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      Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks

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          Abstract

          Decades of research have disclosed a plethora of alterations in protein glycosylation that decisively impact in all stages of disease and ultimately contribute to more aggressive cell phenotypes. The biosynthesis of cancer-associated glycans and its reflection in the glycoproteome is driven by microenvironmental cues and these events act synergistically toward disease evolution. Such intricate crosstalk provides the molecular foundations for the activation of relevant oncogenic pathways and leads to functional alterations driving invasion and disease dissemination. However, it also provides an important source of relevant glyco(neo)epitopes holding tremendous potential for clinical intervention. Therefore, we highlight the transversal nature of glycans throughout the currently accepted cancer hallmarks, with emphasis on the crosstalk between glycans and the tumor microenvironment stromal components. Focus is also set on the pressing need to include glycans and glycoconjugates in comprehensive panomics models envisaging molecular-based precision medicine capable of improving patient care. We foresee that this may provide the necessary rationale for more comprehensive studies and molecular-based intervention.

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          Most cited references229

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Genes that mediate breast cancer metastasis to the brain.

            The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.
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              Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity

              Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models. Together, our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                14 May 2019
                2019
                : 9
                : 380
                Affiliations
                [1] 1Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology , Porto, Portugal
                [2] 2Institute of Biomedical Sciences Abel Salazar, University of Porto , Porto, Portugal
                [3] 3Tumour and Microenvironment Interactions Group, INEB-Institute for Biomedical Engineering , Porto, Portugal
                [4] 4Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto, Portugal
                [5] 5Department of Surgical Oncology, Portuguese Institute of Oncology , Porto, Portugal
                [6] 6Porto Comprehensive Cancer Center , Porto, Portugal
                Author notes

                Edited by: Leonardo Freire-de-Lima, Federal University of Rio de Janeiro, Brazil

                Reviewed by: Feng Guan, Northwest University, China; Monica M. Burdick, Ohio University, United States

                *Correspondence: José Alexandre Ferreira jose.a.ferreira@ 123456ipoporto.min-saude.pt

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2019.00380
                6530332
                31157165
                e88a977e-ebca-471e-9921-99d441cfe52b
                Copyright © 2019 Peixoto, Relvas-Santos, Azevedo, Santos and Ferreira.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 March 2019
                : 23 April 2019
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 303, Pages: 24, Words: 20248
                Funding
                Funded by: Fundação para a Ciência e a Tecnologia 10.13039/501100001871
                Funded by: European Regional Development Fund 10.13039/501100008530
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                cancer,microenvironment,glycans,protein glycosylation,cancer hallmarks
                Oncology & Radiotherapy
                cancer, microenvironment, glycans, protein glycosylation, cancer hallmarks

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