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Effect of Notch expression in glioma stem cells on therapeutic response to chemo-radiotherapy in recurrent glioblastoma

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Abstract

Glioma stem cells (GSCs) have the capacity to repopulate tumors and mediate resistance to radiotherapy and chemotherapy. The Notch signaling pathway is important in proliferation, stem cell maintenance, cell differentiation, and tumorigenesis in GSCs. In this study, we compared CD133, Notch, and VEGF expressions in histological sections of primary and recurrent glioblastomas after radiotherapy and chemotherapy. In vitro study, the γ-secretase inhibitor inhibited NICD, Hes1 and pVEGFR2 expressions in GSCs. GSCs cultured under endothelial conditions undergo endothelial differentiation. Tumor samples were collected from 27 patients at the time of tumor recurrence. We used immunohistochemical techniques to compare expression of CD133, Notch-1 and VEGF. Expressions of CD133-, Notch-1-, and VEGF-positive glioma cells were higher in recurrent glioblastoma after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy followed by a second surgery at recurrence. OS was significantly longer in cases with Notch-1 negativity (8.8 months) than in those with I Notch-1 positivity (6.8 months). We noted that GSCs have the potential for endothelial differentiation with Notch activity. We believe that Notch-1 is a potential target and/or biomarker for antiangiogenic treatments.

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References

  1. Chang SM, Theodosopoulos P, Lamborn K et al (2004) Temozolomide in the treatment of recurrent malignant glioma. Cancer 100:605–611

    Article  CAS  PubMed  Google Scholar 

  2. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    Article  CAS  PubMed  Google Scholar 

  3. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  4. Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  CAS  PubMed  Google Scholar 

  5. Kondo T, Setoguchi T, Taga T (2004) Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 101:781–786

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Ikushima H, Todo T, Ino Y et al (2010) Glioma-initiating cells retain their tumorigenicity through integration of the Sox axis and Oct4 protein. J Biol Chem 286:41434–41441

    Article  Google Scholar 

  7. 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 

  8. Liu G, Yuan X, Zeng Z et al (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67

    Article  PubMed Central  PubMed  Google Scholar 

  9. Wurmser AE, Nakashima K, Summers RG et al (2004) Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430:350–356

    Article  CAS  PubMed  Google Scholar 

  10. Bao S, Wu Q, Sathornsumetee S et al (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848

    Article  CAS  PubMed  Google Scholar 

  11. Folkins C, Shaked Y, Man S et al (2009) Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res 69:7243–7251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Calabrese C, Poppleton H, Kocak M et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82

    Article  CAS  PubMed  Google Scholar 

  13. Gilbertson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nature Rev Cancer 7:733–736

    Article  CAS  Google Scholar 

  14. Lathia JD, Gallagher J, Heddleston JM et al (2010) Integrin α6 regulates glioblastoma stem cells. Cell Stem Cell 6:421–432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16:633–647

    Article  CAS  PubMed  Google Scholar 

  17. Kageyama R, Ohtsuka T (1999) The Notch-Hes pathway in mammalian neural development. Cell Res 9:179–188

    Article  CAS  PubMed  Google Scholar 

  18. Kanamori M, Kawaguchi T, Nigro JM et al (2007) Contribution of Notch signaling activation to human glioblastoma multiforme. J Neurosurg 106:417–427

    Article  PubMed  Google Scholar 

  19. Purow BW, Haque RM, Noel MW et al (2005) Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res 65:2353–2363

    Article  CAS  PubMed  Google Scholar 

  20. Zhu TS, Costello MA, Talsma CE et al (2011) Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res 71:6061–6072

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Wang J, Wakeman TP, Lathia JD et al (2010) Notch promotes radioresistance of glioma stem cells. Stem Cells 28:17–28

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Fan X, Khaki L, Zhu TS et al (2010) Notch pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28:5–16

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Gilbert CA, Daou MC, Moser RP et al (2010) Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence. Cancer Res 70:6870–6879

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Saito N, Fu J, Zheng S et al (2014) A high Notch pathway activation predicts response to γ secretase inhibitors in proneural subtype of glioma tumor-initiating cells. Stem Cells 32:301–312

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Koul D, Jasser SA, Lu Y et al (2002) Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity. Oncogene 21:2357–2364

    Article  CAS  PubMed  Google Scholar 

  26. Bao S, Wu Q, Li Z et al (2008) Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res 68:6043–6048

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Reedijk M, Odorcic S, Zhang H et al (2008) Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol 33:1223–1229

    PubMed Central  PubMed  Google Scholar 

  28. Liu S, Breit S, Danckwardt S et al (2009) Downregulation of Notch signaling by gamma-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines. Ann Hematol 88:613–621

    Article  CAS  PubMed  Google Scholar 

  29. Watters JW, Cheng C, Majumder PK et al (2009) De novo discovery of a gamma-secretase inhibitor response signature using a novel in vivo breast tumor model. Cancer Res 69:8949–8957

    Article  CAS  PubMed  Google Scholar 

  30. Kageyama R, Ohtsuka T, Hatakeyama J et al (2005) Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 306:343–348

    Article  CAS  PubMed  Google Scholar 

  31. Hatakeyama J, Sakamoto S, Kageyama R (2006) Hes1 and Hes5 regulate the development of the cranial and spinal nerve systems. Dev Neurosci 28:92–101

    Article  CAS  PubMed  Google Scholar 

  32. Fan X, Mikolaenko I, Elhassan I et al (2004) Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res 64:7787–7793

    Article  CAS  PubMed  Google Scholar 

  33. Nandhu MS, Hu B, Cole SE et al (2014) Novel paracrine modulation of Notch-DLL4 signaling by fibulin-3 promotes angiogenesis in high-grade gliomas. Cancer Res 74:5435–5448

    Article  CAS  PubMed  Google Scholar 

  34. Patenaude A, Fuller M, Chang L et al (2014) Endothelial-specific Notch blockade inhibits vascular function and tumor growth through an eNOS-dependent mechanism. Cancer Res 74:2402–2411

    Article  CAS  PubMed  Google Scholar 

  35. Ricci-Vitiani L, Pallini R, Biffoni M et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828

    Article  CAS  PubMed  Google Scholar 

  36. Bhat KP, Salazar KL, Balasubramaniyan V et al (2011) The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25:2594–2609

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Chinot OL, Wick W, Mason W et al (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722

    Article  CAS  PubMed  Google Scholar 

  38. Gilbert MR, Dignam JJ, Armstrong TS et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355:1253–1261

    Article  CAS  PubMed  Google Scholar 

  40. Reya T, Morrison SJ, Clarke MF et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  CAS  PubMed  Google Scholar 

  41. Baumann M, Krause M, Hill R et al (2008) Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545–554

    Article  CAS  PubMed  Google Scholar 

  42. Phillips TM, McBride WH, Pajonk F et al (2006) The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777–1785

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Toho University Ohashi Medical Center, 2-17-6, Ohashi, Meguro, Tokyo, Japan

    Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Junya Iwama, Yu Hiramoto, Masashi Ishii, Kenichiro Sato, Haruo Nakayama, Junichi Harashina, Morito Hayashi, Hideaki Izukura, Hitoshi Kimura, Keisuke Ito, Takatoshi Sakurai & Satoshi Iwabuchi

  2. Department of Pathology, Toho University Ohashi Medical Center, Tokyo, Japan

    Yuki Yokouchi, Toshiaki Oharazeki & Kei Takahashi

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  1. Norihiko Saito
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  2. Kazuya Aoki
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  3. Nozomi Hirai
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Correspondence to Norihiko Saito.

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Saito, N., Aoki, K., Hirai, N. et al. Effect of Notch expression in glioma stem cells on therapeutic response to chemo-radiotherapy in recurrent glioblastoma. Brain Tumor Pathol 32, 176–183 (2015). https://doi.org/10.1007/s10014-015-0215-7

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  • DOI: https://doi.org/10.1007/s10014-015-0215-7

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