, Dallas 10.1097/00006676-200304000-00022] MR, Chen L, Zhang Z, Zhang H, Konstantopoulos K, Yarema KJ. 105 Remmers N, Anderson JM, Linde EM, DiMaio DJ, Lazenby AJ, Metabolic flux increases glycoprotein sialylation: implications for Wandall HH, Mandel U, Clausen H, Yu F, Hollingsworth MA. cell adhesion and cancer metastasis. Mol Cell Proteomics 2012; 11: Aberrant expression of mucin core proteins and o-linked glycans M112.017558 [PMID: 22457533 DOI: 10.1074/mcp.M112.017558] associated with progression of pancreatic cancer. Clin Cancer Res 92 Pan S, Chen R, Tamura Y, Crispin DA, Lai LA, May DH, 2013; 19: 1981-1993 [PMID: 23446997 DOI: 10.1158/1078-0432. M c I n t o s h M W, G o o d l e t t D R , B r e n t n a l l TA . Q u a n t i t a t i v e CCR-12-2662] glycoproteomics analysis reveals changes in N-glycosylation level 106 Chen SH, Dallas MR, Balzer EM, Konstantopoulos K. Mucin associated with pancreatic ductal adenocarcinoma. J Proteome Res 16 is a functional selectin ligand on pancreatic cancer cells. 2014; 13: 1293-1306 [PMID: 24471499 DOI: 10.1021/pr4010184] FASEB J 2012; 26: 1349-1359 [PMID: 22159147 DOI: 10.1096/ 93 Foygel K, Wang H, Machtaler S, Lutz AM, Chen R, Pysz M, Lowe fj.11-195669] AW, Tian L, Carrigan T, Brentnall TA, Willmann JK. Detection of 107 Wu YM, Nowack DD, Omenn GS, Haab BB. Mucin glycosylation pancreatic ductal adenocarcinoma in mice by ultrasound imaging of is altered by pro-inflammatory signaling in pancreatic-cancer thymocyte differentiation antigen 1. Gastroenterology 2013; 145: cells. J Proteome Res 2009; 8: 1876-1886 [PMID: 19714813 DOI: 885-894.e3 [PMID: 23791701 DOI: 10.1053/j.gastro.2013.06.011] 10.1021/pr8008379] 94 Chen R, Brentnall TA, Pan S, Cooke K, Moyes KW, Lane Z, 108 Jabbar KS, Verbeke C, Hyltander AG, Sjövall H, Hansson GC, Crispin DA, Goodlett DR, Aebersold R, Bronner MP. Quantitative Sadik R. Proteomic mucin profiling for the identification of cystic proteomics analysis reveals that proteins differentially expressed precursors of pancreatic cancer. J Natl Cancer Inst 2014; 106: in chronic pancreatitis are also frequently involved in pancreatic djt439 [PMID: 24523528 DOI: 10.1093/jnci/djt439] cancer. 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Trends 98 Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Biotechnol 2015; 33: 230-236 [PMID: 25708906 DOI: 10.1016/ Cameron JL, Yeo CJ, Hruban RH, Goggins M. p16 Inactivation in j.tibtech.2015.01.004] pancreatic intraepithelial neoplasias (PanINs) arising in patients 113 M u l t h a u p t H A , L e i t i n g e r B , G u l l b e rg D , C o u c h m a n J R . with chronic pancreatitis. Am J Surg Pathol 2003; 27: 1495-1501 Extracellular matrix component signaling in cancer. Adv Drug [PMID: 14657708 DOI: 10.1097/00000478-200312000-00001] Deliv Rev 2016; 97: 28-40 [PMID: 26519775 DOI: 10.1016/j.addr. 99 Torres MP, Chakraborty S, Souchek J, Batra SK. Mucin-based 2015.10.013] targeted pancreatic cancer therapy. Curr Pharm Des 2012; 18: 114 Pickup MW, Mouw JK, Weaver VM. The extracellular matrix 2472-2481 [PMID: 22372499 DOI: 10.2174/13816128112092472] modulates the hallmarks of cancer. EMBO Rep 2014; 15: 100 Carrara S, Cangi MG, Arcidiacono PG, Perri F, Petrone MC, 1243-1253 [PMID: 25381661 DOI: 10.15252/embr.201439246] Mezzi G, Boemo C, Talarico A, Cin ED, Grassini G, Doglioni 115 Willis AL, Sabeh F, Li XY, Weiss SJ. Extracellular matrix C, Testoni PA. Mucin expression pattern in pancreatic diseases: determinants and the regulation of cancer cell invasion stratagems. WJG|www.wjgnet.com 9297 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer J Microsc 2013; 251: 250-260 [PMID: 23924043 DOI: 10.1111/ [PMID: 9260563 DOI: 10.1046/j.1365-2796.1997.00170.x] jmi.12064] 132 Misra S, Hascall VC, Markwald RR, Ghatak S. Interactions 116 Janik ME, Lityńska A, Vereecken P. Cell migration-the role of between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate integrin glycosylation. Biochim Biophys Acta 2010; 1800: 545-555 the Activities of Inflammation and Cancer. Front Immunol 2015; 6: [PMID: 20332015 DOI: 10.1016/j.bbagen.2010.03.013] 201 [PMID: 25999946 DOI: 10.3389/fimmu.2015.00201] 117 Grzesiak JJ, Ho JC, Moossa AR, Bouvet M. The integrin- 133 Turley EA, Noble PW, Bourguignon LY. Signaling properties of extracellular matrix axis in pancreatic cancer. Pancreas 2007; 35: hyaluronan receptors. J Biol Chem 2002; 277: 4589-4592 [PMID: 293-301 [PMID: 18090233 DOI: 10.1097/mpa.0b013e31811f4526] 11717317 DOI: 10.1074/jbc.R100038200] 118 Camby I, Le Mercier M, Lefranc F, Kiss R. Galectin-1: a small 134 Provenzano PP, Hingorani SR. Hyaluronan, fluid pressure, and protein with major functions. Glycobiology 2006; 16: 137R-157R stromal resistance in pancreas cancer. Br J Cancer 2013; 108: 1-8 [PMID: 16840800 DOI: 10.1093/glycob/cwl025] [PMID: 23299539 DOI: 10.1038/bjc.2012.569] 119 Gallagher WM, Currid CA, Whelan LC. Fibulins and cancer: 135 Itano N, Zhuo L, Kimata K. Impact of the hyaluronan-rich tumor friend or foe? Trends Mol Med 2005; 11: 336-340 [PMID: microenvironment on cancer initiation and progression. Cancer 15961345 DOI: 10.1016/j.molmed.2005.06.001] Sci 2008; 99: 1720-1725 [PMID: 18564137 DOI: 10.1111/ 120 Rabinovich GA. Galectin-1 as a potential cancer target. Br J j.1349-7006.2008.00885.x] Cancer 2005; 92: 1188-1192 [PMID: 15785741 DOI: 10.1038/ 136 Nikitovic D, Tzardi M, Berdiaki A, Tsatsakis A, Tzanakakis GN. sj.bjc.6602493] Cancer microenvironment and inflammation: role of hyaluronan. 121 Pan S, Chen R, Reimel BA, Crispin DA, Mirzaei H, Cooke Front Immunol 2015; 6: 169 [PMID: 25926834 DOI: 10.3389/ K, Coleman JF, Lane Z, Bronner MP, Goodlett DR, McIntosh fimmu.2015.00169] MW, Traverso W, Aebersold R, Brentnall TA. Quantitative 137 Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff proteomics investigation of pancreatic intraepithelial neoplasia. DD, Hingorani SR. Enzymatic targeting of the stroma ablates Electrophoresis 2009; 30: 1132-1144 [PMID: 19373808 DOI: physical barriers to treatment of pancreatic ductal adenocarcinoma. 10.1002/elps.200800752] Cancer Cell 2012; 21: 418-429 [PMID: 22439937 DOI: 10.1016/ 122 Chen R, Pan S, Ottenhof NA, de Wilde RF, Wolfgang CL, Lane j.ccr.2012.01.007] Z, Post J, Bronner MP, Willmann JK, Maitra A, Brentnall TA. 138 Chanmee T, Ontong P, Kimata K, Itano N. Key Roles of Stromal galectin-1 expression is associated with long-term survival Hyaluronan and Its CD44 Receptor in the Stemness and Survival in resectable pancreatic ductal adenocarcinoma. Cancer Biol Ther of Cancer Stem Cells. Front Oncol 2015; 5: 180 [PMID: 26322272 2012; 13: 899-907 [PMID: 22785208 DOI: 10.4161/cbt.20842] DOI: 10.3389/fonc.2015.00180] 123 Chen R, Dawson DW, Pan S, Ottenhof NA, de Wilde RF, 139 Ma Z, Vocadlo DJ, Vosseller K. Hyper-O-GlcNAcylation is anti- Wolfgang CL, May DH, Crispin DA, Lai LA, Lay AR, Waghray apoptotic and maintains constitutive NF-κB activity in pancreatic M, Wang S, McIntosh MW, Simeone DM, Maitra A, Brentnall TA. cancer cells. J Biol Chem 2013; 288: 15121-15130 [PMID: Proteins associated with pancreatic cancer survival in patients with 23592772 DOI: 10.1074/jbc.M113.470047] resectable pancreatic ductal adenocarcinoma. Lab Invest 2015; 95: 140 Westwood JA, Murray WK, Trivett M, Haynes NM, Solomon 43-55 [PMID: 25347153 DOI: 10.1038/labinvest.2014.128] B, Mileshkin L, Ball D, Michael M, Burman A, Mayura-Guru P, 124 Kudo Y, Siriwardena BS, Hatano H, Ogawa I, Takata T. Periostin: Trapani JA, Peinert S, Hönemann D, Miles Prince H, Scott AM, novel diagnostic and therapeutic target for cancer. Histol Smyth MJ, Darcy PK, Kershaw MH. The Lewis-Y carbohydrate Histopathol 2007; 22: 1167-1174 [PMID: 17616943] antigen is expressed by many human tumors and can serve as a 125 Coulson-Thomas YM, Gesteira TF, Norton AL, Kao WW, Nader target for genetically redirected T cells despite the presence of HB, Coulson-Thomas VJ. The role of proteoglycans in the reactive soluble antigen in serum. J Immunother 2009; 32: 292-301 [PMID: stroma on tumor growth and progression. Histol Histopathol 2015; 19242371 DOI: 10.1097/CJI.0b013e31819b7c8e] 30: 33-41 [PMID: 24931397] 141 Sabbatini PJ, Kudryashov V, Ragupathi G, Danishefsky SJ, 126 Chen R, Yi EC, Donohoe S, Pan S, Eng J, Cooke K, Crispin DA, Livingston PO, Bornmann W, Spassova M, Zatorski A, Spriggs D, Lane Z, Goodlett DR, Bronner MP, Aebersold R, Brentnall TA. Aghajanian C, Soignet S, Peyton M, O’Flaherty C, Curtin J, Lloyd Pancreatic cancer proteome: the proteins that underlie invasion, KO. Immunization of ovarian cancer patients with a synthetic metastasis, and immunologic escape. Gastroenterology 2005; 129: Lewis(y)-protein conjugate vaccine: a phase 1 trial. Int J Cancer 1187-1197 [PMID: 16230073 DOI: 10.1053/j.gastro.2005.08.001] 2000; 87: 79-85 [PMID: 10861456 DOI: 10.1002/1097-0215(2000 127 Chen WB, Lenschow W, Tiede K, Fischer JW, Kalthoff H, 0701)87] Ungefroren H. Smad4/DPC4-dependent regulation of biglycan 142 Saleh MN, Sugarman S, Murray J, Ostroff JB, Healey D, Jones D, gene expression by transforming growth factor-beta in pancreatic Daniel CR, LeBherz D, Brewer H, Onetto N, LoBuglio AF. Phase I tumor cells. J Biol Chem 2002; 277: 36118-36128 [PMID: trial of the anti-Lewis Y drug immunoconjugate BR96-doxorubicin 12140283 DOI: 10.1074/jbc.M203709200] in patients with lewis Y-expressing epithelial tumors. J Clin Oncol 128 Köninger J, Giese T, di Mola FF, Wente MN, Esposito I, Bachem 2000; 18: 2282-2292 [PMID: 10829049] MG, Giese NA, Büchler MW, Friess H. Pancreatic tumor cells 143 Dziadek S, Kunz H. Synthesis of tumor-associated glycopeptide influence the composition of the extracellular matrix. Biochem antigens for the development of tumor-selective vaccines. Chem Biophys Res Commun 2004; 322: 943-949 [PMID: 15336555 DOI: Rec 2004; 3: 308-321 [PMID: 14991920 DOI: 10.1002/tcr.10074] 10.1016/j.bbrc.2004.08.008] 144 Sørensen AL, Reis CA, Tarp MA, Mandel U, Ramachandran 129 Köninger J, Giese NA, di Mola FF, Berberat P, Giese T, Esposito K, Sankaranarayanan V, Schwientek T, Graham R, Taylor- I, Bachem MG, Büchler MW, Friess H. Overexpressed decorin Papadimitriou J, Hollingsworth MA, Burchell J, Clausen H. in pancreatic cancer: potential tumor growth inhibition and Chemoenzymatically synthesized multimeric Tn/STn MUC1 attenuation of chemotherapeutic action. Clin Cancer Res 2004; glycopeptides elicit cancer-specific anti-MUC1 antibody responses 10: 4776-4783 [PMID: 15269152 DOI: 10.1158/1078-0432. and override tolerance. Glycobiology 2006; 16: 96-107 [PMID: CCR-1190-03] 16207894 DOI: 10.1093/glycob/cwj044] 130 Weber CK, Sommer G, Michl P, Fensterer H, Weimer M, Gansauge 145 Tarp MA, Clausen H. Mucin-type O-glycosylation and its F, Leder G, Adler G, Gress TM. Biglycan is overexpressed in potential use in drug and vaccine development. Biochim Biophys pancreatic cancer and induces G1-arrest in pancreatic cancer cell Acta 2008; 1780: 546-563 [PMID: 17988798 DOI: 10.1016/ lines. Gastroenterology 2001; 121: 657-667 [PMID: 11522750 j.bbagen.2007.09.010] DOI: 10.1053/gast.2001.27222] 146 Harisi R, Jeney A. Extracellular matrix as target for antitumor 131 Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, therapy. Onco Targets Ther 2015; 8: 1387-1398 [PMID: 26089687] distribution, functions and turnover. J Intern Med 1997; 242: 27-33 147 Karbownik MS, Nowak JZ. Hyaluronan: towards novel anti- WJG|www.wjgnet.com 9298 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer cancer therapeutics. Pharmacol Rep 2013; 65: 1056-1074 [PMID: 149 Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, 24399703 DOI: 10.1016/S1734-1140(13)71465-8] Pshevlotsky EM, Tjulandin SA, Gladkov OA, Holcombe RF, Korn 148 Misra S, Heldin P, Hascall VC, Karamanos NK, Skandalis SS, R, Raghunand N, Dychter S, Jiang P, Shepard HM, Devoe CE. Markwald RR, Ghatak S. Hyaluronan-CD44 interactions as Phase Ib Study of PEGylated Recombinant Human Hyaluronidase potential targets for cancer therapy. FEBS J 2011; 278: 1429-1443 and Gemcitabine in Patients with Advanced Pancreatic Cancer. [PMID: 21362138 DOI: 10.1111/j.1742-4658.2011.08071.x] Clin Cancer Res 2016; 22: 2848-2854 [PMID: 26813359] P- Reviewer: Kucherlapati MH S- Editor: Qi Y L- Editor: A E- Editor: Zhang FF WJG|www.wjgnet.com 9299 November 14, 2016|Volume 22|Issue 42| Published by Baishideng Publishing Group Inc 8226 Regency Drive, Pleasanton, CA 94588, USA Telephone: +1-925-223-8242 Fax: +1-925-223-8243 E-mail: bpgoffice@wjgnet.com Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx http://www.wjgnet.com I S S N 1 0 0 7 - 9 3 2 7 4 2 9 7 7 1 0 0 7 9 3 2 0 45 © 2016 Baishideng Publishing Group Inc. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Journal of Gastroenterology Pubmed Central

Glycoproteins and glycoproteomics in pancreatic cancer

World Journal of Gastroenterology , Volume 22 (42) – Nov 14, 2016

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Pubmed Central
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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
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1007-9327
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2219-2840
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10.3748/wjg.v22.i42.9288
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Abstract

org/10.3748/wjg.v22.i42.9288 Aberrations in protein glycosylation and polysaccha- rides play a pivotal role in pancreatic tumorigenesis, influencing cancer progression, metastasis, immuno- response and chemoresistance. Abnormal expression INTRODUCTION in sugar moieties can impact the function of various Pancreatic cancer is one of the most deadly cancers, in glycoproteins, including mucins, surface receptors, adhesive proteins, proteoglycans, as well as their part because detection of pancreatic cancer is difc fi ult WJG|www.wjgnet.com 9288 November 14, 2016|Volume 22|Issue 42| 65 65 65 65 NS NS 25 NS Pan S et al . Glycoproteomics study in pancreatic cancer Hyaluronan Heparan sulphate Chondroitin sulphate GalNAc Glycosylphosphatidy- N-glycan GlcNAc linositol anchored Gal glycoproteins Gal Man Protein Fuc Etn O-glycan Xyl Sialic acid Ser GlcA Asn ldoA Ser Inositol P Ser/Thr Ser/Thr O-GlcNAc glycoproteins Protein Figure 1 Illustration of protein glycosylation and polysaccharides. [13] at its early stages when surgical and other treatments residues . One unique subclass of O-glycosylation is [1,2] [14] are most effective . In addition, innate or adapted the phosphorylation-like, reversible O-GlcNAcylation . drug-resistance has been a major hurdle in pancreatic Less common forms of glycosylation include glycosyl- [3,4] cancer chemotherapy . Malignance induced changes phosphatidylinositol anchors attached to protein in protein glycosylation, such N-glycosylation and carboxyl terminus, C-glycosylation that occurs on [15] O-glycosylation, can profoundly impact the function tryptophan residues and S-linked glycosylation [16] of a protein in multiple ways, including protein ma- through a sulfur atom on cysteine or methionine . turation, expression, localization, as well as post- In addition to protein glycosylation, proteoglycans and translational modifications, influencing a wide hyaluronan are major components of the extracellular spectrum of glycoproteins and their binding ligands. matrix (ECM), which are implicated in cell proliferation One approach for developing better diagnostic and and migration. therapeutic strategies in pancreatic cancer involves Most secretory and membrane-bound proteins targeting cancer-associated aberrant glycosylation. produced by mammalian cells contain covalently Recent developments of technology in proteomics linked sugar chains with diverse structures. The and chemical biology have thus stimulated growing glycosylation form and density of glycans on a interest in elucidating the complex glycosylation events protein can be altered signic fi antly in association with involved in pancreatic adenocarcinoma. changes in cellular pathways and processes resulted from diseases, such as malignancy. In fact, altered glycosylation patterns have long been recognized as PROTEIN GLYCOSYLATION AND ITS [17-22] hallmarks in epithelial cancer , including pancreatic IMPLICATION IN CANCER ductal adenocarcinoma (PDAC), which accounts for about 90% of pancreatic cancer. Glycosylation Glycosylation is one of the most complex and common [5,6] abnormalities can be characterized by one or both of forms of protein post-translational modifications . the following changes: (1) composition and structural It plays a pivotal role in many biological processes, alterations of glycan; and (2) change in the density such as protein folding, cell adhesion and trafc fi king, of glycosylation at protein sites (hyper, hypo or neo- cell signaling, pathogen recognition and immune [7-11] glycosylation). Ultimately, malignant transforma- response . Protein glycosylation occurs in the tion is usually associated with one or both of these endoplasmic reticulum and Golgi apparatus in multiple types of glycosylation alterations, leading to the enzymatic steps. As illustrated in Figure 1, the most expressional and functional changes of tumor-specic fi common protein glycosylations are N-linked and glycoproteins. Malignancy associated glycosylation O-linked glycosylation. N-linked glycans are attached abnormalities can influence cancer cell proliferation, to the amide group of asparagine residues in a consensus Asn-X-Ser/Thr sequence (X can be any invasion and viability, as well as interactions with [12] amino acid except proline) . O-linked glycans are tumor micro environment. Disruption or inhibition of linked to the hydroxyl group on serine or threonine glycosylation and carbohydrate-dependent cellular WJG|www.wjgnet.com 9289 November 14, 2016|Volume 22|Issue 42| Proteoglycans Pan S et al . Glycoproteomics study in pancreatic cancer Intact glycopeptides Glycans Glycoprotein MS analysis Database search and bioinformatics Deglycosylated peptides Figure 2 Mass spectrometry based glycoproteomics analysis. [15,44-52] pathways may represent potential modalities for glycosites) . Figure 2 illustrates the overall [23,24] cancer therapies . Receptor tyrosine kinases approaches for MS analysis of glycoproteins. Prior (RTKs), which are transmembrane glycoproteins to MS acquisition, glyco-enrichment strategies, [53-56] [57-60] that play important roles in malignancy and drug including lectin afn fi ity , hydrazide chemistry , [61] [62] resistance, have been targets of anti-cancer drug boronic acid , size-exclusion chromatography , [63] development for various malignancies, including and hydrophilic interaction , may be applied to [25,26] pancreatic adenocarcinoma . In addition, many enrich glycoproteins from complex biological samples, of the current blood-based tumor markers are gly- and thus, enhance analytical sensitivity. The direct coproteins, including CA 19-9 for pancreatic cancer, analysis of intact glycopeptides with carbohydrate CA 125 for ovarian cancer, CA 15-3 for breast cancer, attachments is analytically challenging, but allows and CA 242 for gastrointestinal cancer. CA 19-9, which complementary identic fi ation of the peptide backbone detects the epitope of sialyl Lewis (a) on mucins and and the glycan structure in a single measurement, other adhesive molecules such as carcinoembryonic providing site-specific glycosylation characterization [27-29] antigen , is widely used for monitoring the clinical directly. However, this approach is complicated by the [30] course of pancreatic cancer patients . To date, mixed information obtained from the MS signals from while implication of aberrant protein glycosylation in the peptide backbone, the carbohydrate group and the [21,31] malignancy has been well recognized , limited combinations of both, and therefore, is largely limited information is available describing the site specific for analyzing purie fi d glycoproteins or simple systems. glycoproteome changes associated with pancreatic Alternatively, glycans, especially N-linked glycans, cancer. can be enzymatically or chemically cleaved from proteins or peptides and analyzed separately by MS. Using glycan databases and bioinformatics tools, MS GLYCOPROTEOMICS METHODS analysis enables global identic fi ation of glycan species A number of proteomics studies in pancreatic cancer in a complex biological sample. On the other hand, [32-39] have been reported . As a sube fi ld of proteomics, de-glycosylated glycopeptides can also be profiled in glycoproteomics uniquely focuses on analyzing glycosy- a global fashion using shotgun proteomics approach lated proteins to reveal glycoproteome alterations to identify the amino acid sequence of the backbone associated with pancreatic cancer. The major challenge peptides. The N-glycosylation sites can be precisely for a comprehensive glycoproteomics analysis in a mapped using the consensus sequence of Asn-X-Ser/ clinical sample arises from the biological intricacy Thr, in which asparagine is converted to aspartic acid within the molecule of a glycoprotein, including the after PNGase F enzymatic cleavage, which introduces a variety in glycan composition and structure, as well mass difference of 0.9840 Dalton for MS identic fi ation. as the complex linkage to the corresponding protein. By defining the glycan structures and profiling the Mass spectrometry has been the most effective and glycoproteins in complex clinical samples, disease versatile instrument platform for both glycan and associated aberrant glycan forms and site-specific protein analysis. Although various sample preparation occupancy on proteins can be revealed. For quantitative strategies may be applied to collect glycoproteins analysis, additional steps, such as differential stable or glycans from different biological specimens, isotope labeling of the sample and controls, may be a glycoproteomics pipeline typically consists of required. Ultimately, to comprehensively address glyco-enrichment, MS analysis and bioinformatics disease associated aberrant glycosylation, all the data interpretation. The technical details of global analysis obtained from different aspects of the worko fl w need of glycoprotein can be found in a number of reviews [40-43] on the subject of glycomics (analysis of glycans) to be integrated, so that the full extent of glycosylation and glycoproteomics (analysis of glycoproteins and changes with site-specific information can be better WJG|www.wjgnet.com 9290 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer [71] revealed. cancer associated signal . Although the detection of increase level of fucosylated HP alone does not provide sufficient accuracy for pancreatic cancer diagnosis, DISCOVERY OF ABERRANT it is possible that fucosylated HP might be used as an indication of liver metastasis if the biomarker GLYCOSYLATION IN BODILY FLUIDS [72,73] undergoes further validation . The changes in Identification and detection of abnormal protein protein fucosylation and sialylation in pancreatic glycosylation associated with pancreatic cancer in cancer were also investigated by analyzing intact bodily u fl ids may present meaningful targets for cancer glycopeptides. Using immunoprecipitation, partial detection. A variety of carbohydrates and glycoproteins deglycosylation and LC MS/MS, one study suggested have been investigated for pancreatic cancer detection. that the core-fucosylation levels at site N396 and Currently, CA19-9 is the only clinical biomarker test for N1424 in alpha-2-macroglobulin (A2M) were decreased [64] management of pancreatic cancer . While CA19-9 in serum of both pancreatic cancer and chronic is widely used for monitoring the clinical course of [74] pancreatitis compared to non-diseased controls . cancer patients, it does not provide adequate accuracy The investigation of sialylated N-glycopeptide levels for pancreatic cancer diagnosis and early detection, in sera from pancreatic cancer patients in comparison underscoring the importance of obtaining molecular to non-diseased controls and acute pancreatitis details on specific glycosylation events involved in patients identified 13 glycoforms, mainly from high- neoplastic progression. Mucin (MUC) proteins, including abundant serum proteins, with changes associated MUC1, MUC5AC, and MUC16 are major protein carriers [75] with pancreatic cancer group . Mucinous cystic of CA 19-9, and play important roles in pancreatic neoplasms (MCN) and intraductal papillary mucinous cancer tumorigenesis, invasiveness and metastasis, neoplasms (IPMN) are pancreatic cysts that are subject [28,65-67] in part through their characteristic glycoforms . to high risk of malignant transformation. Proteomic Changes of MUC1 and MUC5AC in pancreatic cancer and glycomic investigation of cyst u fl ids collected from serum involved distinct glycan alterations, including patients with MCN and IPMN led to the identification Thomsen-Friedenreich antigen and fucose and Lewis [28] of 80 N-linked glycans, and several hyper-fucosylated antigens . The measurement of CA 19-9 antigen glycoproteins, including triacylglycerol lipase and on MUC1, MUC5AC and MUC16 individually did not [76] pancreatic α-amylase . improve the performance of cancer detection, owing to the biological heterogeneity of the patients in their [68] CA 19-9 protein carriers . However, the combined GLYCOPROTEOMICS OF PANCREATIC measurement of standard CA 19-9 assay and the CANCER CELLS AND TISSUES detection of the CA 19-9 antigen on MUC5AC and MUC16 did improve the performance of pancreatic Known tumor-specific glycoproteins, such as mucins [68] cancer detection . and carcinoembryonic antigen-related cell adhesion In addition to CA19-9, other aberrant protein molecules, have been extensively studied for their glycosylations associated with pancreatic cancer have roles in neoplastic progression and metastasis of [77-81] also been investigated in bodily u fl ids. The glycosylation pancreatic cancer . The emerging technology of serum ribonuclease 1 (RNASE1) - another well- of glycoproteomics has been recently applied to studied pancreas associated protein, showed a 40% interrogate broader changes of glycoproteome in [69] increase in core fucosylation in pancreatic cancer . pancreatic cancer cells and tissue. A large number of Using Concanavalin A lectin afn fi ity chromatography for cell surface proteins are transmembrane glycoproteins, N-glycopeptide enrichment and LC MS/MS, one study including many of cell-surface receptors such as RTKs, identified 92 individual glycosylation sites and 105 which play pivotal roles in signaling, trafficking and unique carbohydrate structures in serum, and observed cell-cell interactions. These cell-surface receptors, such increased branching of N-linked oligosaccharides, as as epithelial growth factor receptor (EGFR), integrins, well as increased protein fucosylation and sialylation in and TGF β receptor (TGFβR) have been important [70] the sera from pancreatic cancer patients . Increased targets for anti-cancer therapy, and their glycosylation [82-85] level of sialyl Lewis X of major serum acute-phase forms impact their functionality . Using a biocytin [86] proteins, including alpha-1-acid glycoprotein (AGP1 hydrazide cell surface capturing technique , or or ORM1), haptoglobin (HP), fetuin (AHSG), alpha- azido sugar based bioorthogonal chemical reporter [87] 1-antitrypsin (SERPINA1) and transferrin (TF) were for metabolic glycan labeling for glycopeptide observed in the sera from patients with advanced enrichment, studies were carried out to prolfi e N-linked pancreatic cancer and chronic pancreatitis - an glycopeptides derived from surface glycoproteins of [88,89] alteration possibly associated with inflammatory pancreatic cancer cells using LC MS/MS . The [71] [88] response . In addition, the observation of an increase studies indicated the overexpression of CD109 and [89] in core fucosylation on AGP1 and HP in the serum of ecto-50-nucleotidase in pancreatic cancer cells and advanced pancreatic cancer may represent a potential tissues. Using multi-lectin affinity chromatography WJG|www.wjgnet.com 9291 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer and LC-MS/MS, another study investigated the the orchestrated glycosylation mechanism underlying differential glycoproteins associated with pancreatic pancreatic tumorigenesis, immune response and + + cancer CD24 CD44 stem-like cells in comparison pancreatic functional changes, remains poorly - + [90] with CD24 CD44 cells . The study indicated understood and warrant further investigation. that the high expression and high positive rate of CD24 was significantly associated with late-stage MUCIN GLYCOSYLATION pancreatic adenocarcinomas, while CD13 expression and positive rate were negatively associated with Mucins are high molecular weight glycoproteins tumor progression. By manipulating exogenous produced by various epithelial cells, and have 21 substrate supply, a study reported that increases in family members. The mucins are heavily glycosylated metabolic flux through the sialic acid pathway could in O- and N-linked glycosylation and implicated dramatically enhance the sialylation of certain N-linked in PDAC through their characteristic glycoforms glycoproteins to influence cancer cell adhesive and influencing tumorigenicity, invasiveness, metastasis mobility properties of SW1990 pancreatic cancer and drug resistance. Mucins have been extensively [91] cells . studied in PDAC, and showed various expressional Glycoproteomic techniques were also applied to and glycosylation changes not only in pancreatic investigate the glycoproteome of pancreatic cancer carcinoma, but also in pancreatic intraepithelial [66,67,99] tissues. In our study, we observed an overall increase neoplasia (PanIN), IPMN and MCN . Several in N-glycosylation level on many glycoproteins in mucins, including MUC1, MUC4, MUC5AC and MUC16, [92] PDAC tissue in comparison with normal pancreas . are frequently upregulated in PDAC. Mucin core protein Supplemental Table 1 summarizes some of the expression and the differential localization in PDAC and glycoproteins with at least one N-glycopeptide its precursor lesions have been well documented in the [66,67,100-103] overexpressed (≥ 2 fold) in pancreatic cancer, literature . In addition, mucin glycoforms also including many pancreatic cancer associated proteins, play an important role in modulating their functionality such as MUC5AC, carcinoembryonic antigen-related in tumorigenesis as well as cancer cell interaction cell adhesion molecule 5, insulin-like growth factor with the tumor microenvironment. In fact, the glycan binding protein (IGFBP3), cathepsin D (CTSD), as component can make up more than 50% of the well as a number of CD antigens (including CD44 - molecular weight of a mucin glycoprotein. a marker of pancreatic cancer stem-like cells) and The glycosylation of cancer associated mucins integrins. Pathway analysis suggested that increased is largely associated with Tn antigen, sialyl Tn and N-glycosylation activities of these proteins were fucosylated core 1 structures, forming the so-called [104] implicated in several pancreatic cancer pathways, tumor-associated antigens . Altered glycoforms of [92] including TGF-β, TNF, and NF-kappa-B . Other MUC1, MUC4 and MUC5AC were observed early in glycoproteins, such as Thy-1 membrane glycoprotein pancreatic cancer progression (PanINs) to late stage [105] (THY1), which was recently developed into an metastatic disease . The elevation of fucosylated ultrasound molecular imaging marker for pancreatic core structures, fucose and Lewis antigen have [93] cancer detection , was found heavily N-glycosylated frequently been detected on MUC1 and MUC5AC in [28] in pancreatic cancer tissues. Further mapping of the blood from patients with pancreatic cancer . N-glycosylation sites revealed that the change of Additionally, MUC16 and its sialofucosylated N-glycosylation level in pancreatic cancer was not structures were reported overexpressed in pancreatic only protein specific, but also glycosylation site cancer cell and acted as a functional ligand for E- specific. Specific N-glycosylation sites within certain and L-selectin to enhance cancer cell metastatic [106] individual proteins can have significantly altered spread . By stimulating pancreatic cancer cells glycosylation occupancy (e.g., a change in glycan with pro-inflammatory conditions, such as oxidative density) in pancreatic cancer, reflecting the complex stress and cytokines, mucin glycosylation can be nature of glycosylation events underlying pancreatic significantly altered in specific pancreatic cancer cell tumorigenesis. Notably, the increase of N-glycosylation lines, suggesting a possible molecular link between of many of these proteins was also found in chro- inflammation, glycosylation alteration and adaptive nic pancreatitis tissue, supporting the notion that [107] responses of those pancreatic cancer cells . Efforts pancreatic cancer and chronic pancreatitis share have also been made to use proteomic approaches [94-98] many common clinical and molecular features . to prolife mucins in cyst u fl ids to enhance the discri - It is also noteworthy to mention that in contrast to mination of malignant pancreatic cyst lesions from many glycoproteins with increased N-glycosylation, [108] those that are benign . pancreatic secretory granule membrane major glycoprotein (GP2) - a pancreas specic fi glycoprotein, showed a reduced N-glycosylated level in both cancer ECM GLYCOPROTEINS, and chronic pancreatitis tissues. While the global data PROTEOGLYCANS AND HYALURONAN have revealed the aberrant N-glycosylation changes of many relevant proteins in pancreatic cancer tissues, In our proteomic study, we observed a large group of WJG|www.wjgnet.com 9292 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer [92,94] ECM associated proteins overexpressed in pancreatic pancreatic tumorigenesis . [97] cancer and chronic pancreatitis tissues . Many of Proteoglycans are heavily glycosylated proteins these proteins are glycoproteins and are involved in with serine attached glycosaminoglycans (GAGs), stellate cell activation and ECM organizational and such as heparan sulphate and chondroitin sulphate (Figure 1). Proteoglycans are an important component structural changes, which regulate pancreatic b fi rosis of ECM and affect multiple biological processes, - one of the fundamental histological abnormalities including cell differentiation and proliferation, binding observed in pancreatic adenocarcinoma and chronic pancreatitis. ECM components, including matrix to cytokines, growth factors and morphogens. proteins, proteoglycan proteins, galectins and hya- During tumorigenesis, the expression and glycosylation patterns of proteoglycans change in the stroma luronan, which interact with each other and form surrounding cancer, influencing tumor growth and supramolecular complexes, are subjected to alterations [125] neoplastic progression . In proteomics and other during cancer progression, leading to cancer asso- [109-115] studies, the increased expression of proteoglycan ciated ECM . Abnormal protein glycosylation proteins, including lumican, decorin, versican, and can significantly affect the mechanical properties of [110,116] biglycan, has been observed in pancreatic cancer ECM, enhancing tumor cell migration . Studies [97,121,126-130] tissues or cells . Since GAGs are large, have shown that ECM components associated with linear polysaccharides, to a certain extent, the integrin-ECM axis are highly up-regulated in pancreatic [117] biological function of proteoglycans can be governed cancer . The glycoforms of integrins, such as the by the interaction of the attached GAGs with other presence of N-linked oligosaccharides, can regulate proteins. Most of proteoglycans also contain N- and integrin function, affecting the cell-ECM interactions. In O-linked glycans. In a quantitative glycoproteomics pancreatic cancer tissues, we observed increased levels study, N-glycosylation levels of several major ECM of N-glycosylation, not only on several integrins (both proteoglycans, including decorin (DCN), biglycan α and β subunits), but also on ECM adhesion proteins, (BGN), lumican (LUM), versican (VCAN), and aggrecan including collagens, b fi ronectin, vitronectin, and laminin [92] (ACAN), were found elevated in pancreatic cancer (Supplemental Table 1) . These observations warrant [92] tissues (Supplemental Table 1) . mechanistic study to better understand how aberrant Hyaluronan is a non sulfated glycosaminoglycan glycosylation of integrins and ECM adhesion ligands that is not covalently attached to proteoglycans and influence pancreatic cancer migration and malignant [131] can have a very high molecule weight . CD44 and phenotypes. Galectins and fibulins play a role in receptor for HA-mediated motility are the two main organization of ECM supramolecular structure, such receptors for the anchorage of hyaluronan-rich ECM to as basement membranes, by forming intramolecular [132,133] the cell surface . Although it has relatively simple bridges, binding to complex carbohydrates and ECM [118-120] chemical composition, as one of the major components adhesive proteins . The core protein expression of ECM, hyaluronan is involved in promoting pancreatic and N-glycosylation level of b fi ulin 1 were both found [132-134] [92,97] cancer progression and chemoresistance . Aberrant up-regulated in pancreatic cancer tissues . Galectin production and deposition of hyaluronan provide a 1 (LGALS1) is a human extracellular lectin that spe- favorable microenvironment to enhance cancer cell cifically binds to β-galactoside sugars, including N- proliferation, migration, invasion, angiogenesis, and limit and O-linked glycans. Galectin 1 was overexpressed [134-137] the delivery of anti-cancer agents . Studies have in the stroma of both pancreatic cancer and PanINs [121] also shown that the interaction between hyaluronan lesions , and its expression was related to pancreatic [122,123] and its CD44 receptor is involved in the stemness and cancer survival . Concurrently, the N-glycosylation [138] survival of cancer stem cells , and may be relevant level of endogenous ligands of galectin-1 in the ECM, + + to pancreatic cancer CD24 CD44 stem-like cells. including fibronectin (FN1), laminins and galectin-3- binding protein (LGALS3BP), were all up-regulated in pancreatic cancer tissue (Supplemental Table 1), IMPLICATIONS IN ANTI-CANCER DRUG implying an intensified interaction of galectins and [92] DEVELOPMENT their major binding partners in pancreatic cancer . Periostin (POSTN), an ECM protein involved in cell Protein glycosylation has become a prominent target [124] mobility and neovascularization , has both up- for drug development. One strategy involves dis- regulated core protein expression and N-glycosylation ruption of the protein glycosylation process, such as [92,97] levels in pancreatic cancer tissue . Cathepsins are inhibition of glycosylation enzymes and hexosamine proteases that are implicated in cancer invasion by biosynthetic pathway, to reduce pancreatic cancer [23,24] degrading ECM, including proteoglycans and collagens. progression and tumor growth . Silencing O-GlcNAc We observed up-regulation of both core protein transferase has shown to inhibit pancreatic cancer [139] expression and N-glycosylation level of cathepsins growth . Inhibition of N-glycosylation can inu fl ence (CTSD, CTSL) (Supplemental Table 1) in pancreatic the maturation and surface expression of RTKs cancer tissue, suggesting its possible functional role in (e.g., EGFR, IGF1R), and enhance chemosensitivity WJG|www.wjgnet.com 9293 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer [82] of drug-resistant pancreatic cancer cells . Lewis-Y technical obstacles may be transient. Nonetheless, carbohydrate antigen is expressed by many epithelial many strategies have been demonstrated to target [24,140] cancers, including pancreatic cancer , and has been protein glycosylation and polysaccharides for diagnostic a target for cancer vaccines and immunoconjugated and therapeutic gains in pancreatic cancer. 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J Biochem 2000; 127: 65-72 [PMID: 10731668 glycosylation profiling of pancreatic cancer serum using capillary DOI: 10.1093/oxfordjournals.jbchem.a022585] liquid phase separation coupled with mass spectrometric analysis. 85 Zheng M, Fang H, Hakomori S. Functional role of N-glycosylation J Proteome Res 2007; 6: 1126-1138 [PMID: 17249709 DOI: in alpha 5 beta 1 integrin receptor. De-N-glycosylation induces 10.1021/pr0604458] dissociation or altered association of alpha 5 and beta 1 subunits WJG|www.wjgnet.com 9296 November 14, 2016|Volume 22|Issue 42| Pan S et al . Glycoproteomics study in pancreatic cancer and concomitant loss of fibronectin binding activity. J Biol Chem findings from EUS-guided fine-needle aspiration biopsies. Am 1994; 269: 12325-12331 [PMID: 7512965] J Gastroenterol 2011; 106: 1359-1363 [PMID: 21647207 DOI: 86 Wollscheid B, Bausch-Fluck D, Henderson C, O’Brien R, 10.1038/ajg.2011.22] Bibel M, Schiess R, Aebersold R, Watts JD. Mass-spectrometric 101 Higashi M, Yokoyama S, Yamamoto T, Goto Y, Kitazono I, Hiraki identification and relative quantification of N-linked cell surface T, Taguchi H, Hashimoto S, Fukukura Y, Koriyama C, Mataki Y, glycoproteins. Nat Biotechnol 2009; 27: 378-386 [PMID: 19349973 Maemura K, Shinchi H, Jain M, Batra SK, Yonezawa S. Mucin DOI: 10.1038/nbt.1532] expression in endoscopic ultrasound-guided fine-needle aspiration 87 Agard NJ, Bertozzi CR. Chemical approaches to perturb, profile, specimens is a useful prognostic factor in pancreatic ductal and perceive glycans. Acc Chem Res 2009; 42: 788-797 [PMID: adenocarcinoma. Pancreas 2015; 44: 728-734 [PMID: 25906442 19361192 DOI: 10.1021/ar800267j] DOI: 10.1097/MPA.0000000000000362] 88 Haun RS, Fan CY, Mackintosh SG, Zhao H, Tackett AJ. CD109 102 Matsuyama M, Kondo F, Ishihara T, Yamaguchi T, Ito R, Overexpression in Pancreatic Cancer Identified by Cell-Surface Tsuyuguchi T, Tawada K, Yokosuka O. 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Mucin glycosylation pancreatic ductal adenocarcinoma in mice by ultrasound imaging of is altered by pro-inflammatory signaling in pancreatic-cancer thymocyte differentiation antigen 1. Gastroenterology 2013; 145: cells. J Proteome Res 2009; 8: 1876-1886 [PMID: 19714813 DOI: 885-894.e3 [PMID: 23791701 DOI: 10.1053/j.gastro.2013.06.011] 10.1021/pr8008379] 94 Chen R, Brentnall TA, Pan S, Cooke K, Moyes KW, Lane Z, 108 Jabbar KS, Verbeke C, Hyltander AG, Sjövall H, Hansson GC, Crispin DA, Goodlett DR, Aebersold R, Bronner MP. Quantitative Sadik R. Proteomic mucin profiling for the identification of cystic proteomics analysis reveals that proteins differentially expressed precursors of pancreatic cancer. J Natl Cancer Inst 2014; 106: in chronic pancreatitis are also frequently involved in pancreatic djt439 [PMID: 24523528 DOI: 10.1093/jnci/djt439] cancer. 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Trends 98 Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Biotechnol 2015; 33: 230-236 [PMID: 25708906 DOI: 10.1016/ Cameron JL, Yeo CJ, Hruban RH, Goggins M. p16 Inactivation in j.tibtech.2015.01.004] pancreatic intraepithelial neoplasias (PanINs) arising in patients 113 M u l t h a u p t H A , L e i t i n g e r B , G u l l b e rg D , C o u c h m a n J R . with chronic pancreatitis. Am J Surg Pathol 2003; 27: 1495-1501 Extracellular matrix component signaling in cancer. Adv Drug [PMID: 14657708 DOI: 10.1097/00000478-200312000-00001] Deliv Rev 2016; 97: 28-40 [PMID: 26519775 DOI: 10.1016/j.addr. 99 Torres MP, Chakraborty S, Souchek J, Batra SK. Mucin-based 2015.10.013] targeted pancreatic cancer therapy. Curr Pharm Des 2012; 18: 114 Pickup MW, Mouw JK, Weaver VM. The extracellular matrix 2472-2481 [PMID: 22372499 DOI: 10.2174/13816128112092472] modulates the hallmarks of cancer. 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Hyper-O-GlcNAcylation is anti- Wolfgang CL, May DH, Crispin DA, Lai LA, Lay AR, Waghray apoptotic and maintains constitutive NF-κB activity in pancreatic M, Wang S, McIntosh MW, Simeone DM, Maitra A, Brentnall TA. cancer cells. J Biol Chem 2013; 288: 15121-15130 [PMID: Proteins associated with pancreatic cancer survival in patients with 23592772 DOI: 10.1074/jbc.M113.470047] resectable pancreatic ductal adenocarcinoma. Lab Invest 2015; 95: 140 Westwood JA, Murray WK, Trivett M, Haynes NM, Solomon 43-55 [PMID: 25347153 DOI: 10.1038/labinvest.2014.128] B, Mileshkin L, Ball D, Michael M, Burman A, Mayura-Guru P, 124 Kudo Y, Siriwardena BS, Hatano H, Ogawa I, Takata T. Periostin: Trapani JA, Peinert S, Hönemann D, Miles Prince H, Scott AM, novel diagnostic and therapeutic target for cancer. Histol Smyth MJ, Darcy PK, Kershaw MH. The Lewis-Y carbohydrate Histopathol 2007; 22: 1167-1174 [PMID: 17616943] antigen is expressed by many human tumors and can serve as a 125 Coulson-Thomas YM, Gesteira TF, Norton AL, Kao WW, Nader target for genetically redirected T cells despite the presence of HB, Coulson-Thomas VJ. The role of proteoglycans in the reactive soluble antigen in serum. J Immunother 2009; 32: 292-301 [PMID: stroma on tumor growth and progression. Histol Histopathol 2015; 19242371 DOI: 10.1097/CJI.0b013e31819b7c8e] 30: 33-41 [PMID: 24931397] 141 Sabbatini PJ, Kudryashov V, Ragupathi G, Danishefsky SJ, 126 Chen R, Yi EC, Donohoe S, Pan S, Eng J, Cooke K, Crispin DA, Livingston PO, Bornmann W, Spassova M, Zatorski A, Spriggs D, Lane Z, Goodlett DR, Bronner MP, Aebersold R, Brentnall TA. Aghajanian C, Soignet S, Peyton M, O’Flaherty C, Curtin J, Lloyd Pancreatic cancer proteome: the proteins that underlie invasion, KO. 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Glycoproteomics study in pancreatic cancer cancer therapeutics. Pharmacol Rep 2013; 65: 1056-1074 [PMID: 149 Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, 24399703 DOI: 10.1016/S1734-1140(13)71465-8] Pshevlotsky EM, Tjulandin SA, Gladkov OA, Holcombe RF, Korn 148 Misra S, Heldin P, Hascall VC, Karamanos NK, Skandalis SS, R, Raghunand N, Dychter S, Jiang P, Shepard HM, Devoe CE. Markwald RR, Ghatak S. Hyaluronan-CD44 interactions as Phase Ib Study of PEGylated Recombinant Human Hyaluronidase potential targets for cancer therapy. FEBS J 2011; 278: 1429-1443 and Gemcitabine in Patients with Advanced Pancreatic Cancer. [PMID: 21362138 DOI: 10.1111/j.1742-4658.2011.08071.x] Clin Cancer Res 2016; 22: 2848-2854 [PMID: 26813359] P- Reviewer: Kucherlapati MH S- Editor: Qi Y L- Editor: A E- Editor: Zhang FF WJG|www.wjgnet.com 9299 November 14, 2016|Volume 22|Issue 42| Published by Baishideng Publishing Group Inc 8226 Regency Drive, Pleasanton, CA 94588, USA Telephone: +1-925-223-8242 Fax: +1-925-223-8243 E-mail: bpgoffice@wjgnet.com Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx http://www.wjgnet.com I S S N 1 0 0 7 - 9 3 2 7 4 2 9 7 7 1 0 0 7 9 3 2 0 45 © 2016 Baishideng Publishing Group Inc. All rights reserved.

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