Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy

Furukawa, Yoshihiro; Tsuda, Masumi; Okada, Kazue; Kimura, Taichi; Piao, Jinhua; Tanaka, Shinya; Shinohara, Yasuro

doi:10.1371/journal.pone.0128300

Cited by 30 publications

(34 citation statements)

References 47 publications

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“…Activation of the Akt pathway or elevation of HIF-1α also resulted in increased levels of fucosylation and to a greater extent, sialylation. The singular activation of these cancer associated pathways lead to more moderate changes in glycosylation as compared to the intrinsic EMT but are consistent with what others have observed following activation of individual cancer pathways 58 .…”

Section: Discussionsupporting

confidence: 91%

Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation

Mehta

Comunale

Rawat

et al. 2016

Sci Rep

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Alterations in N-linked glycosylation have long been associated with cancer but for the most part, the reasons why have remained poorly understood. Here we show that increased core fucosylation is associated with de-differentiation of primary hepatocytes and with the appearance of markers indicative of a transition of cells from an epithelial to a mesenchymal state. This increase in core fucosylation was associated with increased levels of two enzymes involved in α-1,6 linked fucosylation, GDP-mannose 4, 6-dehydratase (Gmds) and to a lesser extent fucosyltransferase 8 (Fut8). In addition, the activation of cancer-associated cellular signaling pathways in primary rat hepatocytes can increase core fucosylation and induce additional glycoform alterations on hepatocyte proteins. Specifically, we show that increased levels of protein sialylation and α-1,6-linked core fucosylation are observed following activation of the β-catenin pathway. Activation of the Akt signaling pathway or induction of hypoxia also results in increased levels of fucosylation and sialylation. We believe that this knowledge will help in the better understanding of the genetic factors associated with altered glycosylation and may allow for the development of more clinically relevant biomarkers.

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Section: Discussionsupporting

confidence: 91%

Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation

Mehta

Comunale

Rawat

et al. 2016

Sci Rep

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“…These findings imply that there is a functional link between integrin mechanosignalling and the expression of bulky glycoproteins, and further indicate that this mechanism is self-reinforcing. Whether the overall structure and function of the glycocalyx in GBM, which is influenced by the nature of glycosylation, including the level of sialylation, fucosylation, N- or O-linked glycosylation 60,61 , would influence integrin mechanosignalling to alter this relationship, and how, remains unclear. Nevertheless, our observations that increased expression of many of the glycoproteins that enhance glycocalyx bulkiness also induces a mesenchymal, stem-like phenotype in GBM suggests that there is an integrin mechanosignalling-linked glycocalyx-mediated regulatory circuit that, once engaged, drives and sustains this treatment-resistant, tumour-initiating phenotype.…”

Section: Discussionmentioning

confidence: 99%

A tension-mediated glycocalyx–integrin feedback loop promotes mesenchymal-like glioblastoma

et al. 2018

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Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignalling and a bulky glycocalyx, implying a causal link towards a mesenchymal, stem-like phenotype in GBMs. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM.

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“…Such as glycoproteins, glycolipids also change during malignant transformation, and these changes seem to be involved in the molecular mechanisms needed for early and late stages of carcinogenesis [126-128]. These changes are also affected by hypoxia, as demonstrated by Tanaka et al in human colorectal cancer cells (Caco-2) under hypoxic conditions (O 2 1%) for three days [129].…”

Section: Hypoxia Changes Membrane Glycoconjugates In Tumor Cellsmentioning

confidence: 99%

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

Silva-filho¹,

Sena²,

Lima

et al. 2017

Cell Physiol Biochem

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Post-translational and co-translational enzymatic addition of glycans (glycosylation) to proteins, lipids, and other carbohydrates, is a powerful regulator of the molecular machinery involved in cell cycle, adhesion, invasion, and signal transduction, and is usually seen in both in vivo and in vitro cancer models. Glycosyltransferases can alter the glycosylation pattern of normal cells, subsequently leading to the establishment and progression of several diseases, including cancer. Furthermore, a growing amount of research has shown that different oxygen tensions, mainly hypoxia, leads to a markedly altered glycosylation, resulting in altered glycan-receptor interactions. Alteration of intracellular glucose metabolism, from aerobic cellular respiration to anaerobic glycolysis, inhibition of integrin 3α1β translocation to the plasma membrane, decreased 1,2-fucosylation of cell-surface glycans, and galectin overexpression are some consequences of the hypoxic tumor microenvironment. Additionally, increased expression of gangliosides carrying N-glycolyl sialic acid can also be significantly affected by hypoxia. For all these reasons, it is possible to realize that hypoxia strongly alters glycobiologic events within tumors, leading to changes in their behavior. This review aims to analyze the complexity and importance of glycoconjugates and their molecular interaction network in the hypoxic context of many solid tumors.

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Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy

Cited by 30 publications

References 47 publications

Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation

Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation

A tension-mediated glycocalyx–integrin feedback loop promotes mesenchymal-like glioblastoma

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

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