Skip to main content
SpringerLink
Log in

Hypoxia in Gliomas: Opening Therapeutical Opportunities Using a Mathematical-Based Approach

  • Chapter
  • First Online:
Systems Biology of Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 936))

Abstract

This chapter explores the use of mathematical models as promising and powerful tools to understand the complexity of tumors and their, frequently, hypoxic environment. We focus on gliomas, which are primary brain tumors derived from glial cells, mainly astrocytes and/or oligodendrocytes. A variety of mathematical models, based on ordinary and/or partial differential equations, have been developed both at the micro and macroscopic levels. The aim here is to describe in a quantitative way key physiopathological mechanisms relevant in these types of malignancies and to suggest optimal therapeutical strategies. More specifically, we consider novel therapies targeting thromboembolic phenomena to decrease cell invasion in high grade glioma or to delay the malignant transformation in low grade gliomas. This study has been the basis of a multidisciplinary collaboration involving, among others, neuro-oncologists, radiation oncologists, pathologists, cancer biologists, surgeons and mathematicians.

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
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

Similar content being viewed by others

References

  1. Asghar W, El Assal R, Shafiee H, Pitteri S, Paulmurugan R, Demirci U (2015) Mater Today 18:539–553 [20pt]

    Google Scholar 

  2. Ayuso JM, Basheer HA, Monge R, Sánchez-Álvarez P, Doblaré M, Shnyder SD, Vinader V, Afarinkia K, Fernández LJ, Ochoa I (2015) Study of the chemotactic response of multicellular spheroids in a microfluidic device. PLoS One 10(10):e0139515

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ayuso JM, Monge R, Martínez-González A, Llamazares GA, Berganzo J, Hernández-Laín A, Santolaria J, Doblaré M, Hubert C, Rich JM, Sánchez-Gómez P, Pérez-García VM, Ochoa I, Fernández LJ (2016) Glioblastoma on a microfluidic chip: generating pseudopalisades and enhancing aggressiveness through thrombotic events. Neuro-oncology [20pt]

    Google Scholar 

  4. Badoual M, Gerin C, Deroulers C, Grammaticos B, Llitjos J-F, Oppenheim C, Varlet P (2014) Oedema-based model for diffuse low-grade gliomas: application to clinical cases under radiotherapy. Cell Prolif 47:369–380

    Article  CAS  PubMed  Google Scholar 

  5. Bastida E, Ordinas A, Escolar G, Jamieson GA (1984) Tissue factor in microvesicles shed from U87MG human glioblastoma cells induces coagulation, platelet aggregation, and thrombogenesis. Blood 64:177–184

    CAS  PubMed  Google Scholar 

  6. Batchelor TT, Byrne TN (2006) Supportive care of brain tumor patients. Hematol Oncol Clin North Am 20:1337–1361

    Article  PubMed  Google Scholar 

  7. Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG (2004) Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 36:1046–1069

    Article  CAS  PubMed  Google Scholar 

  8. Bogdanska MU, Bodnar M, Belmonte-Beitia J, Murek M, Schucht P, Beck J, Pérez-García VM (2016, submitted) A mathematical model of low grade gliomas treated with temozolomide and its therapeutical implications. Math Biosci

    Google Scholar 

  9. Brat DJ, Castellano-Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, Devi SN, Kaur B, Van Meir EG (2004) Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 64:920–927

    Article  CAS  PubMed  Google Scholar 

  10. Brat DJ, Van Meir EG (2004) Vaso-occlusive and prothrombotic mechanims associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest 84:397–405

    Article  CAS  PubMed  Google Scholar 

  11. Candolfi M, Curtin JF, Stephen Nichols W, Muhammad AG, King GD, Elizabeth Pluhar G, McNiel EA, Ohlfest JR, Freese AB, Moore PF, Lerner J, Lowenstein PR, Castro MG (2007) Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression. J Neuro-Oncol 85:133–148

    Article  Google Scholar 

  12. Elstner A, Holtkamp N, von Deimling A (2007) Involvement of Hif-1α in desferrioxamine-induced invasion of glioblastoma cells. Clin Exp Metastasis 24:57–66

    Article  CAS  PubMed  Google Scholar 

  13. Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Furie B, Furie BC (2006) Cancer-associated thrombosis. Blood cells Mol Dis 36:177–181

    Article  CAS  PubMed  Google Scholar 

  16. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    Article  CAS  PubMed  Google Scholar 

  17. Gerin C, Pallud J, Grammaticos B, Mandonnet E, Deroulers C, Varlet P, Capelle L, Taillandier L, Bauchet L, Duffau H, Badoual M (2012) Improving the time-machine: estimating date of birth of grade II gliomas. Cell Prolif 45:76–90

    Article  CAS  PubMed  Google Scholar 

  18. Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21:1624–1636

    Article  CAS  PubMed  Google Scholar 

  19. Gillies R, Gatenby R (2007) Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev 26:311–317

    Article  CAS  PubMed  Google Scholar 

  20. Green D, Kwaan HC (2009) Coagulation in cancer. Springer, New York/London

    Google Scholar 

  21. Hamilton MG, Hull RD, Pineo GF (1994) Prophylaxis of venous thromboembolism in brain tumor patients. J Neurooncol 22:111–126

    Article  CAS  PubMed  Google Scholar 

  22. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  23. Hardee ME, Zagzag D (2012) Mechanisms of glioma-associated neovascularization. Am J Pathol 181:1126–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A (2012) “Go or Grow”: the key to the emergence of invasion in tumour progression. Math Med Biol 29:49–65

    Article  CAS  PubMed  Google Scholar 

  25. Horsman MR, Mortensen LS, Petersen JB, Busk M, Overgaard J (2012) Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol 9:674–687

    Article  CAS  PubMed  Google Scholar 

  26. Huse JT, Holland EC (2010) Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer 10:319–331

    Article  CAS  PubMed  Google Scholar 

  27. Jenkins EO, Schiff D, Mackman N, Key NS (2010) Venous thromboembolism in malignant gliomas. J Thromb Haemost 8:221–227

    Article  CAS  PubMed  Google Scholar 

  28. 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 

  29. Joiner M, Van der Kogel A (2009) Basic clinical radiobiology, 4th edn. Hodder Arnold, London [20pt]

    Google Scholar 

  30. Keith B, Johnson RS, Simon MC (2012) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22

    CAS  Google Scholar 

  31. Keunen O, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA 108:3749–3754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Khorana AA, Francis CW (2008) Cancer associated thrombosis: new findings in translational science, prevention, and treatment. Informa Healthcare, New York

    Google Scholar 

  33. Li Z, Xu J, Zhang C, Liu X, Jiang L, Chen F (2013) Mammalian diaphanous-related formin 1 is required for motility and invadopodia formation in human U87 glioblastoma cells. Int J Mol Med 2:383–391

    Google Scholar 

  34. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) World Health Organization classification of tumours of the central nervous system, 4th edn. Renouf Publishing Co. Ltd., Geneva

    Google Scholar 

  35. Martínez-González A, Calvo GF, Pérez Romasanta LA, Pérez-García VM (2012) Hypoxic cell waves around necrotic cores in glioblastoma: a biomathematical model and its therapeutic implications. Bull Math Biol 74:2875–2896

    Article  PubMed  PubMed Central  Google Scholar 

  36. Martínez-González A, Durán-Prado M, Calvo GF, Alcaín FJ, Pérez-Romasanta LA, Pérez-García VM (2015) Combined therapies of antithrombotics and antioxidants delay in silico brain tumour progression. Math Med Biol 32:239–262

    Article  PubMed  Google Scholar 

  37. Onishi M, Ichikawa T, Kurozumi K, Date I (2011) Angiogenesis and invasion in glioma. Brain Tumor Pathol 28:13–24

    Article  CAS  PubMed  Google Scholar 

  38. Pardo R, Martínez-González A, Pérez-García VM (2016) Hypoxic ghost waves accelerates the progression of high-grade gliomas. Commun Nonlinear Sci Numer Simul 39:360–380

    Article  Google Scholar 

  39. Pérez-García VM, Pérez-Romasanta L (2016) Extreme protraction for low-grade gliomas: theoretical proof of concept of a novel therapeutical strategy. Math Med Biol. doi:10.1093/imammb/dqv017

    PubMed  Google Scholar 

  40. Pérez-García VM, Calvo GF, Belmonte-Beitia J, Diego D, Pérez-Romasanta L (2011). Bright solitary waves in malignant gliomas. Phys Rev E 84:021921

    Article  Google Scholar 

  41. Pérez-García VM, Bogdanska M, Martínez-González A, Belmonte-Beitia J, Schucht P, Pérez-Romasanta L (2015) Delay effects in the response of low grade gliomas to radiotherapy: a mathematical model and its therapeutical implications. Math Med Biol 32:307–329

    Article  PubMed  Google Scholar 

  42. Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR, Malkin MG, Sawaya R, Baker R, Falanga A, Parpia S, Finch T, Levine MN (2010) PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 8:1959–1965

    Article  CAS  PubMed  Google Scholar 

  43. Planes A (2003) Review of bemiparin sodium: a new second-generation low molecular weight heparin and its applications in venous thromboembolism. Expert Opin Pharmacother 4:1551–1561

    CAS  PubMed  Google Scholar 

  44. Pope WB, Young JR, Ellingson BM (2011) Advances in MRI assessment of gliomas and response to anti-VEGF therapy. Cur Neurol Neurosci Rep 11: 336–344

    Article  CAS  Google Scholar 

  45. Rahman R, Smith A, Rahman C, Grundy R (2010) Antiangiogenic therapy and mechanisms of tumor resistance in malignant glioma. J Oncol 2010(251231):1–16

    Article  Google Scholar 

  46. Ranalli NJ, Evans SM, Judy KD (2009) Hypoxia in brain tumors: a review of the literature. Neurosurg Quart 19:1–12

    Article  Google Scholar 

  47. Robins H, ONeill A, Gilbert M, Olsen M, Sapiente R, Berkey B, Mehta M (2008) Effect of dalteparin and radiation on survival and thromboembolic events in glioblastoma multiforme: a phase II ECOG trial. Cancer Chemother Pharmacol 62:227–233

    Article  CAS  PubMed  Google Scholar 

  48. Rong Y, Post DE, Pieper RO, Durden DL, Van Meir EG, Brat DJ (2005) PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 65:1406–1413

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  50. Schneider T, Mawrin C, Scherlach C, Skalej M, Firsching R (2010) Gliomas in adults. Deutsches Arzteblatt International 107:799–807

    PubMed  PubMed Central  Google Scholar 

  51. Simanek R, Vormittag R, Hassler M, Roessler K, Schwarz M, Zielinski C, Pabinger I, Marosi C (2007) Venous thromboembolism and survival in patients with high-grade glioma. Neuro-Oncol 9:89–95

    Article  PubMed  PubMed Central  Google Scholar 

  52. Streiff MB, Segal J, Grossman SA, Kickler TS, Weir EG (2004) ABO blood group is a potent risk factor for venous thromboembolism in patients with malignant gliomas. Cancer 100:1717–1723

    Article  PubMed  Google Scholar 

  53. Svensson KJ, Kucharzewska P, Christianson HC, Sköld S, Löfstedt T, Johansson MC, Mörgelin M, Bengzon J, Ruf W, Belting M (2011) Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc Nat Acad Sci 108:13147–13152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Swanson KR, Rostomily RC, Alvord EC Jr (2008) A mathematical modelling tool for predicting survival of individual patients following resection of glioblastoma: a proof of principle. Br J Cancer 98:113–119

    Article  CAS  PubMed  Google Scholar 

  55. Swanson KR, Rockne RC, Claridge J, Chaplain MA, Alvord EC Jr, Anderson AR (2011) Quantifying the role of angiogenesis in malignant progression of gliomas: in silico modeling integrates imaging and histology. Cancer Res 71:7366–7375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410

    Article  CAS  PubMed  Google Scholar 

  57. Wouters A, Pauwels B, Lardon F, Vermorken J (2007) Implications of in vitro research on the effect of radiotherapy and chemotherapy under hypoxic conditions. The Oncologist 12:690–712

    Article  CAS  PubMed  Google Scholar 

  58. Xu X, Farach-Carson MC, Jia X (2014) Three-dimensional in vitro tumor models for cancer research and drug evaluation. Biotechnol Adv 32(7):1256–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Young A, Chapman O, Connor C, Poole C, Rose P, Kakkar AK (2012) Thrombosis and cancer. Nat Rev Clin Oncol 9:437–449

    Article  CAS  PubMed  Google Scholar 

  60. Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL (2000) Expression of hypoxia-inducible factor 1α in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:2606–2618

    Article  CAS  PubMed  Google Scholar 

  61. Zwicker JI, Furie BC, Furie B (2007) Cancer-associated thrombosis. Clin Rev Oncol Hematol 62:126–136

    Article  Google Scholar 

Download references

Acknowledgements

The work of the Mathematical Oncology Laboratory (MôLAB) on the mathematical modelling of the glioma microenvironment and its therapeutical implications is supported by: University of Castilla-La Mancha; Junta de Comunidades de Castilla-La Mancha, Spain (grant number PEII-2014-031-P); Ministerio de Economía y Competitividad/FEDER, Spain (grant numbers: MTM2012-31073 and MTM2015-71200-R); and James S. Mc. Donnell Foundation twenty-first Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (Special Initiative Collaborative-Planning Grant 220020420 and Collaborative award 220020450). We would like to thank the Pathology Department from Hospital General Universitario de Ciudad Real (Spain) for providing some of the histopathological images and to Dr. Marcial García Rojo from the Pathology Department at Hospital de Jerez de la Frontera, (Spain) for helpful discussions.

Author information

Authors and Affiliations

  1. Mathematical Oncology Laboratory (MôLAB), University of Castilla-La Mancha, Castilla-La Mancha, Spain

    Alicia Martı́nez-González, Gabriel F. Calvo & Víctor M. Pérez-García

  2. Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain

    Jose M. Ayuso, Ignacio Ochoa & Luis J. Fernández

Authors
  1. Alicia Martı́nez-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriel F. Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jose M. Ayuso
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ignacio Ochoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis J. Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Víctor M. Pérez-García
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Víctor M. Pérez-García .

Editor information

Editors and Affiliations

  1. H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA

    Katarzyna A. Rejniak

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Martı́nez-González, A., Calvo, G.F., Ayuso, J.M., Ochoa, I., Fernández, L.J., Pérez-García, V.M. (2016). Hypoxia in Gliomas: Opening Therapeutical Opportunities Using a Mathematical-Based Approach. In: Rejniak, K. (eds) Systems Biology of Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 936. Springer, Cham. https://doi.org/10.1007/978-3-319-42023-3_2

Download citation

Publish with us

Policies and ethics

Search

Navigation