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      A restricted cell population propagates glioblastoma growth following chemotherapy

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          Abstract

          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.

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          Most cited references15

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          Adult hippocampal neurogenesis buffers stress responses and depressive behavior

          Summary Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness 1, 2 . In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis 3 . Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking 4, 5 . Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioral components of the stress response. Using transgenic and radiation methods to specifically inhibit adult neurogenesis, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice compared with intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis 6, 7 . Relative to controls, neurogenesis-deficient mice showed increased food avoidance in a novel environment after acute stress, increased behavioral despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.
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            Human Melanoma Initiating Cells Express Neural Crest Nerve Growth Factor Receptor CD271

            The question whether tumorigenic cancer stem cells exist in human melanomas has arisen recently1. Here we show that in melanomas, tumor stem cells (MTSC) can be isolated prospectively as a highly enriched CD271+ MTSC population using a process that maximizes viable cell transplantation1,6. In this study the tumors sampled were taken from a broad spectrum of sites and stages. High viability FACS isolated cells resuspended in a matrigel vehicle were implanted into T, B, and NK deficient Rag2−/− γc−/− mice (RG) mice. The CD271+ subset of cells was the tumor initiating population in 9/10 melanomas tested. Transplantation of isolated melanoma cells into engrafted human skin or bone in RG mice resulted in melanoma from CD271+ but not CD271− cells. We also showed that tumors transplanted by CD271+ patient cells were capable of metastasis in-vivo. Importantly, CD271+ melanoma cells lacked expression of TYR, MART and MAGE in 86%, 69% and 68% of melanoma patients respectively suggesting why T cell therapies directed at these antigens usually result in only temporary tumor shrinkage.
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              Mosaic analysis with double markers reveals tumor cell of origin in glioma.

              Cancer cell of origin is difficult to identify by analyzing cells within terminal stage tumors, whose identity could be concealed by the acquired plasticity. Thus, an ideal approach to identify the cell of origin is to analyze proliferative abnormalities in distinct lineages prior to malignancy. Here, we use mosaic analysis with double markers (MADM) in mice to model gliomagenesis by initiating concurrent p53/Nf1 mutations sporadically in neural stem cells (NSCs). Surprisingly, MADM-based lineage tracing revealed significant aberrant growth prior to malignancy only in oligodendrocyte precursor cells (OPCs), but not in any other NSC-derived lineages or NSCs themselves. Upon tumor formation, phenotypic and transcriptome analyses of tumor cells revealed salient OPC features. Finally, introducing the same p53/Nf1 mutations directly into OPCs consistently led to gliomagenesis. Our findings suggest OPCs as the cell of origin in this model, even when initial mutations occur in NSCs, and highlight the importance of analyzing premalignant stages to identify the cancer cell of origin. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                17 July 2012
                23 August 2012
                22 February 2013
                : 488
                : 7412
                : 522-526
                Affiliations
                [1 ]Department of Developmental Biology & Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA
                [2 ]Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
                [3 ]Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
                Author notes
                [* ]Correspondence: Luis F. Parada, Ph.D. luis.parada@ 123456utsouthwestern.edu , Tel: 214-648-1822, Fax: 214-648-1960
                [4]

                Present address: Department of Pathology and Cell Biology, Columbia University, New York, NY

                Article
                NIHMS383720
                10.1038/nature11287
                3427400
                22854781
                6a66a3ff-f402-4ed4-a09c-900667880eaf

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA131313 || CA
                Categories
                Article

                Uncategorized
                tumor hierarchy,cancer stem cells,cell ablation,glioma,ganciclovir
                Uncategorized
                tumor hierarchy, cancer stem cells, cell ablation, glioma, ganciclovir

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