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Transforming growth factor-β and stem cell markers are highly expressed around necrotic areas in glioblastoma

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Abstract

Invasion into surrounding normal brain and resistance to genotoxic therapies are the main devastating aspects of glioblastoma (GBM). These biological features may be associated with the stem cell phenotype, which can be induced through a dedifferentiation process known as epithelial-mesenchymal transition (EMT). We show here that tumor cells around pseudopalisading necrotic areas in human GBM tissues highly express the most important EMT inducer, transforming growth factor (TGF-β), concurrently with the EMT-related transcriptional factor, TWIST. In addition, the stem cell markers CD133 and alkaline phosphatase (ALPL) were also highly expressed around necrotic foci in GBM tissues. The high expression of TGF-β around necrotic regions was significantly correlated with shorter progression-free survival and overall survival in patients with GBM. High expression of stem cell markers, ALPL, CD133, and CD44 was also correlated with poor outcomes. These results collectively support the hypothesis that tissue hypoxia induces the stem cell phenotype through TGF-β-related EMT and contributes to the poor outcome of GBM patients.

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References

  1. Aldape K, Zadeh G, von Deimling A et al (2015) Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol 129:829–848

    Article  CAS  PubMed  Google Scholar 

  2. Liu C, Sage JC, Miller MR et al (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146:209–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Iwadate Y, Sakaida T, Hiwasa T et al (2004) Molecular classification and survival prediction in human gliomas based on proteome analysis. Cancer Res 64:2496–2501

    Article  CAS  PubMed  Google Scholar 

  4. Phillips HS, Kharbanda S, Chen R et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173

    Article  CAS  PubMed  Google Scholar 

  5. Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zarkoob H, Taube JH, Singh SK, Mani SA, Kohandel M (2013) Investigating the link between molecular subtype of glioblastoma, epithelial- mesenchymal transition, and CD133 cell surface protein. PLoS One 8:e64169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN (2009) The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8:3274–3284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cooper LAD, Gutman DA, Chisolm C et al (2012) The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. Am J Path. 180:2108–2118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Charles NA, Holland EC, Gilbertson R et al (2011) The brain tumor microenvironment. Glia. 59:1169–1180

    Article  PubMed  Google Scholar 

  10. Jensen RL (2009) Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol 92:317–335

    Article  CAS  PubMed  Google Scholar 

  11. Mani SA, Guo W, Liao M-J et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760

    Article  CAS  PubMed  Google Scholar 

  13. Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K et al (2013) Mesenchymal differentiation mediated by NF-kB promotes radiation resistance in glioblastoma. Cancer Cell 24:331–346

    Article  CAS  PubMed  Google Scholar 

  14. Zhang X, Zhang W, Mao XG, Zhen HN, Cao WD, Hu SJ (2013) Targeting role of glioma stem cells for glioblastoma multiforme. Curr Med Chem 20:1974–1984

    Article  CAS  PubMed  Google Scholar 

  15. Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay 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

    Article  CAS  PubMed  Google Scholar 

  16. Ye X-Z, Xu S-L, Xin Y-H et al (2012) Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol 189:444–453

    Article  CAS  PubMed  Google Scholar 

  17. Piao Y, Liang J, Holmes L et al (2012) Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro-Oncology 14:1379–1392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zeisberg M, Neilson EG (2009) Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119:1429–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mikheeva SA, Mikheev AM, Petit A et al (2010) Twist1 promotes invasion through mesenchymal change in human glioblastoma. Mol Cancer. 9:194

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shinojima N, Hossain A, Takezaki T et al (2012) TGF-β mediated homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells. Cancer Res 73:2333–2344

    Article  Google Scholar 

  22. Kahlert UD, Nikkhah G, Maciaczyk J (2013) Epithelial-to-mesenchymal (-like) transition as a relevant molecular event in malignant gliomas. Cancer Let. 33:131–138

    Article  Google Scholar 

  23. Rong Y, Durden DL, Van Meir EG et al (2006) ‘Pseudopalisading’ necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropath Exp Neurol 65:529–539

    Article  PubMed  Google Scholar 

  24. Bruna A, Darken RS, Rojo F et al (2007) High TGFβ-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cnacer Cell 11:147–160

    Article  CAS  Google Scholar 

  25. Theys J, Jutten B, Habets R et al (2011) E-cadherin loss associated with EMT promotes radioresistance in human tumor cells. Radioth Oncol 99:392–397

    Article  CAS  Google Scholar 

  26. Meng J, Li P, Zhang Q et al (2014) A radiosensitivity gene signature in predicting glioma prognostic via EMT pathway. Oncotarget 5:4683–4693

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hardee ME, Marciscano AE, Medina-Ramirez CM et al (2012) Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β. Cancer Res 72:4119–4129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim Y-H, Yoo K-C, Cui Y-H et al (2014) Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization. Cancer Lett 354:132–141

    Article  CAS  PubMed  Google Scholar 

  29. Zhou YC, Liu JY, Li J et al (2011) Ionizing radiation promotes migration and invasion of cancer cells through transforming growth factor-beta-mediated epithelial- mesenchymal transition. Int J Radiat Oncol Biol Phys 81:1530–1537

    Article  CAS  PubMed  Google Scholar 

  30. Zhang M, Kleber S, Rohrich M et al (2011) Blockade of TGF-beta signaling by the TGFbetaR-1 kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res 71:7155–7167

    Article  CAS  PubMed  Google Scholar 

  31. Timke C, Zieher H, Roth A et al (2008) Combination of vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibition markedly improve radiation tumor therapy. Clin Cancer Res 14:2210–2219

    Article  CAS  PubMed  Google Scholar 

  32. Mahabir R, Tanino M, Elmansuri A et al (2014) Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma. Neuro-Oncology 16:671–685

    Article  CAS  PubMed  Google Scholar 

  33. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  CAS  PubMed  Google Scholar 

  34. Bar EE, Lin A, Mahairaki V, Matsui W, Eberhart CG (2010) Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol 177:1491–1502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Evans SM, Judy KD, Dunphy I et al (2004) Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res 10:8177–8184

  36. Li Z, Bao S, Wu Q et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kaur B, Khwaja FW, Severson EA et al (2005) Hypoxia and hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7:134–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shahrzad S, Bertrand K, Minhas K, Coomber BL (2007) Induction of DNA hypomethylation by tumor hypoxia. Epigenetics 2:119–129

    Article  PubMed  Google Scholar 

  39. Skowronki K, Andrews J, Rodenhiser DI, Coomber BL (2014) Genome-wide analysis in human colorectal cancer cells reveals ischemia-mediated expression of motility genes via DNA hypomethylation. PlosOne 9: e103243

  40. Schonberg DL, Lubelski D, Miller TE, Rich JN (2014) Brain tumor stem cells: molecular characteristics and their impact on therapy. Mol Aspects Med 39:82–101

    Article  CAS  PubMed  Google Scholar 

  41. Bechnan J, Isakson P, Joel M et al (2014) Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells 32:1110–1123

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Neurological Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-2870, Japan

    Yasuo Iwadate, Tomoo Matsutani, Seiichiro Hirono, Natsuki Shinozaki & Naokatsu Saeki

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  1. Yasuo Iwadate
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  2. Tomoo Matsutani
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  3. Seiichiro Hirono
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  4. Natsuki Shinozaki
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  5. Naokatsu Saeki
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Correspondence to Yasuo Iwadate.

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Iwadate, Y., Matsutani, T., Hirono, S. et al. Transforming growth factor-β and stem cell markers are highly expressed around necrotic areas in glioblastoma. J Neurooncol 129, 101–107 (2016). https://doi.org/10.1007/s11060-016-2145-6

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  • DOI: https://doi.org/10.1007/s11060-016-2145-6

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