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Isolation of glioma cancer stem cells in relation to histological grades in glioma specimens

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Abstract

Purpose

The existence of cancer stem cells (CSCs) in glioblastoma has been proposed. However, the unknown knowledge that is yet to be revealed is the presence of glioma CSCs (gCSCs) in correlation to each WHO grades of glioma. We approached this study with a hypothesis that specimens from high-grade gliomas would have higher isolation rate of gCSCs in comparison to those of lower-grade gliomas.

Methods

The glioma specimens were obtained from patients and underwent gliomasphere assay. The gliomaspheres were chosen to be analyzed with immunocytochemisty for surface markers. Then the selected gliomaspheres were exposed to neural differentiation conditions. Lastly, we made mouse orthotopic glioma models to examine the capacity of gliomagenesis.

Results

The gliomaspheres were formed in WHO grade IV (13 of 21) and III (two of nine) gliomas. Among them, WHO grade IV (11 of 13) and III (two of two) gliomaspheres showed similar surface markers to gCSCs and were capable of neural differentiation. Lastly, among the chosen cells, 10 of 11 WHO grade IV and two of two WHO grade III gliomaspheres were capable of gliomagenesis. Thus, overall, the rates of existence of gCSCs were more prominent in high-grade gliomas: 47.6 % (10 of 21) in WHO grade IV gliomas and 22.2 % (two of nine) in WHO grade III gliomas, whereas WHO grade II and I gliomas showed virtually no gCSCs.

Conclusions

This trend of stage-by-stage increase of gCSCs in gliomas showed statistical significance by chi-square test linear-by-linear association. We prove that the rates of existence of gCSCs increase proportionally as the WHO grades of gliomas rise.

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References

  1. Adams JM, Strasser A (2008) Is tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Res 68(11):4018–4021

    PubMed  CAS  Google Scholar 

  2. Ajayi A, Yu X, Lindberg S, Langel U, Strom AL (2012) Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible spinocerebellar ataxia type 7 (SCA7) model. BMC Neurosci 13(1):86

    Google Scholar 

  3. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988

    PubMed  CAS  Google Scholar 

  4. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760

    PubMed  CAS  Google Scholar 

  5. Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848

    PubMed  CAS  Google Scholar 

  6. Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP (2007) CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67(9):4010–4015

    PubMed  CAS  Google Scholar 

  7. Bidlingmaier S, Zhu X, Liu B (2008) The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med (Berl) 86(9):1025–1032

    CAS  Google Scholar 

  8. Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67(1):1–5

    PubMed  CAS  Google Scholar 

  9. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737

    PubMed  CAS  Google Scholar 

  10. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951

    PubMed  CAS  Google Scholar 

  11. Dean M (2005) Cancer stem cells: implications for cancer causation and therapy resistance. Discov Med 5(27):278–282

    PubMed  Google Scholar 

  12. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284

    PubMed  CAS  Google Scholar 

  13. Dingli D, Michor F (2006) Successful therapy must eradicate cancer stem cells. Stem Cells 24(12):2603–2610

    PubMed  CAS  Google Scholar 

  14. Dirks PB (2008) Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol 26(17):2916–2924

    PubMed  Google Scholar 

  15. Ehrmann J, Kolar Z, Mokry J (2005) Nestin as a diagnostic and prognostic marker: immunohistochemical analysis of its expression in different tumours. J Clin Pathol 58(2):222–223

    PubMed  CAS  Google Scholar 

  16. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021

    PubMed  CAS  Google Scholar 

  17. Gan PP, Pasquier E, Kavallaris M (2007) Class III beta-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer. Cancer Res 67(19):9356–9363

    PubMed  CAS  Google Scholar 

  18. Ghods AJ, Irvin D, Liu G, Yuan X, Abdulkadir IR, Tunici P, Konda B, Wachsmann-Hogiu S, Black KL, Yu JS (2007) Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells 25(7):1645–1653

    PubMed  CAS  Google Scholar 

  19. Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, Scott EW, Ghivizzani SC, Ignatova TN, Steindler DA (2005) Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 7(11):967–976

    PubMed  CAS  Google Scholar 

  20. Hambardzumyan D, Squatrito M, Holland EC (2006) Radiation resistance and stem-like cells in brain tumors. Cancer Cell 10(6):454–456

    PubMed  CAS  Google Scholar 

  21. Hayatsu N, Kaneko MK, Mishima K, Nishikawa R, Matsutani M, Price JE, Kato Y (2008) Podocalyxin expression in malignant astrocytic tumors. Biochem Biophys Res Commun 374(2):394–398

    PubMed  CAS  Google Scholar 

  22. Hayden EC (2009) Personalized cancer therapy gets closer. Nature 458(7235):131–132

    PubMed  CAS  Google Scholar 

  23. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100(25):15178–15183

    PubMed  CAS  Google Scholar 

  24. Hill RP (2006) Identifying cancer stem cells in solid tumors: case not proven. Cancer Res 66(4):1891–1895, discussion 1890

    PubMed  CAS  Google Scholar 

  25. Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39(3):193–206

    PubMed  Google Scholar 

  26. Kaneko Y, Sakakibara S, Imai T, Suzuki A, Nakamura Y, Sawamoto K, Ogawa Y, Toyama Y, Miyata T, Okano H (2000) Musashi1: an evolutionally conserved marker for CNS progenitor cells including neural stem cells. Dev Neurosci 22(1–2):139–153

    PubMed  CAS  Google Scholar 

  27. Kang SG, Shinojima N, Hossain A, Gumin J, Yong RL, Colman H, Marini F, Andreeff M, Lang FF (2010) Isolation and perivascular localization of mesenchymal stem cells from mouse brain. Neurosurgery 67(3):711–720

    PubMed  Google Scholar 

  28. Kim SM, Kang SG, Park NR, Mok HS, Huh YM, Lee SJ, Jeun SS, Hong YK, Park CK, Lang FF (2011) Presence of glioma stroma mesenchymal stem cells in a murine orthotopic glioma model. Childs Nerv Syst 27(6):911–922

    PubMed  Google Scholar 

  29. Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, Yong WH, Vinters HV, Liau LM, Lazareff JA, Mischel PS, Cloughesy TF, Horvath S, Kornblum HI (2009) Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells 27(4):980–987

    PubMed  Google Scholar 

  30. Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF (2000) An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg 92(2):326–333

    PubMed  CAS  Google Scholar 

  31. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367(6464):645–648

    PubMed  CAS  Google Scholar 

  32. Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60(4):585–595

    PubMed  CAS  Google Scholar 

  33. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037

    PubMed  CAS  Google Scholar 

  34. Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67

    PubMed  Google Scholar 

  35. Long LE, Lind J, Webster M, Shannon Weickert C (2012) Developmental trajectory of the endocannabinoid system in human dorsolateral prefrontal cortex. BMC Neurosci 13(1):87

    Google Scholar 

  36. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109

    PubMed  Google Scholar 

  37. Mangiola A, Lama G, Giannitelli C, De Bonis P, Anile C, Lauriola L, La Torre G, Sabatino G, Maira G, Jhanwar-Uniyal M, Sica G (2007) Stem cell marker nestin and c-Jun NH2-terminal kinases in tumor and peritumor areas of glioblastoma multiforme: possible prognostic implications. Clin Cancer Res 13(23):6970–6977

    PubMed  CAS  Google Scholar 

  38. Mishima K, Kato Y, Kaneko MK, Nishikawa R, Hirose T, Matsutani M (2006) Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression. Acta Neuropathol 111(5):483–488

    PubMed  CAS  Google Scholar 

  39. Mozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, Gallo D, Martinelli E, Ranelletti FO, Ferrandina G, Scambia G (2005) Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res 11(1):298–305

    PubMed  CAS  Google Scholar 

  40. O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    PubMed  Google Scholar 

  41. Panosyan EH, Laks DR, Masterman-Smith M, Mottahedeh J, Yong WH, Cloughesy TF, Lazareff JA, Mischel PS, Moore TB, Kornblum HI (2010) Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation. Pediatr Blood Cancer 55(4):644–651

    Google Scholar 

  42. Piccirillo SG, Binda E, Fiocco R, Vescovi AL, Shah K (2009) Brain cancer stem cells. J Mol Med (Berl) 87(11):1087–1095

    Google Scholar 

  43. Raica M, Cimpean AM, Ribatti D (2008) The role of podoplanin in tumor progression and metastasis. Anticancer Res 28(5B):2997–3006

    PubMed  Google Scholar 

  44. Reynolds BA, Tetzlaff W, Weiss S (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12(11):4565–4574

    PubMed  CAS  Google Scholar 

  45. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255(5052):1707–1710

    PubMed  CAS  Google Scholar 

  46. Reynolds BA, Weiss S (1996) Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175(1):1–13

    PubMed  CAS  Google Scholar 

  47. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115

    PubMed  CAS  Google Scholar 

  48. Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT (2004) CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117(Pt 16):3539–3545

    PubMed  CAS  Google Scholar 

  49. Sakakibara S, Nakamura Y, Yoshida T, Shibata S, Koike M, Takano H, Ueda S, Uchiyama Y, Noda T, Okano H (2002) RNA-binding protein Musashi family: roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation. Proc Natl Acad Sci U S A 99(23):15194–15199

    PubMed  CAS  Google Scholar 

  50. Shibahara J, Kashima T, Kikuchi Y, Kunita A, Fukayama M (2006) Podoplanin is expressed in subsets of tumors of the central nervous system. Virchows Arch 448(4):493–499

    PubMed  CAS  Google Scholar 

  51. Sikora K (2004) Personalized cancer therapy—the key to the future. Pharmacogenomics 5(3):225–228

    PubMed  Google Scholar 

  52. Singec I, Knoth R, Meyer RP, Maciaczyk J, Volk B, Nikkhah G, Frotscher M, Snyder EY (2006) Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology. Nat Methods 3(10):801–806

    PubMed  CAS  Google Scholar 

  53. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828

    PubMed  CAS  Google Scholar 

  54. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401

    PubMed  CAS  Google Scholar 

  55. Stiles CD, Rowitch DH (2008) Glioma stem cells: a midterm exam. Neuron 58(6):832–846

    PubMed  CAS  Google Scholar 

  56. Sulman E, Aldape K, Colman H (2008) Brain tumor stem cells. Curr Probl Cancer 32(3):124–142

    PubMed  Google Scholar 

  57. Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson RJ (2005) Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8(4):323–335

    PubMed  CAS  Google Scholar 

  58. Tommasi S, Mangia A, Lacalamita R, Bellizzi A, Fedele V, Chiriatti A, Thomssen C, Kendzierski N, Latorre A, Lorusso V, Schittulli F, Zito F, Kavallaris M, Paradiso A (2007) Cytoskeleton and paclitaxel sensitivity in breast cancer: the role of beta-tubulins. Int J Cancer 120(10):2078–2085

    PubMed  CAS  Google Scholar 

  59. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A 97(26):14720–14725

    PubMed  CAS  Google Scholar 

  60. Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, Prestegarden L, Rosland G, Thorsen F, Stuhr L, Molven A, Bjerkvig R, Enger PO (2008) CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer 122(4):761–768

    PubMed  CAS  Google Scholar 

  61. Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23(58):9392–9400

    PubMed  CAS  Google Scholar 

  62. Zheng X, Shen G, Yang X, Liu W (2007) Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Res 67(8):3691–3697

    PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2009-0071299 and 2010-0004506) and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020340).

Conflict of interest

The authors declare no potential conflict of interest.

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Authors and Affiliations

  1. Department of Medical Science, The Catholic University of Korea College of Medicine, Seoul, South Korea

    Byung Ho Kong

  2. Department of Neurosurgery, Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, South Korea

    Na-Ri Park, Hye-Jin Shin & Yong-Kil Hong

  3. Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea

    Jin-Kyoung Shim, Bo-Kyung Kim, Ji-Hyun Lee, Eui-Hyun Kim, Eun-Kyung Park, Jong Hee Chang, Dong-Seok Kim, Sun Ho Kim & Seok-Gu Kang

  4. Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Yong-Min Huh

  5. Department of Chemistry, Hanyang University, Seoul, South Korea

    Su-Jae Lee

  6. Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Se-Hoon Kim

  7. Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Frederick F. Lang

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  1. Byung Ho Kong
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  2. Na-Ri Park
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  17. Frederick F. Lang
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Corresponding author

Correspondence to Seok-Gu Kang.

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Byung Ho Kong and Na-Ri Park contributed equally to this manuscript.

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Kong, B.H., Park, NR., Shim, JK. et al. Isolation of glioma cancer stem cells in relation to histological grades in glioma specimens. Childs Nerv Syst 29, 217–229 (2013). https://doi.org/10.1007/s00381-012-1964-9

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