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      Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

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          Abstract

          The current clinical care of glioblastomas leaves behind invasive, radio‐ and chemo‐resistant cells. We recently identified mammary‐derived growth inhibitor ( MDGI/ FABP3 ) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient‐derived glioma cells via lysosomal membrane permeabilization ( LMP). In a preclinical model, treatment of glioma‐bearing mice with an antihistaminergic LMP‐inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re‐positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo‐resistant glioma cells from sustaining disease progression and recurrence.

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          Most cited references52

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          European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas.

          The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
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            Brain tumour cells interconnect to a functional and resistant network.

            Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
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              Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy.

              The PI3K/Akt signal transduction cascade has been investigated extensively for its roles in oncogenic transformation. Initial studies implicated both PI3K and Akt in prevention of apoptosis. However, more recent evidence has also associated this pathway with regulation of cell cycle progression. Uncovering the signaling network spanning from extracellular environment to the nucleus should illuminate biochemical events contributing to malignant transformation. Here, we discuss PI3K/Akt-mediated signal transduction including its mechanisms of activation, signal transducing molecules, and effects on gene expression that contribute to tumorigenesis. Effects of PI3K/Akt signaling on important proteins controlling cellular proliferation are emphasized. These targets include cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors. Furthermore, strategies used to inhibit the PI3K/Akt pathway are presented. The potential for cancer treatment with agents inhibiting this pathway is also addressed.
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                Author and article information

                Contributors
                Pirjo.laakkonen@helsinki.fi
                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                08 May 2019
                June 2019
                : 11
                : 6 ( doiID: 10.1002/emmm.v11.6 )
                : e9034
                Affiliations
                [ 1 ] Translational Cancer Medicine Research Program Faculty of Medicine University of Helsinki Helsinki Finland
                [ 2 ] Helsinki University Lipidomics Unit Helsinki Institute of Life Science (HiLIFE) and Molecular and Integrative Biosciences Research Programme University of Helsinki Helsinki Finland
                [ 3 ] Research Programs Unit Genome‐Scale Biology University of Helsinki Helsinki Finland
                [ 4 ] Department of Microbiology, Tumour and Cell Biology (MTC) Karolinska Institutet Stockholm Sweden
                [ 5 ] Department of Neurology and Brain Tumour Center University Hospital Zurich and University of Zurich Zurich Switzerland
                [ 6 ] Department of Oncology Helsinki University Hospital Helsinki Finland
                [ 7 ] Department of Pathology Haartman Institute University of Helsinki and HUSLAB Helsinki Finland
                [ 8 ] Kuopio University Hospital Kuopio Finland
                [ 9 ] Laboratory Animal Centre Helsinki Institute of Life Science (HiLIFE) University of Helsinki Helsinki Finland
                Author notes
                [*] [* ]Corresponding author. Tel: +358 2 941 58100; Fax: +358 9 19125510; E‐mail: Pirjo.laakkonen@ 123456helsinki.fi
                [†]

                These authors contributed equally to this work

                Author information
                https://orcid.org/0000-0001-8153-8563
                https://orcid.org/0000-0002-9620-095X
                Article
                EMMM201809034
                10.15252/emmm.201809034
                6554674
                31068339
                b8a79e35-6934-47a1-8a57-6906b95e1d6d
                © 2019 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 February 2018
                : 03 April 2019
                : 05 April 2019
                Page count
                Figures: 11, Tables: 1, Pages: 21, Words: 15311
                Funding
                Funded by: Ida Montin
                Funded by: Oskar Öflunds Stiftelse
                Funded by: K. Albin Johanssons Stiftelse
                Funded by: Finnish Cancer Organizations
                Funded by: Jane & Aatos Erkko Foundation
                Funded by: Sigrid Juselius Foundation
                Funded by: Doctoral Programme of Biomedicine, University of Helsinki
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                emmm201809034
                June 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:07.06.2019

                Molecular medicine
                antihistamine,glioma,lmp,mdgi,pufa,cancer
                Molecular medicine
                antihistamine, glioma, lmp, mdgi, pufa, cancer

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