Skip to main content
SpringerLink
Log in
SpringerLink
Log in

In Vitro Models of Brain Cancer

  • Chapter
  • First Online:
Emerging Concepts in Neuro-Oncology

  • 1185 Accesses

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain malignancy in adults. Despite continuing advances in surgical treatment and combined chemoradiotherapy, little improvement in overall median survival has been seen. Therapeutic advances in neuro-oncology are likely to arise through the systematic dissection of the fascinating tumor biology that exists in GBM. If we are to tackle questions such as “What is the cell of origin in brain cancer?” and “How do these cells evade standard treatment methods and ultimately identify the Achilles’ heel of this aggressive disease?” a scientific prerequisite is the availability of a robust and reliable in vitro model of glioma. What follows in this chapter is a discussion of the current state of knowledge in the generation of in vitro models of glioblastoma. Past and current models will be considered with their advantages and shortcomings highlighted. We will discuss the principles of in vitro cytotoxic assays and how translatable therapies emerge from this approach. We discuss the cell of mutation and cell of origin in GBM and how modeling oncogenic transformation can shed new light on this controversial topic. This chapter, we hope, will function as a timeline in the evolution of in vitro models of brain cancer. It illustrates how far we have come in our understanding of brain cancer but additionally highlights the barriers we face and must overcome to ensure that a cure remains within sight.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bigner SH, Mark J, Bigner DD. Chromosomal progression of malignant human gliomas from biopsy to establishment as permanent lines in vitro. Cancer Genet Cytogenet. 1987;24(1):163–76.

    Article  PubMed  CAS  Google Scholar 

  2. Mahesparan R, Read TA, Lund-Johansen M, Skaftnesmo KO, Bjerkvig R, Engebraaten O. Expression of extracellular matrix components in a highly infiltrative in vivo glioma model. Acta Neuropathol. 2003;105(1):49–57.

    PubMed  CAS  Google Scholar 

  3. Engebraaten O, Hjortland GO, Hirschberg H, Fodstad O. Growth of precultured human glioma specimens in nude rat brain. J Neurosurg. 1999;90(1):125–32.

    PubMed  CAS  Google Scholar 

  4. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005;353(8):811–22.

    Article  PubMed  CAS  Google Scholar 

  5. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.

    Article  PubMed  CAS  Google Scholar 

  6. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.

    Article  Google Scholar 

  7. Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci. 1992;12(11):4565–74.

    PubMed  CAS  Google Scholar 

  8. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9(5):391–403.

    Article  PubMed  CAS  Google Scholar 

  9. Günther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S, Soriano R, Modrusan Z, Meissner H, Westphal M, Lamszus K. Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene. 2008;27(20):2897–909.

    Article  PubMed  Google Scholar 

  10. Gritti A, Parati EA, Cova L, Frolichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vescovi AL. Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci. 1996;16(3):1091–100.

    PubMed  CAS  Google Scholar 

  11. Fael Al-Mayhani TM, Ball SL, Zhao JW, Fawcett J, Ichimura K, Collins PV, Watts C. An efficient method for derivation and propagation of glioblastoma cell lines that conserves the molecular profile of their original tumours. J Neurosci Methods. 2009;176(2):192–9.

    Article  PubMed  CAS  Google Scholar 

  12. Kenney-Herbert EM, Ball SL, Al-Mayhani TM, Watts C. Glioblastoma cell lines derived under serum-free conditions can be used as an in vitro model system to evaluate therapeutic response. Cancer Lett. 2011;305(1):50–7.

    Article  PubMed  CAS  Google Scholar 

  13. Bigner SH, Mark J, Bigner DD. Cytogenetics of human brain tumors. Cancer Genet Cytogenet. 1990;47(2):141–54.

    Article  PubMed  CAS  Google Scholar 

  14. De Witt Hamer PC, Van Tilborg AA, Eijk PP, Sminia P, Troost D, Van Noorden CJ, Ylstra B, Leenstra S. The genomic profile of human malignant glioma is altered early in primary cell culture and preserved in spheroids. Oncogene. 2008;27(14):2091–6.

    Article  PubMed  Google Scholar 

  15. Spruck III CH, Gonzalez-Zulueta M, Shibata A, Shimoneau AR, Lin M-F, Gonzales F, Tsai YC, Jones PA. p16 gene in uncultured tumours. Nature. 1994;370:183–4.

    Article  PubMed  Google Scholar 

  16. Hartmann C, Kluwe L, Lücke M, Westphal M. The rate of homozygous CDKN2A/p16 deletions in glioma cell lines and in primary tumors. Int J Oncol. 1999;15(5):975–82.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011–21.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. Wang J, Sakariassen PØ, Tsinkalovsky O, Immervoll H, Bøe SO, Svendsen A, Prestegarden L, Røsland G, Thorsen F, Stuhr L, Molven A, Bjerkvig R, Enger PØ. CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 2008;122(4):761–8.

    Article  PubMed  CAS  Google Scholar 

  21. Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 2008;27(12):1749–58.

    Article  PubMed  CAS  Google Scholar 

  22. Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, De Maria R. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006;13(7):1238–41.

    Article  PubMed  CAS  Google Scholar 

  23. Ghods AJ, Irvin D, Liu G, Yuan X, Abdulkadir IR, Tunici P, Konda B, Wachsmann-Hogiu S, Black KL, Yu JS. Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells. 2007;25(7):1645–53.

    Article  PubMed  CAS  Google Scholar 

  24. Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R, Bayani J, Head R, Lee M, Bernstein M, Squire JA, Smith A, Dirks P. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell. 2009;4(6):568–80.

    Article  PubMed  CAS  Google Scholar 

  25. Ekwall B, Silano V, Paganuzzi-Stammati A, Zucco F. Chap. 7: Toxicity tests with mammalian cell cultures. In: Short-term toxicity tests for non-genotoxic effects. SCOPE. Chichester: Wiley; 1990.

    Google Scholar 

  26. Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K. Chemotherapy wafers for high grade glioma. Cochrane Database Syst Rev. 2011;3: CD007294. doi:10.1002/14651858.CD007294.pub2.

  27. Watts C. CRUK/10/009: GALA-5 TRIAL: an evaluation of the tolerability and feasibility of combining 5-Amino-Levulinic Acid (5-ALA) with carmustine wafers (Gliadel) in the surgical management of primary glioblastoma. http://science.cancerresearchuk.org/research/who-and-what-we-fund/browse-by-location/cambridge/university-of-cambridge/grants/colin-watts-11869-cruk-10-009-gala-5-trial-an-evaluation.

  28. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by ­preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.

    Article  PubMed  CAS  Google Scholar 

  29. Tamura K, Aoyagi M, Wakimoto H, Ando N, Nariai T, Yamamoto M, Ohno K. Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation. J Neurosurg. 2010;113(2):310–8.

    Article  PubMed  Google Scholar 

  30. Mannino M, Chalmers AJ. Radioresistance of glioma stem cells: intrinsic characteristic or property of the ‘microenvironment-stem cell unit’? Mol Oncol. 2011;5(4):374–86.

    Article  PubMed  CAS  Google Scholar 

  31. Schwarz G. UeberDesensibilisierunggegenröntgen- und radiumstrahlen. ­MunchenerMedizinischeWochenschrift. 1909;24:1–2.

    Google Scholar 

  32. Horsman MR, Overgaard J. The oxygen effect and tumour microenvironment. In: Steel G, editor. Basic clinical radiobiology. London: Arnold; 2002. p. 158–68.

    Google Scholar 

  33. Duic JP. NCT00936052. Phase II pilot trial of hyperbaric hyperoxygenation in conjunction with radiotherapy and temozolomide in adults with newly diagnosed glioblastomas. http://clinicaltrials.gov/ct2/show/NCT00936052.

  34. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15(6):501–13.

    Article  PubMed  CAS  Google Scholar 

  35. Guo Z, Kumagai A, Wang SX, Dunphy WG. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev. 2000;14(21):2745–56.

    Article  PubMed  CAS  Google Scholar 

  36. Sørensen CS, Hansen LT, Dziegielewski J, Syljuåsen RG, Lundin C, Bartek J, Helleday T. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol. 2005;7(2):195–201.

    Article  PubMed  Google Scholar 

  37. NCT01115790. A phase 1 study of LY2606368 in patients with advanced cancer. www.clinicaltrials.gov.

  38. Visvader JE. Cells of origin in cancer. Nature. 2011;469(7330):314–22.

    Article  PubMed  CAS  Google Scholar 

  39. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature. 2008;456(7222):593–8.

    Article  PubMed  CAS  Google Scholar 

  40. Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell. 2005;8(2):119–30.

    Article  PubMed  CAS  Google Scholar 

  41. Lindberg N, Kastemar M, Olofsson T, Smits A, Uhrbom L. Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene. 2009;28(23):2266–75.

    Article  PubMed  CAS  Google Scholar 

  42. Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, Foreman O, Bronson RT, Nishiyama A, Luo L, Zong H. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell. 2011;146(2):209–21.

    Article  PubMed  CAS  Google Scholar 

  43. Al-Mayhani MT, Grenfell R, Narita M, Piccirillo S, Kenney-Herbert E, Fawcett JW, et al. NG2 expression in glioblastoma identifies an actively proliferating population with an aggressive molecular signature. Neuro Oncol. 2011;13(8):830–45.

    Article  PubMed  Google Scholar 

  44. Rangarajan A, Weinberg RA. Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer. 2003;3(12):952–9.

    Article  PubMed  CAS  Google Scholar 

  45. Vickerman V, Blundo J, Chung S, Kamm R. Design, fabrication and implementation of a novel multi-parameter control microfluidic platform for three-dimensional cell culture and real-time imaging. Lab Chip. 2008;8(9):1468–77.

    Article  PubMed  CAS  Google Scholar 

  46. Stoppini L, Buchs PA, Muller D. A simple method for organotypic cultures of nervous tissue. J Neurosci Methods. 1991;37(2):173–82.

    Article  PubMed  CAS  Google Scholar 

  47. Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H, Correia AS, Soulet D, Major T, Menon J, Tabar V. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells. 2010;28(6):1019–29.

    Article  PubMed  CAS  Google Scholar 

  48. Levenberg S, Huang NF, Lavik E, Rogers AB, Itskovitz-Eldor J, Langer R. Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Proc Natl Acad Sci USA. 2003;100(22):12741–6.

    Article  PubMed  CAS  Google Scholar 

  49. Cunha C, Panseri S, Villa O, Silva D, Gelain F. 3D culture of adult mouse neural stem cells within functionalized self-assembling peptide scaffolds. Int J Nanomedicine. 2011;6:943–55.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Mouse Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK

    David J. Ryan MB, BCh, BAO, BMedSc, MRCS

  2. Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK

    Colin Watts MBBS, Ph.D. (Cantab), FRCS (SN)

Authors
  1. David J. Ryan MB, BCh, BAO, BMedSc, MRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Colin Watts MBBS, Ph.D. (Cantab), FRCS (SN)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Colin Watts MBBS, Ph.D. (Cantab), FRCS (SN) .

Editor information

Editors and Affiliations

  1. , Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, United Kingdom

    Colin Watts

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag London

About this chapter

Cite this chapter

Ryan, D.J., Watts, C. (2013). In Vitro Models of Brain Cancer. In: Watts, C. (eds) Emerging Concepts in Neuro-Oncology. Springer, London. https://doi.org/10.1007/978-0-85729-458-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-0-85729-458-6_5

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-0-85729-457-9

  • Online ISBN: 978-0-85729-458-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation