Differential glycosylation of MUC1 and CEACAM5 between normal mucosa and tumour tissue of colon cancer patients

Saeland, Eiríkur; Belo, Ana I.; Mongera, Sandra; Die, Irma van; Meijer, Gerrit A.; Kooyk, Yvette van

doi:10.1002/ijc.26354

Cited by 96 publications

(74 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These include prominent biomarkers that are widely used in patients with prostate cancer (prostate-specific antigen (PSA)) 187 , ovarian cancer (carcinoma antigen 125 (CA125; also known as mucin-16 (MUC16))) 188 , colon cancer (SLe a , CA19-9, 3,49 and carcinoembryonic antigen (CEA) 189 ), breast cancer (aberrantly glycosylated MUC1 (also known as CA15-3)) 190,191 gastric cancer (SLe a , CA19-9) 3,49 and pancreatic cancer (SLe a, , CA19-9) 192 (TABLE 1). Although all of these serological biomarkers have been shown to have an aberrant glyco sylation in cancer [193][194][195] , they have limited application owing to their relative low specificity, precluding their use for screening strategies and diagnostic potential. The reduced specificity and sensitivity of these assays for early detection of cancer has driven a search for novel biomarkers based on the detection and measurement of specific glycoforms of a certain protein that could contribute to the establishment of a biomarker with higher specificity for early detection of cancer or for diagnosis at a precancerous stage.…”

Section: Glycans In Cancer Diagnosis and Treatmentmentioning

confidence: 99%

Glycosylation in cancer: mechanisms and clinical implications

2015

View full text Add to dashboard Cite

Despite recent progress in understanding the cancer genome, there is still a relative delay in understanding the full aspects of the glycome and glycoproteome of cancer. Glycobiology has been instrumental in relevant discoveries in various biological and medical fields, and has contributed to the deciphering of several human diseases. Glycans are involved in fundamental molecular and cell biology processes occurring in cancer, such as cell signalling and communication, tumour cell dissociation and invasion, cell-matrix interactions, tumour angiogenesis, immune modulation and metastasis formation. The roles of glycans in cancer have been highlighted by the fact that alterations in glycosylation regulate the development and progression of cancer, serving as important biomarkers and providing a set of specific targets for therapeutic intervention. This Review discusses the role of glycans in fundamental mechanisms controlling cancer development and progression, and their applications in oncology.

show abstract

Section: Glycans In Cancer Diagnosis and Treatmentmentioning

confidence: 99%

Glycosylation in cancer: mechanisms and clinical implications

2015

View full text Add to dashboard Cite

show abstract

“…Given that highly specific changes in glycosylation regulate diverse proteins like Notch (130), dystroglycan (131)(132)(133), amyloid precursor protein (134,135), and MUC1 (136), one can speculate that UPR regulates these proteins under some conditions. For example, in cancer cells, the global glycosylation of proteins is impacted (137,138), which includes MUC1, a major activator of the proliferative RAS-MEK-ERK MAPK pathway (9,139,140). Aberrantly glycosylated MUC1 and other proteins may be recognized by QC pathways in this setting, which may impact signaling pathway outputs.…”

Section: Discussionmentioning

confidence: 99%

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Vadaie

Chow

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

bSignaling mucins are evolutionarily conserved regulators of signal transduction pathways. The signaling mucin Msb2p regulates the Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. The cleavage and release of the glycosylated inhibitory domain of Msb2p is required for MAPK activation. We show here that proteolytic processing of Msb2p was induced by underglycosylation of its extracellular domain. Cleavage of underglycosylated Msb2p required the unfolded protein response (UPR), a quality control (QC) pathway that operates in the endoplasmic reticulum (ER). The UPR regulator Ire1p, which detects misfolded/underglycosylated proteins in the ER, controlled Msb2p cleavage by regulating transcriptional induction of Yps1p, the major protease that processes Msb2p. Accordingly, the UPR was required for differentiation to the filamentous cell type. Cleavage of Msb2p occurred in conditional trafficking mutants that trap secretory cargo in the endomembrane system. Processed Msb2p was delivered to the plasma membrane, and its turnover by the ubiquitin ligase Rsp5p and ESCRT attenuated the filamentous-growth pathway. We speculate that the QC pathways broadly regulate signaling glycoproteins and their cognate pathways by recognizing altered glycosylation patterns that can occur in response to extrinsic cues. Signaling mucins are evolutionarily conserved regulators of signal transduction pathways (1-4). Signaling mucins are composed of a highly glycosylated extracellular domain that contains a mucin homology domain (MHD), which is defined by tandem repeats rich in Ser/Thr/Pro residues. The extracellular domain is connected by a single-pass transmembrane (TM) alpha helix to a cytosolic signaling domain, which associates with a diverse array of proteins that regulate mitogen-activated protein kinase (MAPK) pathways, Akt, ␤-catenin, and other pathways (5-8). Signaling mucins are overexpressed in different cancers, where they contribute to cell proliferation and metastasis (6). They are diagnostic biomarkers for cancers (9) and targets for immunotherapies (10,11). Therefore, the mechanisms by which signaling mucins and related glycoproteins are regulated is of intense interest.In the budding yeast Saccharomyces cerevisiae, the mucin-like glycoprotein Msb2p regulates the MAPK pathway that controls filamentous growth, a cell differentiation behavior that occurs in response to nutrient limitation (12-14). The extracellular domain of Msb2p is extensively glycosylated. Msb2p is modified by Nlinked and O-linked glycosylation and contains a canonical MHD that is itself highly glycosylated (15, 16). In a landmark study, Yang et al. identified Pmt4p as the major O-mannosyltransferase for Msb2p (17). Pmt4p is a member of an evolutionarily conserved protein mannosyl transferase (Pmt) gene family (2, 18). Msb2p also contains a cytosolic signaling domain. The cytosolic domain of Msb2p associates with the Rho GTPase Cdc42p (15), which is a ubiquitous regulator of cell polarity and signaling...

show abstract

“…Certain pathogenic infections and tumors are marked by the presence of tolerogenic DCs and T cells (6)(7)(8)(9)). An often overlooked feature shared by these pathological conditions is the presence of aberrant glycosylation patterns (7,(10)(11)(12). In particular, increased levels of sialic acids have been demonstrated in these situations.…”

mentioning

confidence: 99%

Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells

Perdicchio

Ilarregui

Verstege

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

148

120

View full text Add to dashboard Cite

Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigenspecific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4 + and CD8 + T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen-loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E-mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro-established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelinreactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance. sialic acids | regulatory T cells | dendritic cells | tolerance | glycans

show abstract

Differential glycosylation of MUC1 and CEACAM5 between normal mucosa and tumour tissue of colon cancer patients

Cited by 96 publications

References 44 publications

Glycosylation in cancer: mechanisms and clinical implications

Glycosylation in cancer: mechanisms and clinical implications

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells

Contact Info

Product

Resources

About