Glycosylation: a hallmark of cancer?
TL;DR: The results provide the evidence that altered glycosylation is linked to tumor initiation, progression and metastasis and can be considered as a new hallmark of cancer development and strategies to develop novel gly cosylation targeted molecules should be strengthened.
Abstract: The hallmarks of cancer are characterized by functional capabilities that allow cancer cells to survive, proliferate and disseminate during the multistep tumorigenesis. Cancer being a cellular disease, changes in cellular glycoproteins play an important role in malignant transformation and cancer progression. The present review summarizes various studies that depicted correlation of glycosylation with tumor initiation, progression and metastasis, which are helpful in early diagnosis, disease monitoring and prognosis. The results are further strengthened by our reports, which depicted alterations in sialylation and fucosylation in different cancers. Alterations in glycosyltransferases are also involved in formation of various tumor antigens (e.g. Sialyl Lewis x) which serves as ligand for the cell adhesion molecule, selectin which is involved in adhesion of cancer cells to vascular endothelium and thus contributes to hematogenous metastasis. Increased glycosylation accompanied by alterations in glycosyltranferases, glycosidases, glycans and mucins (MUC)s are also involved in loss of E-cadherin, a key molecule implicated in metastatic dissemination of cells. The present review also summarizes the correlation of glycosylation with all the hallmarks of cancer. The enormous progress in the design of novel inhibitors of pathway intermediates of sialylation and fucosylation can prove wonders in combating the dreadful disease. The results provide the evidence that altered glycosylation is linked to tumor initiation, progression and metastasis. Hence, it can be considered as a new hallmark of cancer development and strategies to develop novel glycosylation targeted molecules should be strengthened.
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TL;DR: Sialidases (neuraminidases), which liberate sialic acids from cellular compounds, had been known from very early on from studies with influenza viruses, and are studied because of their significance in development and, for instance, in cancer.
Abstract: Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their structural analysis, occurrence, and functions is fascinating and described in this review. Reports from different researchers on apparently similar substances from a variety of biological materials led to the identification of a 9-carbon monosaccharide, which in 1957 was designated "sialic acid." The most frequently occurring member of the sialic acid family is N-acetylneuraminic acid, followed by N-glycolylneuraminic acid and O-acetylated derivatives, and up to now over about 80 neuraminic acid derivatives have been described. They appeared first in the animal kingdom, ranging from echinoderms up to higher animals, in many microorganisms, and are also expressed in insects, but are absent in higher plants. Sialic acids are masks and ligands and play as such dual roles in biology. Their involvement in immunology and tumor biology, as well as in hereditary diseases, cannot be underestimated. N-Glycolylneuraminic acid is very special, as this sugar cannot be expressed by humans, but is a xenoantigen with pathogenetic potential. Sialidases (neuraminidases), which liberate sialic acids from cellular compounds, had been known from very early on from studies with influenza viruses. Sialyltransferases, which are responsible for the sialylation of glycans and elongation of polysialic acids, are studied because of their significance in development and, for instance, in cancer. As more information about the functions in health and disease is acquired, the use of sialic acids in the treatment of diseases is also envisaged.
184 citations
TL;DR: The discussion focuses on mechanisms during immune evasion and metastasis that can be therapeutically targeted by blocking these cell-cell interactions.
Abstract: Cell-cell interactions and cell adhesion are key mediators of cancer progression and facilitate hallmarks of cancer including immune evasion and metastatic dissemination. Many cell adhesion molecules within the tumor microenvironment are changed and significant alterations of glycosylation are observed. These changes in cell adhesion molecules alter the ability of tumor cells to interact with other cells and extracellular matrix proteins. Three families of cell-cell interaction molecules selectins, Siglecs and integrins have been associated with cancer progression in many preclinical studies, yet inhibition of cell adhesion as therapeutic target is just beginning to be explored. We review how cell-cell interactions mediated by integrins and the glycan-binding receptors selectins and Siglec receptors are supporting cancer progression. The discussion is focused on mechanisms during immune evasion and metastasis that can be therapeutically targeted by blocking these cell-cell interactions.
135 citations
Cites background from "Glycosylation: a hallmark of cancer..."
...Malignant transformation changes not only the expression of cell adhesion molecules but also causes profound changes in cell surface glycosylation (3, 4)....
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...(3) Tumor cell interaction with the endothelium, leading to adherence, is...
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TL;DR: This review focuses on summarizing PD-L1 regulation and its potential roles in regulating antitumor immune response, with purpose to optimize anti-PD-1/PD- L1 therapies, benefiting a wider cancer patient population.
132 citations
TL;DR: Total serum sialylation levels appear to be increased with various malignancies and show a potential for clinical applications, especially for disease monitoring and prognosis.
Abstract: Cancer is a major cause of death in both developing and developed countries. Early detection and efficient therapy can greatly enhance survival. Aberrant glycosylation has been recognized to be one of the hallmarks of cancer as glycans participate in many cancer-associated events. Cancer-associated glycosylation changes often involve sialic acids which play important roles in cell-cell interaction, recognition and immunological response. This review aims at giving a comprehensive overview of the literature on changes of sialylation in serum of cancer patients. Furthermore, the methods available to measure serum and plasma sialic acids as well as possible underlying biochemical mechanisms involved in the serum sialylation changes are surveyed. In general, total serum sialylation levels appear to be increased with various malignancies and show a potential for clinical applications, especially for disease monitoring and prognosis. In addition to overall sialic acid levels and the amount of sialic acid per total protein, glycoprofiling of specific cancer-associated glycoproteins, acute phase proteins and immunoglobulins in serum as well as the measurements of sialylation-related enzymes such as sialidases and sialyltransferases have been reported for early detection of cancer, assessing cancer progression and improving prognosis of cancer patients. Moreover, sialic-acid containing glycan antigens such as CA19-9, sialyl Lewis X and sialyl Tn on serum proteins have also displayed their value in cancer diagnosis and management whereby increased levels of these factors positively correlated with metastasis or poor prognosis.
110 citations
TL;DR: In this chapter, the biochemistry and function of glycoprotein, glycan and enzyme markers are reviewed and various enzyme-linked lectin assays (ELLA) have been developed for diagnosis, monitoring and prognosis.
Abstract: Alteration of glycosylation, a hallmark of cancer, results in the production of tumor-associated glycans or glycoproteins. These molecules are subsequently secreted or membrane-shed into the blood stream and thus serve as tumor-associated markers. Increased glycosylation in cancer is triggered by overexpression of glycoproteins that carry certain specific glycans, increase or decrease of nucleotide sugar donors and altered expression of glycosyltransferase and glycosidase enzymes. In this chapter, the biochemistry and function of glycoprotein, glycan and enzyme markers are reviewed. These glycosylation markers, applicable for detection and monitoring of cancer, include CA19-9, CA125, CEA, PSA and AFP. Because of their specific affinity to distinct sugar moieties, lectins are useful for developing assays to detect these tumor associated glycans and glycoproteins in clinical samples. As such, various enzyme-linked lectin assays (ELLA) have been developed for diagnosis, monitoring and prognosis. Because glycosylation changes occur early in cancer, the detection of tumor associated glycosylation markers using lectin based assays is an effective strategy to improve diagnosis and treatment resulting better outcomes clinically.
109 citations
References
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TL;DR: The roles of glycans are 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.
Abstract: 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.
1,920 citations
TL;DR: Current studies further emphasise the critical importance of EMT and provide a better molecular and functional definition of mesenchymal cells and how they emerged >500 million years ago as a key event in evolution.
1,697 citations
"Glycosylation: a hallmark of cancer..." refers background in this paper
...Earlier reports have suggested several classes of receptor tyrosine kinases, including EGFR, Her2-neu, insulin-like growth factor 1 receptor (IGF-1R) and c-Met, which can inhibit Ecadherin–dependent adhesion when they induce epithelialmesenchymal transition (EMT) [83, 84]....
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...CEA Carcinoembryonic antigen ECM Extra cellular matrix EGFR Epidermal growth factor receptor EMT Epithelial mesenchymal transition GDP Guanosine diphosphate IGF Insulin like growth factor FUT Fucosyl transferase MMPs Matrix metalloproteinase MUC Mucin OSCC Oral squamous cell carcinoma SLe Sialyl Lewis ST Sialyltransferase TSA Total sialic acid VEGF Vascular endothelial growth factor...
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...Earlier reports have suggested several classes of receptor tyrosine kinases, including EGFR, Her2-neu, insulin-like growth factor 1 receptor (IGF-1R) and c-Met, which can inhibit Ecadherin–dependent adhesion when they induce epithelialmesenchymal transition (EMT) [83, 84]....
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...Moreover, the ERK1/2 blockade prevents EMT in lung cancer cells and promotes sensitivity to EGFR inhibition [87]....
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TL;DR: This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of M MPIs.
Abstract: Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs.
1,373 citations
"Glycosylation: a hallmark of cancer..." refers background in this paper
...Matrix metalloproteinases (MMPs) are the enzymes which play an important role in metastasis and invasion by proteolytic degradation of extracellular matrix (ECM), disruption of cell-cell and cell matrix adhesion, migration and angiogenesis [65, 66]....
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TL;DR: In addition to their adhesive functions, cell-adhesion molecules modulate signal-transduction pathways by interacting with molecules such as receptor tyrosine kinases, components of the WNT signalling pathway and RHO-family GTPases, which have a crucial role in tumour progression.
Abstract: In addition to their adhesive functions, cell-adhesion molecules modulate signal-transduction pathways by interacting with molecules such as receptor tyrosine kinases, components of the WNT signalling pathway and RHO-family GTPases. So, changes in the expression of cell-adhesion molecules affect not only the adhesive repertoire of a cell, but also its signal-transduction status. Conversely, signalling pathways can modulate the function of cell-adhesion molecules, altering the interactions between cells and their environment. Recent experimental evidence indicates that such processes have a crucial role in tumour progression, in particular during invasion and metastasis.
1,295 citations
TL;DR: The findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models.
Abstract: Epithelia are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are largely unrecognized as effectors of carcinogenesis. However, both types of mucins are intimately involved in inflammation and cancer. Moreover, diverse human malignancies overexpress transmembrane mucins to exploit their role in signalling cell growth and survival. Mucins have thus been identified as markers of adverse prognosis and as attractive therapeutic targets. Notably, the findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models.
1,158 citations
"Glycosylation: a hallmark of cancer..." refers background in this paper
...Phosphorylation of the MUC1-C cytoplasmic domain regulates interactions between MUC1-C and the Wnt pathway effector, β-catenin [94]....
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