Skip to main content
SpringerLink
Log in

Glioma Cell Death: Cell–Cell Interactions and Signalling Networks

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The prognosis for patients with malignant gliomas is poor, but improvements may emerge from a better understanding of the pathophysiology of glioma signalling. Recent therapeutic developments have implicated lipid signalling in glioma cell death. Stress signalling in glioma cell death involves mitochondria and endoplasmic reticulum. Lipid mediators also signal via extrinsic pathways in glioma cell proliferation, migration and interaction with endothelial and microglial cells. Glioma cell death and tumour regression have been reported using polyunsaturated fatty acids in animal models, human ex vivo explants, glioma cell preparations and in clinical case reports involving intratumoral infusion. Cell death signalling was associated with generation of reactive oxygen intermediates and mitochondrial and other signalling pathways. In this review, evidence for mitochondrial responses to stress signals, including polyunsaturated fatty acids, peroxidising agents and calcium is presented. Additionally, evidence for interaction of glioma cells with primary brain endothelial cells is described, modulating human glioma peroxidative signalling. Glioma responses to potential therapeutic agents should be analysed in systems reflecting tumour connectivity and CNS structural and functional integrity. Future insights may also be derived from studies of signalling in glioma-derived tumour stem cells.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AA:

arachidonic acid

Akt:

serine–threonine protein kinase

CHOP/GADD153:

CCAAT/enhancer binding protein homologous transcription factor

CNS:

central nervous system

COX:

cyclo-oxygenase

ΔΨm:

transmembrane mitochondrial potential

ER:

endoplasmic reticulum

ERK:

extracellular signal-regulated kinase

GLA:

gamma linolenic acid

GF:

growth factors

GFAP:

glial fibrillary acidic protein

GRP78/BiP:

ER glucose-regulated protein 78

H2O2 :

hydrogen peroxide

iNOS:

inducible nitric oxide synthetase

LO:

lipoxygenase

MEK-1/2:

mitogen-activated protein kinase kinase 1/2

MPT:

mitochondrial permeability transition pore

PARP:

pol(ADP-ribosyl) polymerase

PBR:

peripheral benzodiazepine receptor

PDGF:

platelet-derived growth factor

PDR:

peripheral benzodiazepine receptor

Plase A2:

phospholipase A2

PKAII:

type II protein kinase A

PUFA:

polyunsaturated fatty acids

roi:

reactive oxygen intermediates

TLR:

Toll-like receptor-2

TNF:

tumour necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

roi:

reactive oxygen intermediates

VEGFR:

vascular endothelial cell growth factor receptor

References

  1. Anderson E, Grant R, Lewis SC, Whittle IR (2008) Randomised phase III controlled trials of therapy in malignant glioma: where are we after 40 years? Br J Neurosurg 22:339–349

    Article  CAS  PubMed  Google Scholar 

  2. Colquhoun A (2010) Lipids, mitochondria and cell death: implications in neuro-oncology. Mol Neurobiol special edition Cell Death Signalling. doi:10.1007/s12035-010-8134-4

  3. Piccirillo SGM, Combi R, Cajola L, Patrizi A, Redaelli S, Bentivegna A, Baronchelli S, Maira G, Pollo B, Mangiola A, DiMeco F, Dalprà L, Vescovi AL (2009) Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene 28:1807–1811

    Article  CAS  PubMed  Google Scholar 

  4. Evans SM, Judy KD, Dunphy I, Jenkins WT, Hwang WT, Nelson PT, Lustig RA, Jenkins WT, Hwang WT, Nelson PT, Lustig RA, Jenkins K, Magarelli DP, Hahn SM, Collins RA, Grady MS, Koch CJ (2004) Hypoxia is important in the biology and aggression of human glial brain tumours. Clin Cancer Res 10:8177–8184

    Article  CAS  PubMed  Google Scholar 

  5. Camandola S, Poli G, Mattson MP (2000) Lipid peroxidation product, 4-hydroxy NE, increases AP-1 binding through caspase activity in neurones. J Neurochem 74:159–165

    Article  CAS  PubMed  Google Scholar 

  6. Colquhoun A (2002) GLA alters the composition of mitochondrial subfractions, decreases outer mitochondrial binding of hexokinase and alters carnitine palitoyltransferase I properties in Walker 256 rat tumour. Biochim Biophys Acta 1583:74–84

    CAS  PubMed  Google Scholar 

  7. Coyle JT, Puttfarken P (1993) Oxidative stress, glutamate and neurodegenerative disorders. Science 262:689–695

    Article  CAS  PubMed  Google Scholar 

  8. Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, Edwards MR, Michelsen KS, Kroeger KM, Liu C, Muhammad AKMG, Clark MC, Arditi M, Comin-Anduix B, Ribas A, Lowenstein PR, Castro MG (2009) HMGB1 mediates endogenous TLR2 activation and brain tumour regression. PLoS Med 6:e-1000010

    Article  CAS  Google Scholar 

  9. Falsig J, Markus L, Leist M (2004) Defined inflammatory states in astrocyte cultures: correlation with susceptibility towards CD95-driven apoptosis. J Neurochem 88:181–193

    Article  CAS  PubMed  Google Scholar 

  10. Graeber TG, Osmanian C, Jacks T, Houseman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature; 379:88–91

    Article  CAS  PubMed  Google Scholar 

  11. Higuchi Y, Yoshimoto T (2002) AA converts glutathione depletion into necrosis by promoting lipid peroxidation in rat glioma cells. Arch Biochem Biophys 400:133–140

    Article  CAS  PubMed  Google Scholar 

  12. Jenkins K, Mararelli DP, Hahn SM, Collins RA, Grady MS, Koch CJ (2004) Hypoxia is important in the biology and aggression of human glial brain tumours. Clin Cancer Res 10:8177–8184

    Article  PubMed  Google Scholar 

  13. Jeremias I, Steiner HH, Benner A, Debatin KM, Herold-Mende C (2004) Cell death induction by betulinic acid, ceramide and TRAIL in primary glioblastoma multiforme cells. Acta Neurochir 146:721–729

    Article  CAS  Google Scholar 

  14. Kardosh A, Golden EB, Pyrko P, Uddin J, Hofman FM, Chen TC, Louie SG, Petasis NA, Schönthal AH (2008) Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl–celecoxib. Cancer Res 68:843–851

    Article  CAS  PubMed  Google Scholar 

  15. Keller JN, Mark RJ, Bruce AJ, Blanc E, Rothstein JD, Uchida K, Waeg G, Mattson MP (1997) 4-Hydoxynonetal, an aldehydic product of lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience 80:685–696

    Article  CAS  PubMed  Google Scholar 

  16. Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN. Brain mitochondrial lipid abnormalities in mice susceptible to spontaneous glioma. Lipids;43:951–959

  17. Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, Dostie J, Pyronnet S, Kaufman RJ, Weppler SA, Voncken JW, Lambin P, Koumenis C, Sonenberg N, Bradly G, Wouters BG (2006) Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J 25:1114–1125

    Article  CAS  PubMed  Google Scholar 

  18. Leaver HA, Williams JR, CraiG SR, Gregor A, Ironside JW, Whittle IR, Yap PL (1997) Network analysis of arachidonic acid pathophysiology in human phagocytes and primary brain tumours. Ann NY Acad Sci 832:200–214

    Article  CAS  PubMed  Google Scholar 

  19. Leaver HA, Williams JR, Gregor A, Ironside JW, Miller EP, Su BH, Prescott RJ, Whittle IR (1999) Dynamics of reactive oxygen intermediate production by human brain tumours: n-6 essential fatty acid effects. Eur J Clin Invest 29:220–231

    Article  CAS  PubMed  Google Scholar 

  20. Leaver HA, Williams JR, Smith C, Whittle IR (2004) Intracellular oxidation by human glioma cell populations: effect of arachidonic acid. Prostagl Leukot Essent Fatty Acids 70:449–453

    Article  CAS  Google Scholar 

  21. Lee YW, Ha MS, Kim YK (2001) H2O2-induced cell death in human glioma cells: role of lipid peroxidation and PARP activation. Neurochem Res 26:337–342

    Article  CAS  PubMed  Google Scholar 

  22. Lee WC, Choi CH, Cha SH, Oh HY, Kim YK (2005) Role of ERK in hydrogen peroxide induced cell death in human glioma cells. Neurochem Res 30:263–270

    Article  CAS  PubMed  Google Scholar 

  23. Malagarie-Canenave S, Andrie-Abadie N, Segul B, Gouaze V, Tardy C, Cuvillier O, Levade T (2002) Sphingolipid signalling: molecular basis and role in TNFα signalling. Rev Mol Med 4:1–15

    Google Scholar 

  24. Marangolo M, McGee MM, Tipton KF, Williams DC, Zisterer DM (2009) Oxidative stress induces apoptosis in C6 glioma cells: involvement of MAP kinases and NfκB. Neurotox Res 3:397–409

    Article  Google Scholar 

  25. Renschler MF (2004) The emerging role of reactive oxygen species in cancer therapy. Eur J Cancer 40:1934–1940

    Article  CAS  PubMed  Google Scholar 

  26. Rush GF, Khan S, Bamisaiye G, Bidwell P, Leaver HA, Rizzo MT (2007) c-jun amin-terminal kinase and mitogen activated protein kinase mediate hepatocyte growth factor-induced migration of brain endothelial cells. Exper Cell Res 313:121–132

    Article  CAS  Google Scholar 

  27. Watjen W, Beyersman D (2004) Cadmium induced apoptosis in C6 glioma cells: influence of oxidative stress. Biometals 17:65–78

    Article  PubMed  Google Scholar 

  28. Wu Y, Zhang H, Dong Y, Park YM, Ip C (2005) Endoplasmic reticulum stress signal mediators are targets of selenium action. Cancer Res 65:9073–9079

    Article  CAS  PubMed  Google Scholar 

  29. Yoshida S, Busto R, Watson BD, Santiso M, Ginsberg MD (2006) Postischemic cerebral lipid peroxidation in vitro. J Neurochem 44:1593–1601

    Article  Google Scholar 

  30. Bazán NG (1976) Free arachidonic acid and other lipids in the nervous system during early ischemia and after electroshock. Adv Exp Med Biol 72:317–335

    PubMed  Google Scholar 

  31. Lukiw WJ, Bazan NG (2010) Inflammatory, apoptotic and survival gene signalling in Alzheimer’s disease Mol Neurobiol special edition: Cell Death. doi:10.1007/s12035-010-8126-4

  32. Meves H (2008) Arachidonic acid and ion channels: an update. Br J Pharmacol 155:4–16

    Article  CAS  PubMed  Google Scholar 

  33. Payner T, Leaver HA, Knapp B, Whittle IR, Trifan OC, Miller S, Rizzo MT (2006) Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E2-dependent activation of type II protein kinase A. Mol Cancer Ther 5:1817–1826

    Article  CAS  PubMed  Google Scholar 

  34. Rizzo MT, Pudlo N, Farrell L, Leaver HA (2002) Specificity of arachidonic acid-induced inhibition of growth and activation of c-jun kinases and p38 mitogen-activated protein kinase in hemaptopietic cells. Prostagl, Leucotr Essen Fatty Acids 66:31–40

    Article  CAS  Google Scholar 

  35. Rizzo MT, Leaver HA, Yu WM, Kovacs RJ (1999) Arachidonic acid induces mobilization of calcium stores and c-jun gene expression: evidence that intracellular calcium release is associated with c-jun. Prostagl Leucotr Essen Fatty Acids 60:187–198

    Article  CAS  Google Scholar 

  36. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980

    Article  CAS  PubMed  Google Scholar 

  37. Bell HS, Wharton SB, Leaver HA, Whittle IR (1999) Effects of n-6 essential fatty acids on glioma invasion and growth: experimental studies using human and rodent glioma spheroids in collagen gels. J Neurosurg 91:989–998

    Article  CAS  PubMed  Google Scholar 

  38. Chan PH, Fishman RA (1982) Alterations in membrane integrity and cellular constituents in neuroblastoma and glioma cells. Brain Res 248:151–157

    Article  CAS  PubMed  Google Scholar 

  39. Vartak S, Robbins MEC, Spector AA (1997) Polyunsaturated fatty acids increase the sensitivity of 36B10 rat astrocytoma cells to radiation-induced cell kill. Lipids 32:283–292

    Article  CAS  PubMed  Google Scholar 

  40. Das UN (2004) From the bench to the clinic: GLA therapy of human glioma. Prostaglandins Leukot Essent Fatty Acids 70:539–552

    Article  CAS  PubMed  Google Scholar 

  41. Leaver HA, Bell HS, Rizzo MT, Ironside JW, Gregor A, Wharton S, Whittle IR (2002) Anti-tumour and pro-apoptotic actions of highly unsaturated fatty acids in glioma. Prostaglandins, Leucot Essent Fatty Acids 66:19–29

    Article  CAS  Google Scholar 

  42. Leaver HA, Wharton S, Bell HS, Whittle IR (2002) Highly unsaturated fatty acid induced tumour regression in experimental glioma: pharmacodynamics and bioavailability of a novel anti-tumour agent, gamma linolenic acid, in an implantation glioma model: effects on tumour biomass, apoptosis and normal neuronal tissue. Prostagl, Leucotr Essen Fatty Acids 67:283–292

    Article  CAS  Google Scholar 

  43. Llado V, Gutierrez A, Martinez J, Casas J, Teres S, Higuera M, Galmes A, Saus C, Busquets X, Escriba PV (2008) Minerval induces apoptosis in jurkat and other cancer cells. J Cell Mol Med “postprint”; doi:10.1111/j.1582-4934.2008.00625.x

  44. Serini S, Piccioni E, Merendino N, Calviello G (2009) Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer. Apoptosis 14:135–152

    Article  CAS  PubMed  Google Scholar 

  45. Williams JR, Leaver HA, Ironside JW, Gregor A, Miller EP, Whittle IR (1998) Apoptosis in human gliomas: actions of arachidonic acid. Prostagl, Leucotr Essen Fatty Acids 58:193–200

    Article  CAS  Google Scholar 

  46. Zhang J, Shipston MJ, Brown S (2010) A role for potassium permeability in the recognition, clearance and anti-inflammatory effects of apoptotic cells. Mol Neurobiol: special edition Cell Death Signalling. doi:10.1007/s12035-010-8127-3

  47. Wyllie AH (2010) Where, O Death, Is Thy Sting? A brief review of apoptosis biology, Molecular Neurobiology special edition Cell Death Signalling. doi:10.1007/s12035-010-8125-5

    Google Scholar 

  48. Ordys BB, Launay S, Deighton RF, McCulloch J, Whittle IR (2010) The role of Mitochondria in Glioma pathophysiology. Mol Neurobiol special edition. Cell Death Signalling. doi:10.1007/s12035-010-8133-5

  49. Rizzo MT, Leaver A (2010) Brain endothelial cell death: modes, signalling, pathways and relevance to neural development, homeostasis and disease. Mol Neurobiol special edition Cell Death Signalling. doi:10.1007/s12035-010-8132-6

  50. Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144–148

    Article  CAS  PubMed  Google Scholar 

  51. Michell RH (1975) Inositol lipids and cell surface receptor function. Bichem Biophys Acta 415:81–147

    CAS  Google Scholar 

  52. Jacobson J, Duchen MR (2002) Mitochondrial oxidative stress and cell death in astrocytes—requirement for stored Ca2+ and sustained opening of the permeability pore. J Cell Sci 115:1175–1188

    CAS  PubMed  Google Scholar 

  53. Parnas M, Katz B, Lev S, Tzarfaty V, Dadon D, Shaag G, Metzner H, Yaka R, Minke B (2009) Membrane lipid modulations remove divalent open channel block from TRP-like and NMDA channels. J Neurosci 29:2371–2383

    Article  CAS  PubMed  Google Scholar 

  54. Kerr JFR, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    CAS  PubMed  Google Scholar 

  55. Chang CJ, Hsu CC, Yung MC, Chen KY, Tzao C, Wu WF, Chou HY, Lee YY, Lu KH, Chiou SH, Ma HI (2009) Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression. Biochem Biophys Res Comm 380:236–242

    Article  CAS  PubMed  Google Scholar 

  56. Garcia-Escudero V, Gargini R, Izquierdo M (2008) Glioma regression in vitro and in vivo by a suicide combined treatment. Mol Canc Res 6:407–417

    Article  CAS  Google Scholar 

  57. Horrobin DF (1979) Schizophrenia: reconciliation of the dopamine, prostaglandin, and opioid concepts and the role of the pineal. Lancet 313(8115):529–531

    Article  Google Scholar 

  58. Yacoub A, Gupta P, Park MA, Rhamani M, Hamed H, Hanna D, Zhang G, Sarkar D, Lebedeva IV, Emdad L, Koumenis C, Curiel DT, Grant S, Fisher PB, Dent P (2008) Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. Mol Cancer Ther 7:314–329

    Article  CAS  PubMed  Google Scholar 

  59. Yacoub A, Mitchell C, Hong Y, Gopalkrishnan RV, Su ZZ, Gupta P, Sauane M, Lebedeva IV, Curiel DT, Mahasreshti PJ, Rosenfeld MR, Broaddus WC, James CD, Grant S, Fisher PB, Dent P (2004) MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. Cancer Biol Ther 8:739–751

    Google Scholar 

  60. Ma Y, Yuan R, Fan S, Hu C, Goldberg ID, Laterra JJ, Rosen EM (2006) Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum. Anticancer Drugs 17:733–751

    Article  CAS  PubMed  Google Scholar 

  61. Liao H, Duka T, Teng FYH, Sun L, Bu W, Ahmed S, Tang BL, Xiao Z (2004) Nogo-66 and myelin-associated glycoprotein (MAG) inhibit the adhesion and migration of Nogo-66 receptor expressing human glioma cells. J Neurochem 90:1156–1162

    Article  CAS  PubMed  Google Scholar 

  62. Chelli B, Lena A, Vanacore R, Pozzo E, Costa B, Rossi L, Salvetti A, Scatena F, Ceruti S, Abbracchio MP, Gremigni V, Martini C (2004) Peripheral benzodiazepine receptor ligands: mitochondrial transmembrane potential depolarisation and apoptosis in rat C6 glioma. Biochem Pharmacol 68:125–134

    Article  CAS  PubMed  Google Scholar 

  63. Bell HS, Whittle IR, Walker M, Leaver HA, Wharton SB (2001) Development of necrosis and apoptosis in glioma: experimental findings using spheroid culture systems. Neuropathol Appl Neurobiol 27:291–304

    Article  CAS  PubMed  Google Scholar 

  64. Bian XW, Jiang XF, Chen JH, Bai JS, Dai C, Quing-Liang W, Lu JY, Zhao W, Xin R, Liu MY, Shi JQ, Ji MW (2006) Increased angiogenesis capabilities of endothelial cells from microvessels of malignant human glioma. Int Immunopharm 6:90–99

    Article  CAS  Google Scholar 

  65. Hurst RD, Fritz IB (1996) Properties of an immortalised vascular endothelial/glioma cell co-culture model on the blood–brain barrier. J Cell Physiol 167:81–88

    Article  CAS  PubMed  Google Scholar 

  66. Norden AD, Drappatz J, Wen PY (2008) Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol 7:1152–1160

    Article  CAS  PubMed  Google Scholar 

  67. Zhuang W, Qin Z, Liang Z (2009) The role of autophagy in sensitising malignant glioma cells to radiation therapy. Acta Biochim Biophys Sin 41:341–351

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are very grateful to Amarin Neurosciences and to the Chest, Heart and Stroke Association Scotland for financial support, to Simon Brown (Inflammation Research, University of Edinburgh) for cell imaging facilities and to Ujval Anilkumar, Svitlana Loughridge, Viera Muzola, Sarah Bott and Claire Machin for laboratory project work and to Colin Smith (Pathology, University of Edinburgh) for providing neuro-pathology information.

Author information

Authors and Affiliations

  1. Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK

    H. Anne Leaver & Ian R. Whittle

  2. Cell Biology R&D, SNBTS Edinburgh, 21, Ellen’s Glen Road, Edinburgh, EH17 7QT, UK

    H. Anne Leaver

  3. Signal Transduction Laboratory, Methodist Research Institute, Indianapolis, IA, USA

    Maria Theresa Rizzo

Authors
  1. H. Anne Leaver
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Theresa Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian R. Whittle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Anne Leaver.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leaver, H.A., Rizzo, M.T. & Whittle, I.R. Glioma Cell Death: Cell–Cell Interactions and Signalling Networks. Mol Neurobiol 42, 89–96 (2010). https://doi.org/10.1007/s12035-010-8135-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-010-8135-3

Keyword

Search

Navigation