Special Issue "Cancer and Glycosylation"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 March 2016)

Special Issue Editor

Guest Editor
Prof. Dr. Franz-Georg Hanisch

Medical Faculty, Institute of Biochemistry II, University of Cologne, Joseph-Stezmann-Str. 52, 50931 Köln, Germany
Website | E-Mail
Interests: MUC1; O-glycosylation; cancer-associated glyco-markers

Special Issue Information

Dear Colleagues,

Evidence has accumulated that carbohydrate-peptide epitopes do play a role in classical MHC-mediated immune responses. T-cell recognition of O-glycosylated peptides is potentially of high biomedical significance, because it can mediate the immune protection against microorganisms, and in particular the vaccination in anti-tumor therapies.

Research over three decades has revealed a series of tumor target antigens with proven potential in clinical diagnostics or in immunotherapeutic approaches. Among these are the Carcinoembryonic Antigen (CEA), the ovarian carcinoma marker CA125 (MUC16), and the epithelial tumor markers MUC1 and HER2neu. A common feature of the epithelial tumor markers is that they belong to the family of glycoproteins.

Tremendous progress has been made in recent years with respect to the mass spectrometric elucidation of site-specific glycosylation of proteins and to cancer-associated aspects of immunology, including the search for new markers in tumor diagnostics and the development of mucin glycopeptide-based cancer vaccines.

The purpose of this Special Issue is to convey the latest advances toward an understanding of the multiple roles N- and in particular O-glycosylation might play in epithelial cancers. Particular emphasis will be layed on mucin-linked epitopes in diagnostics and in the development of therapeutics, like those based on MUC1-glycopeptides in the context of active specific immunization.

We look forward to reading your contributions,

Prof. Dr. Franz-Georg Hanisch
Guest Editor

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Keywords

  • epithelial cancer
  • carcinoma
  • glycosylation
  • glycoprotein
  • MUCI
  • inflammation and cancer progression
  • breast cancer vaccines
  • tumor evasion

Published Papers (6 papers)

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Research

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Open AccessArticle Aberrant Glycosylation of Anchor-Optimized MUC1 Peptides Can Enhance Antigen Binding Affinity and Reverse Tolerance to Cytotoxic T Lymphocytes
Biomolecules 2016, 6(3), 31; doi:10.3390/biom6030031
Received: 30 April 2016 / Revised: 7 June 2016 / Accepted: 7 June 2016 / Published: 29 June 2016
Cited by 1 | PDF Full-text (1908 KB) | HTML Full-text | XML Full-text
Abstract
Cancer vaccines have often failed to live up to their promise, although recent results with checkpoint inhibitors are reviving hopes that they will soon fulfill their promise. Although mutation-specific vaccines are under development, there is still high interest in an off-the-shelf vaccine to
[...] Read more.
Cancer vaccines have often failed to live up to their promise, although recent results with checkpoint inhibitors are reviving hopes that they will soon fulfill their promise. Although mutation-specific vaccines are under development, there is still high interest in an off-the-shelf vaccine to a ubiquitous antigen, such as MUC1, which is aberrantly expressed on most solid and many hematological tumors, including more than 90% of breast carcinomas. Clinical trials for MUC1 have shown variable success, likely because of immunological tolerance to a self-antigen and to poor immunogenicity of tandem repeat peptides. We hypothesized that MUC1 peptides could be optimized, relying on heteroclitic optimizations of potential anchor amino acids with and without tumor-specific glycosylation of the peptides. We have identified novel MUC1 class I peptides that bind to HLA-A*0201 molecules with significantly higher affinity and function than the native MUC1 peptides. These peptides elicited CTLs from normal donors, as well as breast cancer patients, which were highly effective in killing MUC1-expressing MCF-7 breast cancer cells. Each peptide elicited lytic responses in greater than 6/8 of normal individuals and 3/3 breast cancer patients. The CTLs generated against the glycosylated-anchor modified peptides cross reacted with the native MUC1 peptide, STAPPVHNV, suggesting these analog peptides may offer substantial improvement in the design of epitope-based vaccines. Full article
(This article belongs to the Special Issue Cancer and Glycosylation)
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Review

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Open AccessReview Intra- and Extra-Cellular Events Related to Altered Glycosylation of MUC1 Promote Chronic Inflammation, Tumor Progression, Invasion, and Metastasis
Biomolecules 2016, 6(4), 39; doi:10.3390/biom6040039
Received: 8 July 2016 / Revised: 29 August 2016 / Accepted: 27 September 2016 / Published: 13 October 2016
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Abstract
Altered glycosylation of mucin 1 (MUC1) on tumor cells compared to normal epithelial cells was previously identified as an important antigenic modification recognized by the immune system in the process of tumor immunosurveillance. This tumor form of MUC1 is considered a viable target
[...] Read more.
Altered glycosylation of mucin 1 (MUC1) on tumor cells compared to normal epithelial cells was previously identified as an important antigenic modification recognized by the immune system in the process of tumor immunosurveillance. This tumor form of MUC1 is considered a viable target for cancer immunotherapy. The importance of altered MUC1 glycosylation extends also to its role as a promoter of chronic inflammatory conditions that lead to malignant transformation and cancer progression. We review here what is known about the role of specific cancer-associated glycans on MUC1 in protein-protein interactions and intracellular signaling in cancer cells and in their adhesion to each other and the tumor stroma. The tumor form of MUC1 also creates a different landscape of inflammatory cells in the tumor microenvironment by controlling the recruitment of inflammatory cells, establishing specific interactions with dendritic cells (DCs) and macrophages, and facilitating tumor escape from the immune system. Through multiple types of short glycans simultaneously present in tumors, MUC1 acquires multiple oncogenic properties that control tumor development, progression, and metastasis at different steps of the process of carcinogenesis. Full article
(This article belongs to the Special Issue Cancer and Glycosylation)
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Figure 1

Open AccessReview Functional Consequences of Differential O-glycosylation of MUC1, MUC4, and MUC16 (Downstream Effects on Signaling)
Biomolecules 2016, 6(3), 34; doi:10.3390/biom6030034
Received: 3 June 2016 / Revised: 18 July 2016 / Accepted: 21 July 2016 / Published: 30 July 2016
PDF Full-text (1277 KB) | HTML Full-text | XML Full-text
Abstract
Glycosylation is one of the most abundant post-translational modifications that occur within the cell. Under normal physiological conditions, O-linked glycosylation of extracellular proteins is critical for both structure and function. During the progression of cancer, however, the expression of aberrant and truncated
[...] Read more.
Glycosylation is one of the most abundant post-translational modifications that occur within the cell. Under normal physiological conditions, O-linked glycosylation of extracellular proteins is critical for both structure and function. During the progression of cancer, however, the expression of aberrant and truncated glycans is commonly observed. Mucins are high molecular weight glycoproteins that contain numerous sites of O-glycosylation within their extracellular domains. Transmembrane mucins also play a functional role in monitoring the surrounding microenvironment and transducing these signals into the cell. In cancer, these mucins often take on an oncogenic role and promote a number of pro-tumorigenic effects, including pro-survival, migratory, and invasive behaviors. Within this review, we highlight both the processes involved in the expression of aberrant glycan structures on mucins, as well as the potential downstream impacts on cellular signaling. Full article
(This article belongs to the Special Issue Cancer and Glycosylation)
Figures

Open AccessReview Mucin-Type O-Glycosylation in Gastric Carcinogenesis
Biomolecules 2016, 6(3), 33; doi:10.3390/biom6030033
Received: 2 May 2016 / Revised: 1 July 2016 / Accepted: 4 July 2016 / Published: 11 July 2016
PDF Full-text (1825 KB) | HTML Full-text | XML Full-text
Abstract
Mucin-type O-glycosylation plays a crucial role in several physiological and pathological processes of the gastric tissue. Modifications in enzymes responsible for key glycosylation steps and the consequent abnormal biosynthesis and expression of their glycan products constitute well-established molecular hallmarks of disease state.
[...] Read more.
Mucin-type O-glycosylation plays a crucial role in several physiological and pathological processes of the gastric tissue. Modifications in enzymes responsible for key glycosylation steps and the consequent abnormal biosynthesis and expression of their glycan products constitute well-established molecular hallmarks of disease state. This review addresses the major role played by mucins and associated O-glycan structures in Helicobacter pylori adhesion to the gastric mucosa and the subsequent establishment of a chronic infection, with concomitant drastic alterations of the gastric epithelium glycophenotype. Furthermore, alterations of mucin expression pattern and glycan signatures occurring in preneoplastic lesions and in gastric carcinoma are also described, as well as their impact throughout the gastric carcinogenesis cascade and in cancer progression. Altogether, mucin-type O-glycosylation alterations may represent promising biomarkers with potential screening and prognostic applications, as well as predictors of cancer patients’ response to therapy. Full article
(This article belongs to the Special Issue Cancer and Glycosylation)
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Figure 1

Open AccessReview A Bitter Sweet Symphony: Immune Responses to Altered O-glycan Epitopes in Cancer
Biomolecules 2016, 6(2), 26; doi:10.3390/biom6020026
Received: 30 March 2016 / Revised: 20 April 2016 / Accepted: 22 April 2016 / Published: 3 May 2016
Cited by 2 | PDF Full-text (2865 KB) | HTML Full-text | XML Full-text
Abstract
The appearance of aberrant glycans on the tumor cell surface is one of the emerging hallmarks of cancer. Glycosylation is an important post-translation modification of proteins and lipids and is strongly affected by oncogenesis. Tumor-associated glycans have been extensively characterized regarding their composition
[...] Read more.
The appearance of aberrant glycans on the tumor cell surface is one of the emerging hallmarks of cancer. Glycosylation is an important post-translation modification of proteins and lipids and is strongly affected by oncogenesis. Tumor-associated glycans have been extensively characterized regarding their composition and tumor-type specific expression patterns. Nevertheless whether and how tumor-associated glycans contribute to the observed immunomodulatory actions by tumors has not been extensively studied. Here, we provide a detailed overview of the current knowledge on how tumor-associated O-glycans affect the anti-tumor immune response, thereby focusing on truncated O-glycans present on epithelial tumors and mucins. These tumor-associated O-glycans and mucins bind a variety of lectin receptors on immune cells to facilitate the subsequently induction of tolerogenic immune responses. We, therefore, postulate that tumor-associated glycans not only support tumor growth, but also actively contribute to immune evasion. Full article
(This article belongs to the Special Issue Cancer and Glycosylation)
Figures

Open AccessReview Enzymes for N-Glycan Branching and Their Genetic and Nongenetic Regulation in Cancer
Biomolecules 2016, 6(2), 25; doi:10.3390/biom6020025
Received: 23 March 2016 / Revised: 15 April 2016 / Accepted: 21 April 2016 / Published: 28 April 2016
Cited by 13 | PDF Full-text (1541 KB) | HTML Full-text | XML Full-text
Abstract
N-glycan, a fundamental and versatile protein modification in mammals, plays critical roles in various physiological and pathological events including cancer progression. The formation of N-glycan branches catalyzed by specific N-acetylglucosaminyltransferases [GnT-III, GnT-IVs, GnT-V, GnT-IX (Vb)] and a fucosyltransferase, Fut8, provides
[...] Read more.
N-glycan, a fundamental and versatile protein modification in mammals, plays critical roles in various physiological and pathological events including cancer progression. The formation of N-glycan branches catalyzed by specific N-acetylglucosaminyltransferases [GnT-III, GnT-IVs, GnT-V, GnT-IX (Vb)] and a fucosyltransferase, Fut8, provides functionally diverse N-glycosylated proteins. Aberrations of these branches are often found in cancer cells and are profoundly involved in cancer growth, invasion and metastasis. In this review, we focus on the GlcNAc and fucose branches of N-glycans and describe how their expression is dysregulated in cancer by genetic and nongenetic mechanisms including epigenetics and nucleotide sugar metabolisms. We also survey the roles that these N-glycans play in cancer progression and therapeutics. Finally, we discuss possible applications of our knowledge on basic glycobiology to the development of medicine and biomarkers for cancer therapy. Full article
(This article belongs to the Special Issue Cancer and Glycosylation)

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