Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications

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  • 1 Department of Neurosurgery,
  • 2 Medical Scientist Training Program, and
  • 3 Comprehensive Cancer Center, University of Alabama at Birmingham, Alabama
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Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.

ABBREVIATIONS CIMP− = CpG island methylator phenotype negative; CIMP+ = CIMP positive; EGFR = epidermal growth factor receptor; GBM = glioblastoma; GSC = glioma stem cell; IDH = isocitrate dehydrogenase; ITH = intratumoral heterogeneity; NSC = neural stem cell; SVZ = subventricular zone.

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Contributor Notes

Correspondence Ichiro Nakano: University of Alabama at Birmingham, AL. inakano@uabmc.edu.

INCLUDE WHEN CITING Published online August 23, 2019; DOI: 10.3171/2019.5.JNS19364.

J.D.B. and J.H.M. contributed equally to this work.

Disclosures Dr. Bernstock hold positions and equity in Avidea Technologies and CITC Ltd. He is a member of the Board of Scientific Advisors for POCKiT Diagnostics.

  • 1

    Albert G, Wassef S, Dahdaleh NS, Lindley T, Bruch L, Hitchon P: Intracranial glioblastoma with drop metastases to the spine after stereotactic biopsy. J Neurol Surg A Cent Eur Neurosurg 74 (Suppl 1):e221e224, 2013 (Erratum in J Neurol Surg A Cent Eur Neurosurg 74 [Suppl 1]:e284, 2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Alcantara Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, : Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15:4556, 2009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Aubry M, de Tayrac M, Etcheverry A, Clavreul A, Saikali S, Menei P, : From the core to beyond the margin: a genomic picture of glioblastoma intratumor heterogeneity. Oncotarget 6:1209412109, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, : Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756760, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Barajas RF Jr, Hodgson JG, Chang JS, Vandenberg SR, Yeh RF, Parsa AT, : Glioblastoma multiforme regional genetic and cellular expression patterns: influence on anatomic and physiologic imaging. Radiology 254:564576, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Bernstock JD, Ye D, Gessler FA, Lee YJ, Peruzzotti-Jametti L, Baumgarten P, : Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming. Sci Rep 7:7425, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, : Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell 24:331346, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Bhat KPL, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, : The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25:25942609, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Bogoslovsky T, Bernstock JD, Bull G, Gouty S, Cox BM, Hallenbeck JM, : Development of a systems-based in situ multiplex biomarker screening approach for the assessment of immunopathology and neural tissue plasticity in male rats after traumatic brain injury. J Neurosci Res 96:487500, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, : Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:16271639, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, : Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123135, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, : The somatic genomic landscape of glioblastoma. Cell 155:462477, 2013

  • 13

    Capdevila C, Rodríguez Vázquez L, Martí J: Glioblastoma multiforme and adult neurogenesis in the ventricular-subventricular zone: a review. J Cell Physiol 232:15961601, 2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Chaudhry H Jr, Goenka A: Subventricular zone (SVZ) radiation dose and outcomes in patients with glioblastoma multiforme (GBM). Int J Radiat Oncol Biol Phys 102 (3 Suppl):e195, 2018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Cosset É, Ilmjärv S, Dutoit V, Elliott K, von Schalscha T, Camargo MF, : Glut3 addiction is a druggable vulnerability for a molecularly defined subpopulation of glioblastoma. Cancer Cell 32:856868.e5, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Czepko R, Kwinta B, Adamek D, Uhl H, Betlej M, Lopatka P: [Multiple cerebral glioma or tumor dissemination via CSF pathways? Case report.] Neurol Neurochir Pol 37:13071315, 2003 (Polish)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Darmanis S, Sloan SA, Croote D, Mignardi M, Chernikova S, Samghababi P, : Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Reports 21:13991410, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    deCarvalho AC, Kim H, Poisson LM, Winn ME, Mueller C, Cherba D, : Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat Genet 50:708717, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Du B, Shim JS: Targeting epithelial-mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules 21:E965, 2016

  • 20

    Flavahan WA, Wu Q, Hitomi M, Rahim N, Kim Y, Sloan AE, : Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci 16:13731382, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Francis JM, Zhang CZ, Maire CL, Jung J, Manzo VE, Adalsteinsson VA, : EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 4:956971, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Gill BJ, Pisapia DJ, Malone HR, Goldstein H, Lei L, Sonabend A, : MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc Natl Acad Sci U S A 111:1255012555, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Goffart N, Kroonen J, Di Valentin E, Dedobbeleer M, Denne A, Martinive P, : Adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling. Neuro Oncol 17:8194, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Ho IAW, Shim WSN: Contribution of the microenvironmental niche to glioblastoma heterogeneity. BioMed Res Int 2017:9634172, 2017

  • 25

    Hu LS, Ning S, Eschbacher JM, Baxter LC, Gaw N, Ranjbar S, : Radiogenomics to characterize regional genetic heterogeneity in glioblastoma. Neuro Oncol 19:128137, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Jamal M, Rath BH, Tsang PS, Camphausen K, Tofilon PJ: The brain microenvironment preferentially enhances the radioresistance of CD133+ glioblastoma stem-like cells. Neoplasia 14:150158, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Jin X, Kim LJY, Wu Q, Wallace LC, Prager BC, Sanvoranart T, : Targeting glioma stem cells through combined BMI1 and EZH2 inhibition. Nat Med 23:13521361, 2017

  • 28

    Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, : Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189193, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Kathagen A, Schulte A, Balcke G, Phillips HS, Martens T, Matschke J, : Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells. Acta Neuropathol 126:763780, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Kim H, Zheng S, Amini SS, Virk SM, Mikkelsen T, Brat DJ, : Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution. Genome Res 25:316327, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, : Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:2334, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN: Cancer stem cells in glioblastoma. Genes Dev 29:12031217, 2015

  • 33

    Lee JH, Lee JE, Kahng JY, Kim SH, Park JS, Yoon SJ, : Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560:243247, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Lee JK, Wang J, Sa JK, Ladewig E, Lee HO, Lee IH, : Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet 49:594599, 2017

  • 35

    Lehtinen MK, Zappaterra MW, Chen X, Yang YJ, Hill AD, Lun M, : The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69:893905, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, : Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501513, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Lombard A, Goffart N, Rogister B: Glioblastoma circulating cells: reality, trap or illusion? Stem Cells Int 2015:182985, 2015

  • 38

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, : The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131:803820, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, : IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474478, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Lu F, Chen Y, Zhao C, Wang H, He D, Xu L, : Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma. Cancer Cell 29:669683, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Mao H, Lebrun DG, Yang J, Zhu VF, Li M: Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Invest 30:4856, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, : Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci U S A 110:86448649, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Mazor T, Pankov A, Johnson BE, Hong C, Hamilton EG, Bell RJA, : DNA methylation and somatic mutations converge on the cell cycle and define similar evolutionary histories in brain tumors. Cancer Cell 28:307317, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Miller AM, Shah RH, Pentsova EI, Pourmaleki M, Briggs S, Distefano N, : Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 565:654658, 2019

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Minata M, Audia A, Shi J, Lu S, Bernstock J, Pavlyukov MS, : Phenotypic plasticity of invasive edge glioma stem-like cells in response to ionizing radiation. Cell Reports 26:18931905.e7, 2019

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Nakano I: Stem cell signature in glioblastoma: therapeutic development for a moving target. J Neurosurg 122:324330, 2015

  • 47

    Nathanson DA, Gini B, Mottahedeh J, Visnyei K, Koga T, Gomez G, : Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343:7276, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Nishioka H, Saito F, Haraoka J, Miwa T: [Glioblastoma of the cerebellum: report of an autopsy case associated with intratumoral hemorrhage and CSF seedings.] No Shinkei Geka 19:547552, 1991 (Japanese)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Ohgaki H, Kleihues P: Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100:22352241, 2009

  • 50

    Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, : Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol 20:674686, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Parker NR, Hudson AL, Khong P, Parkinson JF, Dwight T, Ikin RJ, : Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma. Sci Rep 6:22477, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Parsons DW, Jones S, Zhang X, Lin JCH, Leary RJ, Angenendt P, : An integrated genomic analysis of human glioblastoma multiforme. Science 321:18071812, 2008

  • 53

    Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, : Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344:13961401, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Pelloski CE, Mahajan A, Maor M, Chang EL, Woo S, Gilbert M, : YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res 11:33263334, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, : Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157173, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Qazi MA, Vora P, Venugopal C, Sidhu SS, Moffat J, Swanton C, : Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma. Ann Oncol 28:14481456, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Sadahiro H, Kang KD, Gibson JT, Minata M, Yu H, Shi J, : Activation of the receptor tyrosine kinase AXL regulates the immune microenvironment in glioblastoma. Cancer Res 78:30023013, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Sanai N, Tramontin AD, Quiñones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, : Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740744, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Sciacovelli M, Frezza C: Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J 284:31323144, 2017

  • 60

    Smith AW, Mehta MP, Wernicke AG: Neural stem cells, the subventricular zone and radiotherapy: implications for treating glioblastoma. J Neurooncol 128:207216, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, : Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A 110:40094014, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, : Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287290, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, : Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987996, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64

    Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, : Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425437, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, : Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci U S A 109:30413046, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, : Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98110, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Villa GR, Hulce JJ, Zanca C, Bi J, Ikegami S, Cahill GL, : An LXR-cholesterol axis creates a metabolic co-dependency for brain cancers. Cancer Cell 30:683693, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68

    Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, : Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res 20:52905301, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Wang J, Cazzato E, Ladewig E, Frattini V, Rosenbloom DI, Zairis S, : Clonal evolution of glioblastoma under therapy. Nat Genet 48:768776, 2016

  • 70

    Watts C, Piccirillo SG: Clonal diversity in glioblastoma: is it clinically relevant? Future Oncol 11:17031706, 2015 (Erratum in Future Oncol 11:2851, 2015)

  • 71

    Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, : Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375384, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, : Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol 18:13731385, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73

    Wen PY, Kesari S: Malignant gliomas in adults. N Engl J Med 359:492507, 2008

  • 74

    Xu H, Rahimpour S, Nesvick CL, Zhang X, Ma J, Zhang M, : Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy. Oncotarget 6:1188211893, 2015

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, : Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 86:343349, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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