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      Glioblastoma Multiforme Therapy and Mechanisms of Resistance

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          Abstract

          Glioblastoma multiforme (GBM) is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only provides patients with a 12–14 month survival period post-diagnosis. Long-term survival for GBM patients remains uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy.

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          A restricted cell population propagates glioblastoma growth following chemotherapy

          Jian Chen, Yanjiao Li, Tzong-Shiue Yu … (2012)
          Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, with a median survival of about one year 1 . This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal. Precisely how recurrence occurs is unknown. Using a genetically-engineered mouse model of glioma, we identify a subset of endogenous tumor cells that are the source of new tumor cells after the drug, temozolomide (TMZ), is administered to transiently arrest tumor growth. A Nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumor cells. Upon arrest of tumor cell proliferation with TMZ, pulse-chase experiments demonstrate a tumor re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumor growth and combined TMZ-ganciclovir treatment impeded tumor development. These data indicate the existence of a relatively quiescent subset of endogenous glioma cells that are responsible for sustaining long-term tumor growth through the production of transient populations of highly proliferative cells.
          Article 0 comments Cited 840 times – based on 0 reviews     Review now
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            Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.

            Kyle B. Reynolds, Thomas S. Weiss (1992)
            Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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              Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.

              Lin Lin Cheng, Zhi Huang, Wenchao Zhou … (2013)
              Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy. Copyright © 2013 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 333 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmaceuticals (Basel)
                Journal ID (iso-abbrev): Pharmaceuticals (Basel)
                Journal ID (publisher-id): pharmaceuticals
                Title: Pharmaceuticals
                Publisher: MDPI
                ISSN (Electronic): 1424-8247
                Publication date (Electronic): 25 November 2013
                Publication date Collection: December 2013
                Volume: 6
                Issue: 12
                Pages: 1475-1506
                Affiliations
                [1 ]Department of Biochemistry and Molecular Pharmacology and Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA; E-Mails: Yulian.Ramirez@ 123456umassmed.edu (Y.P.R.); Jessica.Weatherbee@ 123456umassmed.edu (J.L.W.)
                [2 ]School of Pharmacy, University of Bradford, Bradford BD7 1DP, UK; E-Mail: r.t.wheelhouse@ 123456bradford.ac.uk
                Author notes
                [†]

                These authors contributed equally to works.

                [* ] Author to whom correspondence should be addressed; E-Mail: Alonzo.Ross@ 123456umassmed.edu ; Tel.: +1-508-856-8016; Fax: +1-508-856-2003.
                Article
                Publisher ID: pharmaceuticals-06-01475
                DOI: 10.3390/ph6121475
                PMC ID: 3873674
                PubMed ID: 24287492
                SO-VID: 2a2f3bd0-dae7-4848-a9df-4b5c6513723e
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 11 September 2013
                Date revision received : 04 November 2013
                Date accepted : 12 November 2013
                Categories
                Subject: Review

                Keywords: angiogenesis,autophagy,imidazotetrazine,mgmt,dna repair,temozolomide,cancer stem cells
                Data availability:
                Keywords: angiogenesis, autophagy, imidazotetrazine, mgmt, dna repair, temozolomide, cancer stem cells

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