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Glioblastomas located in proximity to the subventricular zone (SVZ) exhibited enrichment of gene expression profiles associated with the cancer stem cell state

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Abstract

Introduction

Conflicting results have been reported in the association between glioblastoma proximity to the subventricular zone (SVZ) and enrichment of cancer stem cell properties. Here, we examined this hypothesis using magnetic resonance (MR) images derived from 217 The Cancer Imaging Archive (TCIA) glioblastoma subjects.

Methods

Pre-operative MR images were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Distances were calculated from the centroid of CE tumor volumes to the SVZ and correlated with gene expression profiles of the corresponding glioblastomas. Correlative analyses were performed between SVZ distance, gene expression patterns, and clinical survival.

Results

Glioblastoma located in proximity to the SVZ showed increased mRNA expression patterns associated with the cancer stem-cell state, including CD133 (P = 0.006). Consistent with the previous observations suggesting that glioblastoma stem cells exhibit increased DNA repair capacity, glioblastomas in proximity to the SVZ also showed increased expression of DNA repair genes, including MGMT (P = 0.018). Reflecting this enhanced DNA repair capacity, the genomes of glioblastomas in SVZ proximity harbored fewer single nucleotide polymorphisms relative to those located distant to the SVZ (P = 0.003). Concordant with the notion that glioblastoma stem cells are more aggressive and refractory to therapy, patients with glioblastoma in proximity to SVZ exhibited poorer progression free and overall survival (P < 0.01).

Conclusion

An unbiased analysis of TCIA suggests that glioblastomas located in proximity to the SVZ exhibited mRNA expression profiles associated with stem cell properties, increased DNA repair capacity, and is associated with poor clinical survival.

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References

  1. Ming G-L, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Cowan WM (1979) The development of the brain. Sci Am 241:112–133

    Google Scholar 

  3. Tan X, Shi S-H (2013) Neocortical neurogenesis and neuronal migration. Wiley Interdiscip Rev Dev Biol 2:443–459

    CAS  PubMed  Google Scholar 

  4. Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811–822

    CAS  PubMed  Google Scholar 

  5. Berendsen S, van Bodegraven E, Seute T et al (2019) Adverse prognosis of glioblastoma contacting the subventricular zone: biological correlates. PLoS ONE 14:e0222717

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lim DA, Cha S, Mayo MC et al (2007) Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9:424–429

    PubMed  PubMed Central  Google Scholar 

  7. Young GS, Macklin EA, Setayesh K et al (2011) Longitudinal MRI evidence for decreased survival among periventricular glioblastoma. J Neurooncol 104:261–269

    PubMed  Google Scholar 

  8. Chaichana KL, McGirt MJ, Frazier J et al (2008) Relationship of glioblastoma multiforme to the lateral ventricles predicts survival following tumor resection. J Neurooncol 89:219–224

    PubMed  Google Scholar 

  9. Jafri NF, Clarke JL, Weinberg V et al (2013) Relationship of glioblastoma multiforme to the subventricular zone is associated with survival. Neuro Oncol 15:91–96

    CAS  PubMed  Google Scholar 

  10. Bohman L-E, Swanson KR, Moore JL et al (2010) Magnetic resonance imaging characteristics of glioblastoma multiforme: implications for understanding glioma ontogeny. Neurosurgery 67:1319–1327

    PubMed  PubMed Central  Google Scholar 

  11. Kappadakunnel M, Eskin A, Dong J et al (2010) Stem cell associated gene expression in glioblastoma multiforme: relationship to survival and the subventricular zone. J Neurooncol 96:359–367

    CAS  PubMed  Google Scholar 

  12. Steed TC, Treiber JM, Patel KS et al (2015) Iterative probabilistic voxel labeling: automated segmentation for analysis of The Cancer Imaging Archive glioblastoma images. AJNR Am J Neuroradiol 36:678–685

    CAS  PubMed  Google Scholar 

  13. Brennan CW, Verhaak RGW, McKenna A et al (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Irizarry RA, Hobbs B, Collin F et al (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264

    Google Scholar 

  15. Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform 12:323

    CAS  Google Scholar 

  16. Barbie DA, Tamayo P, Boehm JS et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462:108–112

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gooya A, Pohl KM, Bilello M et al (2012) GLISTR: glioma image segmentation and registration. IEEE Trans Med Imag 31:1941–1954

    Google Scholar 

  18. Tustison NJ, Avants BB, Cook PA et al (2010) N4ITK: improved N3 bias correction. IEEE Trans Med Imag 29:1310–1320

    Google Scholar 

  19. Avants BB, Tustison NJ, Stauffer M et al (2014) The Insight ToolKit image registration framework. Front Neuroinform 8:44

    PubMed  PubMed Central  Google Scholar 

  20. Li J, Taich ZJ, Goyal A et al (2014) Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas. Oncotarget 5:7342–7356

    PubMed  PubMed Central  Google Scholar 

  21. Steed TC, Treiber JM, Patel K et al (2016) Differential localization of glioblastoma subtype: implications on glioblastoma pathogenesis. Oncotarget 7:24899–24907

    PubMed  PubMed Central  Google Scholar 

  22. Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    CAS  PubMed  Google Scholar 

  23. Li Z (2013) CD133: a stem cell biomarker and beyond. Exp Hematol Oncol 2:17

    PubMed  PubMed Central  Google Scholar 

  24. Glumac PM, LeBeau AM (2018) The role of CD133 in cancer: a concise review. Clin Transl Med 7:18

    PubMed  PubMed Central  Google Scholar 

  25. Chalmers AJ (2007) Radioresistant glioma stem cells—therapeutic obstacle or promising target? DNA Repair 6:1391–1394

    CAS  PubMed  Google Scholar 

  26. Wang Y, Zhao G, Yu T (2016) CD133 expression may be useful as a prognostic indicator in glioblastoma multiforme: a meta-analysis. Int J Clin Exp Pathol 9:12407–12414

    CAS  Google Scholar 

  27. Murat A, Migliavacca E, Gorlia T et al (2008) Stem cell-related“ self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26:3015–3024

    CAS  PubMed  Google Scholar 

  28. Kitange GJ, Mladek AC, Carlson BL et al (2012) Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts. Clin Cancer Res 18:4070–4079

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hegi ME, Diserens A-C, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003

    CAS  PubMed  Google Scholar 

  30. Zhang W, Zhang J, Hoadley K et al (2012) miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression. Neuro Oncol 14:712–719

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kushwaha D, Ramakrishnan V, Ng K et al (2014) A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas. Oncotarget 5:4026–4039

    PubMed  PubMed Central  Google Scholar 

  32. Chumakova A, Lathia JD (2018) Outlining involvement of stem cell program in regulation of O6-methylguanine DNA methyltransferase and development of temozolomide resistance in glioblastoma: An Editorial Highlight for “Transcriptional control of O6-methylguanine DNA methyltransferase expression and temozolomide resistance in glioblastoma”on page 780. J Neurochem 144:688–690

    CAS  PubMed  Google Scholar 

  33. Ramakrishnan V, Xu B, Akers J, Nguyen T, Ma J, Dhawan S, Ning J, Mao Y, Hua W, Kokkoli E, Furnari F, Carter BS, Chen CC (2020) Radiation-induced extracellular vesicle (EV) release of miR-603 promotes an insulin-like growth factor (IGF1) signaling induced stem cell state in glioblastomas. EBioMedicine 55:102736

    PubMed  PubMed Central  Google Scholar 

  34. Ramakrishnan V, Kushwaha D, Koay DC et al (2012) Post-transcriptional regulation of O 6-methylguanine-DNA methyltransferase MGMT in glioblastomas. Cancer Biomark 10:185–193

    Google Scholar 

  35. Gaspar N, Marshall L, Perryman L et al (2010) MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase–mediated HOX/stem cell gene signature. Cancer Res 70(22):9243–9252

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Bartkova J, Hamerlik P, Stockhausen M-T et al (2010) Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas. Oncogene 29:5095–5102

    CAS  PubMed  Google Scholar 

  37. Morgan ER, Norman A, Laing K, Seal MD (2017) Treatment and outcomes for glioblastoma in elderly compared with non-elderly patients: a population-based study. Curr Oncol 24:e92–e98

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Noorbakhsh A, Tang JA, Marcus LP et al (2014) Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg 120:31–39

    PubMed  Google Scholar 

  39. Steed TC, Treiber JM, Brandel MG et al (2018) Quantification of glioblastoma mass effect by lateral ventricle displacement. Sci Rep 8:2827

    PubMed  PubMed Central  Google Scholar 

  40. Kerkhof M, Hagenbeek RE, van der Kallen BFW et al (2016) Interobserver variability in the radiological assessment of magnetic resonance imaging (MRI) including perfusion MRI in glioblastoma multiforme. Eur J Neurol 23:1528–1533

    CAS  PubMed  Google Scholar 

  41. Provenzale JM, Ison C, Delong D (2009) Bidimensional measurements in brain tumors: assessment of interobserver variability. AJR Am J Roentgenol 193:W515–W522

    PubMed  Google Scholar 

  42. Aguirre A, Gallo V (2004) Postnatal neurogenesis and gliogenesis in the olfactory bulb from NG2-expressing progenitors of the subventricular zone. J Neurosci 24:10530–10541

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Matarredona ER, Pastor AM (2019) Neural stem cells of the subventricular zone as the origin of human glioblastoma stem cells. Ther Implic Front Oncol 9:779

    Google Scholar 

  44. Heddleston JM, Hitomi M, Venere M et al (2011) Glioma stem cell maintenance: the role of the microenvironment. Curr Pharm Des 17:2386–2401

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hambardzumyan D, Bergers G (2015) Glioblastoma: Defining Tumor Niches. Trends Cancer Res 1:252–265

    Google Scholar 

  46. Doetsch F, Caillé I, Lim DA et al (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716

    CAS  PubMed  Google Scholar 

  47. Evers P, Lee PP, DeMarco J et al (2010) Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma. BMC Cancer 10:384

    PubMed  PubMed Central  Google Scholar 

  48. Gupta T, Nair V, Paul SN et al (2012) Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma? J Neurooncol 109:195–203

    PubMed  Google Scholar 

  49. Lee P, Eppinga W, Lagerwaard F et al (2013) Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis. Int J Radiat Oncol Biol Phys 86:609–615

    PubMed  Google Scholar 

  50. Chen L, Guerrero-Cazares H, Ye X et al (2013) Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection. Int J Radiat Oncol Biol Phys 86:616–622

    PubMed  PubMed Central  Google Scholar 

  51. McDuff SGR, Taich ZJ, Lawson JD et al (2013) Neurocognitive assessment following whole brain radiation therapy and radiosurgery for patients with cerebral metastases. J Neurol Neurosurg Psychiatry 84:1384–1391

    PubMed  Google Scholar 

  52. Zhu Y, Guignard F, Zhao D et al (2005) Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8:119–130

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hambardzumyan D, Amankulor NM, Helmy KY et al (2009) Modeling adult gliomas using RCAS/t-va technology. Transl Oncol 2:89–95

    PubMed  PubMed Central  Google Scholar 

  54. Swanson KR, Bridge C, Murray JD, Alvord EC Jr (2003) Virtual and real brain tumors: using mathematical modeling to quantify glioma growth and invasion. J Neurol Sci 216:1–10

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Emory School of Surgery, Atlanta, GA, USA

    Tyler C. Steed

  2. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA

    Jeffrey M. Treiber

  3. Department of Neurosurgery, University of Minnesota, D429 Mayo Memorial Building, 420 Delaware St. S. E., MMC96, Minneapolis, MN, 55455, USA

    Birra Taha & Clark C. Chen

  4. Division of Medical Genetics, Department of Medicine, University of California, La Jolla, San Diego, CA, USA

    H. Billur Engin & Hannah Carter

  5. Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA, USA

    Kunal S. Patel

  6. Multimodal Imaging Laboratory, University of California San Diego, La Jolla, San Diego, CA, USA

    Anders M. Dale

  7. Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

    Bob S. Carter

  8. Department of Radiology, University of California San Diego, La Jolla, San Diego, CA, USA

    Anders M. Dale

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Correspondence to Clark C. Chen.

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Steed, T.C., Treiber, J.M., Taha, B. et al. Glioblastomas located in proximity to the subventricular zone (SVZ) exhibited enrichment of gene expression profiles associated with the cancer stem cell state. J Neurooncol 148, 455–462 (2020). https://doi.org/10.1007/s11060-020-03550-4

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  • DOI: https://doi.org/10.1007/s11060-020-03550-4