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Glycoconjugate Journal Aug 2021Mucins are highly O-glycosylated glycoproteins that carry a heterogenous variety of O-glycan structures. Tumor cells tend to overexpress specific mucins, such as the... (Review)
Review
Mucins are highly O-glycosylated glycoproteins that carry a heterogenous variety of O-glycan structures. Tumor cells tend to overexpress specific mucins, such as the cell surface mucins MUC1 and MUC4 that are engaged in signaling and cell growth, and exhibit abnormal glycosylation. In particular, the Tn and T antigens and their sialylated forms are common in cancer mucins. We review herein methods chosen to use cancer-associated glycans and mucins as targets for the design of anti-cancer immunotherapies. Mucin peptides from the glycosylated and transmembrane domains have been combined with immune-stimulating adjuvants in a wide variety of approaches to produce anti-tumor antibodies and vaccines. These mucin conjugates have been tested on cancer cells in vitro and in mice with significant successes in stimulating anti-tumor responses. The clinical trials in humans, however, have shown limited success in extending survival. It seems critical that the individual-specific epitope expression of cancer mucins is considered in future therapies to result in lasting anti-tumor responses.
Topics: Cancer Vaccines; Humans; Membrane Glycoproteins; Mucins; Neoplasms
PubMed: 33704667
DOI: 10.1007/s10719-021-09986-8 -
Frontiers in Immunology 2024The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in... (Review)
Review
The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in establishing protective mucosal barriers, serving as defenses against pathogenic assaults. Intriguingly, the aberrant expression of specific MUC proteins, notably Mucin 1 (MUC1) and Mucin 16 (MUC16), within tumor cells, is intimately associated with oncogenesis, proliferation, and metastasis. This association involves various mechanisms, including cellular proliferation, viability, apoptosis resistance, chemotherapeutic resilience, metabolic shifts, and immune surveillance evasion. Due to their distinctive biological roles and structural features in oncology, MUC proteins have attracted considerable attention as prospective targets and biomarkers in cancer therapy. The current review offers an exhaustive exploration of the roles of MUC1 and MUC16 in the context of cancer biomarkers, elucidating their critical contributions to the mechanisms of cellular signal transduction, regulation of immune responses, and the modulation of the tumor microenvironment. Additionally, the article evaluates the latest advances in therapeutic strategies targeting these mucins, focusing on innovations in immunotherapies and targeted drugs, aiming to enhance customization and accuracy in cancer treatments.
Topics: Animals; Mucin-1; CA-125 Antigen; Mucins; Neoplasms; Immunity; Mammals; Tumor Microenvironment
PubMed: 38361923
DOI: 10.3389/fimmu.2024.1356913 -
ChemPlusChem Dec 2020Mucins are bottlebrush biopolymers that are glycoproteins on the surfaces of cells and as hydrogels secreted inside and outside the body. Mucin function in biology... (Review)
Review
Mucins are bottlebrush biopolymers that are glycoproteins on the surfaces of cells and as hydrogels secreted inside and outside the body. Mucin function in biology includes cell-cell recognition, signaling, protection, adhesion, and lubrication. Because of their attractive and diverse properties, mucins have recently become the focus of synthetic efforts by researchers who hope to understand and emulate these biomaterials. This review is focused on the development of methodologies for preparing mucin-inspired synthetic oligomers and glycopolymers, including solid-phase synthesis, polymerization of glycosylated monomers, and post-polymerization grafting of glycans to polymer chains. How these synthetic mucins have been used in health applications is discussed. Natural mucins are formed from a conserved set of monomers that are combined into chains of different sequences and lengths to achieve materials with widely diverse properties. Adopting this design paradigm from natural mucins could lead to next-generation bioinspired synthetic materials.
Topics: Humans; Mucins; Polymers
PubMed: 33346954
DOI: 10.1002/cplu.202000637 -
Glycobiology Mar 2022The intestinal epithelium is protected from direct contact with gut microbes by a mucus layer. This mucus layer consists of secreted mucin glycoproteins. The outer mucus... (Review)
Review
The intestinal epithelium is protected from direct contact with gut microbes by a mucus layer. This mucus layer consists of secreted mucin glycoproteins. The outer mucus layer in the large intestine forms a niche that attracts specific gut microbiota members of which several gut commensals can degrade mucin. Mucin glycan degradation is a complex process that requires a broad range of glycan degrading enzymes, as mucin glycans are intricate and diverse molecules. Consequently, it is hypothesized that microbial mucin breakdown requires concerted action of various enzymes in a network of multiple resident microbes in the gut mucosa. This review investigates the evolutionary relationships of microbial carbohydrate-active enzymes that are potentially involved in mucin glycan degradation and focuses on the role that microbial enzymes play in the degradation of gut mucin glycans in microbial cross-feeding and syntrophic interactions.
Topics: Gastrointestinal Microbiome; Hydrolases; Intestinal Mucosa; Mucins; Polysaccharides
PubMed: 34939101
DOI: 10.1093/glycob/cwab105 -
Advanced Drug Delivery Reviews May 2022The secreted mucus layer that lines and protects epithelial cells is conserved across diverse species. While the exact composition of this protective layer varies... (Review)
Review
The secreted mucus layer that lines and protects epithelial cells is conserved across diverse species. While the exact composition of this protective layer varies between organisms, certain elements are conserved, including proteins that are heavily decorated with N-acetylgalactosamine-based sugars linked to serines or threonines (O-linked glycosylation). These heavily O-glycosylated proteins, known as mucins, exist in many forms and are able to form hydrated gel-like structures that coat epithelial surfaces. In vivo studies in diverse organisms have highlighted the importance of both the mucin proteins as well as their constituent O-glycans in the protection and health of internal epithelia. Here, we summarize in vivo approaches that have shed light on the synthesis and function of these essential components of mucus.
Topics: Epithelial Cells; Glycosylation; Humans; Mucins; Mucus; Polysaccharides
PubMed: 35278522
DOI: 10.1016/j.addr.2022.114182 -
Macromolecular Bioscience Aug 2017The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held... (Review)
Review
The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held in Munster on 2-3 September 2015 as a satellite event of the ICCC 13th-EUCHIS 12th. After a brief outline of the new issues, the focus is on mucus description, purification, and mucus/mucin characterization, all steps that are pivotal to the understanding of mucus related phenomena and the choice of the correct mucosal model for in vitro and ex vivo experiments, alternative bio/mucomimetic materials are also presented. Then a selection of preparative techniques and testing methods are described (at molecular as well as micro and macroscale) that may support the pharmaceutical development of mucus interactive systems and assist formulators in the scale-up and industrialization steps. Recent applications of mucoadhesive systems (including medical devices) intended for different routes of administration (oral, gastrointestinal, vaginal, nasal, ocular, and intravesical) and for the treatment of difficult to treat pathologies or the alleviation of symptoms are described.
Topics: Animals; Biomedical Research; Biomimetic Materials; Humans; Mucins; Mucus
PubMed: 28378910
DOI: 10.1002/mabi.201600534 -
Nature Chemical Biology Jun 2023Mucinolytic bacteria modulate host-microbiota symbiosis and dysbiosis through their ability to degrade mucin O-glycans. However, how and to what extent bacterial enzymes...
Mucinolytic bacteria modulate host-microbiota symbiosis and dysbiosis through their ability to degrade mucin O-glycans. However, how and to what extent bacterial enzymes are involved in the breakdown process remains poorly understood. Here we focus on a glycoside hydrolase family 20 sulfoglycosidase (BbhII) from Bifidobacterium bifidum, which releases N-acetylglucosamine-6-sulfate from sulfated mucins. Glycomic analysis showed that, in addition to sulfatases, sulfoglycosidases are involved in mucin O-glycan breakdown in vivo and that the released N-acetylglucosamine-6-sulfate potentially affects gut microbial metabolism, both of which were also supported by a metagenomic data mining analysis. Enzymatic and structural analysis of BbhII reveals the architecture underlying its specificity and the presence of a GlcNAc-6S-specific carbohydrate-binding module (CBM) 32 with a distinct sugar recognition mode that B. bifidum takes advantage of to degrade mucin O-glycans. Comparative analysis of the genomes of prominent mucinolytic bacteria also highlights a CBM-dependent O-glycan breakdown strategy used by B. bifidum.
Topics: Mucins; Ecosystem; Polysaccharides; Bacteria
PubMed: 36864192
DOI: 10.1038/s41589-023-01272-y -
Clinical Cancer Research : An Official... Dec 2021Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy demonstrating aberrant and progressive expression of mucins. The contribution of individual mucins...
PURPOSE
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy demonstrating aberrant and progressive expression of mucins. The contribution of individual mucins has been extensively investigated in PDAC; however, comprehensive mucin profiling including splice variants in PDAC tumors has not been reported.
EXPERIMENTAL DESIGN
Using publicly available RNA sequencing (RNA-seq) datasets, we assess the expression of mucin family members and their splice variants (SV) in PDAC tumor samples for the first time. Mucin SVs that are correlated with PDAC patient survival are validated in a cohort of patient tumor samples. Further, we use computational methods to derive novel pancreatic tumor subtypes using mucin expression signatures and their associated activated pathways.
RESULTS
Principal component analysis identified four novel mucin-based PDAC subtypes. Pathway analysis implicated specific biological signatures for each subtype, labeled (i) immune activated, (ii) progressive, (iii) pancreatitis-initiated, and (iv) anti-inflammatory/PanIN-initiated. Assessing mucin SVs, significantly longer survival is observed with higher expression of 4 and 1 SVs, whereas patients expressing 2 and 1 SVs had shorter survival. Using a whole-transcriptome correlation, a three-gene panel, including , , and , is designated to assess PDAC tumor sample cellularity by PCR. One SV and one SV are quantified in a separate PDAC patient cohort, and their effects on survival are experimentally validated.
CONCLUSIONS
Altogether, we demonstrate the unique expression pattern of mucins, four mucin-based PDAC subtypes, and the contribution of , , and SVs in PDAC patient survival.
Topics: Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Gene Expression Regulation, Neoplastic; Humans; Mucin-1; Mucin-4; Mucins; Pancreatic Ducts; Pancreatic Neoplasms
PubMed: 34615717
DOI: 10.1158/1078-0432.CCR-21-1591 -
Seminars in Immunology Sep 2023A complex mucus network made up of large polymers of the mucin-family glycoprotein MUC2 exists between the large intestinal microbial mass and epithelial and immune... (Review)
Review
A complex mucus network made up of large polymers of the mucin-family glycoprotein MUC2 exists between the large intestinal microbial mass and epithelial and immune cells. This has long been understood as an innate immune defense barrier against the microbiota and other luminal threats that reinforces the barrier function of the epithelium and limits microbiota contact with the tissues. However, past and recent studies have provided new evidence of how critical the mucus network is to act as a 'liaison' between host and microbe to mediate anti-inflammatory, mutualistic interactions with the microbiota and protection from pathogens. This review summarizes historical and recent insights into the formation of the gut mucus network, how the microbes and immune system influence mucus, and in turn, how the mucus influences immune responses to the microbiota.
Topics: Humans; Intestinal Mucosa; Mucin-2; Mucus; Mucins; Microbiota
PubMed: 37478802
DOI: 10.1016/j.smim.2023.101807 -
International Journal of Molecular... Dec 2021Maintaining intestinal health requires clear segregation between epithelial cells and luminal microbes. The intestinal mucus layer, produced by goblet cells (GCs), is a... (Review)
Review
Maintaining intestinal health requires clear segregation between epithelial cells and luminal microbes. The intestinal mucus layer, produced by goblet cells (GCs), is a key element in maintaining the functional protection of the epithelium. The importance of the gut mucus barrier is highlighted in mice lacking , the major form of secreted mucins. These mice show closer bacterial residence to epithelial cells, develop spontaneous colitis and became moribund when infected with the attaching and effacing pathogen, . Furthermore, numerous observations have associated GCs and mucus layer dysfunction to the pathogenesis of inflammatory bowel disease (IBD). However, the molecular mechanisms that regulate the physiology of GCs and the mucus layer remain obscured. In this review, we consider novel findings describing divergent functionality and expression profiles of GCs subtypes within intestinal crypts. We also discuss internal (host) and external (diets and bacteria) factors that modulate different aspects of the mucus layer as well as the contribution of an altered mucus barrier to the onset of IBD.
Topics: Animals; Colitis; Epithelial Cells; Gastrointestinal Microbiome; Goblet Cells; Humans; Inflammatory Bowel Diseases; Mice; Mucins
PubMed: 34948435
DOI: 10.3390/ijms222413642