Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic dormancy to delay postsurgical glioma recurrence: the past, present and promise of focal hypothermia

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Surgery precedes both radiotherapy and chemotherapy as the first-line therapy for glioma. However, despite multimodal treatment, most glioma patients die from local recurrence in the resection margin. Glioma surgery is inherently lesional, and the response of brain tissue to surgery includes hemostasis, angiogenesis, reactive gliosis and inflammation. Unfortunately, these processes are also associated with tumorigenic side-effects. An increasing amount of evidence indicates that the response to a surgery-related brain injury is hijacked by residual glioma cells and participates in the local regeneration of tumor tissues at the resection margin. Inducing therapeutic hypothermia in the brain has long been used to treat the secondary damage, such as neuroinflammation and edema, that are caused by accidental traumatic brain injuries. There is compelling evidence to suggest that inducing therapeutic hypothermia at the resection margin would delay the local recurrence of glioma by (i) limiting cell proliferation, (ii) disrupting the pathological connection between inflammation and glioma recurrence, and (iii) limiting the consequences of the functional heterogeneity and complexity inherent to the tumor ecosystem. While the global whole-body cooling methods that are currently used to treat stroke in clinical practice may not adequately treat the resection margin, the future lies in implantable focal microcooling devices similar to those under development for the treatment of epilepsy. Preclinical and clinical strategies to evaluate focal hypothermia must be implemented to prevent glioma recurrence in the resection margin. Placing the resection margin in a state of hibernation may potentially provide such a long-awaited therapeutic breakthrough.

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

Similar content being viewed by others

References

  1. Hamard L, Ratel D, Selek L et al (2016) The brain tissue response to surgical injury and its possible contribution to glioma recurrence. J Neurooncol 128:1–8. doi:10.1007/s11060-016-2096-y

    Article  CAS  PubMed  Google Scholar 

  2. Ratel D, van der Sanden B, Wion D (2016) Glioma resection and tumor recurrence: back to Semmelweis. Neuro-Oncology 18:1688–1689. doi:10.1093/neuonc/now201

    Article  PubMed  Google Scholar 

  3. Deelman HT (1927) The part played by injury and repair in the development of cancer. Br Med J 1:872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fisher B, Fisher ER (1959) Experimental evidence in support of the dormant tumor cell. Science 130:918–919

    Article  CAS  PubMed  Google Scholar 

  5. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. doi:10.1016/j.cell.2010.01.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kuraishy A, Karin M, Grivennikov SI (2011) Tumor promotion via injury- and death-induced inflammation. Immunity 35:467–477. doi:10.1016/j.immuni.2011.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grivennikov SI, Karin M (2010) Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 20:65–71. doi:10.1016/j.gde.2009.11.004

    Article  CAS  PubMed  Google Scholar 

  8. Grivennikov SI, Karin M (2010) Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21:11–19. doi:10.1016/j.cytogfr.2009.11.005

    Article  CAS  PubMed  Google Scholar 

  9. Coffey JC, Wang JH, Smith MJF et al (2003) Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol 4:760–768

    Article  CAS  PubMed  Google Scholar 

  10. Demicheli R, Retsky MW, Hrushesky WJM et al (2008) The effects of surgery on tumor growth: a century of investigations. Ann Oncol 19:1821–1828. doi:10.1093/annonc/mdn386

    Article  CAS  PubMed  Google Scholar 

  11. Hingtgen S, Figueiredo J-L, Farrar C et al (2013) Real-time multi-modality imaging of glioblastoma tumor resection and recurrence. J Neurooncol 111:153–161. doi:10.1007/s11060-012-1008-z

    Article  PubMed  Google Scholar 

  12. Zhu H, Leiss L, Yang N et al (2017) Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking immunotherapy. Oncotarget. doi:10.18632/oncotarget.14553

    Google Scholar 

  13. Tabatabaei P, Visse E, Bergström P et al (2016) Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study. J Neurooncol. doi:10.1007/s11060-016-2271-1

    PubMed  PubMed Central  Google Scholar 

  14. Zhou W, Jiang Z, Li X et al (2015) Cytokines: shifting the balance between glioma cells and tumor microenvironment after irradiation. J Cancer Res Clin Oncol 141:575–589. doi:10.1007/s00432-014-1772-6

    Article  CAS  PubMed  Google Scholar 

  15. Vlashi E, Pajonk F (2015) Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol 31:28–35. doi:10.1016/j.semcancer.2014.07.001

    Article  CAS  PubMed  Google Scholar 

  16. Auffinger B, Tobias AL, Han Y et al (2014) Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death Differ 21:1119–1131. doi:10.1038/cdd.2014.31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hellweg CE (2015) The Nuclear Factor κB pathway: A link to the immune system in the radiation response. Cancer Lett 368:275–289. doi:10.1016/j.canlet.2015.02.019

    Article  CAS  PubMed  Google Scholar 

  18. Barcellos-Hoff MH, Park C, Wright EG (2005) Radiation and the microenvironment–tumorigenesis and therapy. Nat Rev Cancer 5:867–875. doi:10.1038/nrc1735

    Article  CAS  PubMed  Google Scholar 

  19. Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19:20–27. doi:10.1038/nn.4185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Predina J, Eruslanov E, Judy B et al (2013) Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc Natl Acad Sci USA 110:E415–E424. doi:10.1073/pnas.1211850110

    Article  CAS  PubMed  Google Scholar 

  21. Tazzyman S, Niaz H, Murdoch C (2013) Neutrophil-mediated tumour angiogenesis: subversion of immune responses to promote tumour growth. Semin Cancer Biol 23:149–158. doi:10.1016/j.semcancer.2013.02.003

    Article  CAS  PubMed  Google Scholar 

  22. Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274. doi:10.1038/nrc1586

    Article  CAS  PubMed  Google Scholar 

  23. Karnatovskaia LV, Wartenberg KE, Freeman WD (2014) Therapeutic hypothermia for neuroprotection: history, mechanisms, risks, and clinical applications. The Neurohospitalist 4:153–163. doi:10.1177/1941874413519802

    Article  PubMed  PubMed Central  Google Scholar 

  24. Polderman KH (2004) Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: indications and evidence. Intensive Care Med 30:556–575. doi:10.1007/s00134-003-2152-x

    Article  PubMed  Google Scholar 

  25. Gage AA, Baust JM, Baust JG (2009) Experimental cryosurgery investigations in vivo. Cryobiology 59:229–243. doi:10.1016/j.cryobiol.2009.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dietrich WD, Bramlett HM (2016) Therapeutic hypothermia and targeted temperature management in traumatic brain injury: clinical challenges for successful translation. Brain Res 1640:94–103. doi:10.1016/j.brainres.2015.12.034

    Article  CAS  PubMed  Google Scholar 

  27. Talma N, Kok WF, de Veij Mestdagh CF et al (2016) Neuroprotective hypothermia—why keep your head cool during ischemia and reperfusion. Biochim Biophys Acta 1860:2521–2528. doi:10.1016/j.bbagen.2016.07.024

    Article  CAS  PubMed  Google Scholar 

  28. de Groot J, Sontheimer H (2011) Glutamate and the biology of gliomas. Glia 59:1181–1189. doi:10.1002/glia.21113

    Article  PubMed  Google Scholar 

  29. Horiguchi T, Shimizu K, Ogino M et al (2003) Postischemic hypothermia inhibits the generation of hydroxyl radical following transient forebrain ischemia in rats. J Neurotrauma 20:511–520. doi:10.1089/089771503765355577

    Article  PubMed  Google Scholar 

  30. Yenari MA, Han HS (2006) Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFκB). Neurochem Int 49:164–169. doi:10.1016/j.neuint.2006.03.016

    Article  CAS  PubMed  Google Scholar 

  31. Wang GJ, Deng HY, Maier CM et al (2002) Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience 114:1081–1090

    Article  CAS  PubMed  Google Scholar 

  32. Han HS, Karabiyikoglu M, Kelly S et al (2003) Mild hypothermia inhibits nuclear factor-κB translocation in experimental stroke. J Cereb Blood Flow Metab 23:589–598. doi:10.1097/01.WCB.0000059566.39780.8D

    Article  CAS  PubMed  Google Scholar 

  33. Webster CM, Kelly S, Koike MA et al (2009) Inflammation and NFκB activation is decreased by hypothermia following global cerebral ischemia. Neurobiol Dis 33:301–312. doi:10.1016/j.nbd.2008.11.001

    Article  CAS  PubMed  Google Scholar 

  34. Messmer MN, Kokolus KM, Eng JW-L et al (2014) Mild cold-stress depresses immune responses: implications for cancer models involving laboratory mice. Bioessays 36:884–891. doi:10.1002/bies.201400066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Michelson N, Rincon-Torroella J, Quiñones-Hinojosa A, Greenfield JP (2016) Exploring the role of inflammation in the malignant transformation of low-grade gliomas. J Neuroimmunol 297:132–140. doi:10.1016/j.jneuroim.2016.05.019

    Article  CAS  PubMed  Google Scholar 

  36. Tong G, Endersfelder S, Rosenthal L-M et al (2013) Effects of moderate and deep hypothermia on RNA-binding proteins RBM3 and CIRP expressions in murine hippocampal brain slices. Brain Res 1504:74–84. doi:10.1016/j.brainres.2013.01.041

    Article  CAS  PubMed  Google Scholar 

  37. Kalamida D, Karagounis IV, Mitrakas A et al (2015) Fever-range hyperthermia vs. hypothermia effect on cancer cell viability, proliferation and HSP90 expression. PloS ONE 10:e0116021. doi:10.1371/journal.pone.0116021

    Article  PubMed  PubMed Central  Google Scholar 

  38. Matijasevic Z (2002) Selective protection of non-cancer cells by hypothermia. Anticancer Res 22:3267–3272

    PubMed  Google Scholar 

  39. Lyman CP, Fawcett DW (1954) The effect of hibernation on the growth of sarcoma in the hamster. Cancer Res 14:25–28

    CAS  PubMed  Google Scholar 

  40. Popovic VP, Masironi R (1966) Effect of generalized hypothermia on normothermic tumors. Am J Physiol 211:462–466

    CAS  PubMed  Google Scholar 

  41. Sano ME, Smith LW (1940) A critical histopathologic study. Fifty post-mortem patients with cancer subjected to local or generalized refrigeration compared to a similar control group of 37 nonrefrigerated patients. J Lab Clin Med 26:443–456. doi:10.5555/uri:pii:S0022214340900014

    Google Scholar 

  42. Smith LW, Fay T (1940) Observations on human beings with cancer, maintained at reduced temperatures of 75°–90° Fahrenheit. Am J Clin Pathol 10:1–11. doi:10.1093/ajcp/10.1.1

    Article  CAS  Google Scholar 

  43. Popovic VP, Masironi R (1966) Disappearance of normothermic tumors in shallow (30 °C) hypothermia. Cancer Res 26:863–864

    CAS  PubMed  Google Scholar 

  44. Fay T (1959) Early experiences with local and generalized refrigeration of the human brain. J Neurosurg 16:239–259. doi:10.3171/jns.1959.16.3.0239

    Article  CAS  PubMed  Google Scholar 

  45. Fay T, Smith GW (1941) Observations On Reflex Responses During Prolonged Periods Of Human Refrigeration. Arch Neurol Psychiatry 45:215–222. doi:10.1001/archneurpsyc.1941.02280140025002

    Article  Google Scholar 

  46. Kristiansen K, Krog J, Lund I (1960) Experiences with selective cooling of the brain. Acta Chir Scand Suppl 253:151–161

    PubMed  Google Scholar 

  47. Marshall M, Hankinson J, Leslie WG (1964) An Extracorporeal Circuit For Unilateral Brain Perfusion And Cooling. Br J Surg 51:701–703

    Article  CAS  PubMed  Google Scholar 

  48. Rowbotham GF, Haigh AL, Leslie WG (1959) Cooling cannula for use in the treatment of cerebral neoplasms. The Lancet 1:12–15

    Article  CAS  Google Scholar 

  49. Berger RL (1990) Nazi science—the Dachau hypothermia experiments. N Engl J Med 322:1435–1440. doi:10.1056/NEJM199005173222006

    Article  CAS  PubMed  Google Scholar 

  50. Shankaran S, Laptook AR, Ehrenkranz RA et al (2005) Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353:1574–1584. doi:10.1056/NEJMcps050929

    Article  CAS  PubMed  Google Scholar 

  51. Azzopardi D, Strohm B, Marlow N et al (2014) Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 371:140–149. doi:10.1056/NEJMoa1315788

    Article  CAS  PubMed  Google Scholar 

  52. Holzer M (2010) Targeted temperature management for comatose survivors of cardiac arrest. N Engl J Med 363:1256–1264. doi:10.1056/NEJMct1002402

    Article  CAS  PubMed  Google Scholar 

  53. Chen J, Liu L, Zhang H et al (2016) Endovascular hypothermia in acute ischemic stroke: pilot study of selective intra-arterial cold saline infusion. Stroke 47:1933–1935. doi:10.1161/STROKEAHA.116.012727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Smyth MD, Rothman SM (2011) Focal cooling devices for the surgical treatment of epilepsy. Neurosurg Clin N Am 22(533–546):vii. doi:10.1016/j.nec.2011.07.011

    Google Scholar 

  55. D’Ambrosio R, Eastman CL, Darvas F et al (2013) Mild passive focal cooling prevents epileptic seizures after head injury in rats. Ann Neurol 73:199–209. doi:10.1002/ana.23764

    Article  PubMed  Google Scholar 

  56. Fujii M, Inoue T, Nomura S et al (2012) Cooling of the epileptic focus suppresses seizures with minimal influence on neurologic functions. Epilepsia 53:485–493. doi:10.1111/j.1528-1167.2011.03388.x

    Article  PubMed  Google Scholar 

  57. Smyth MD, Han RH, Yarbrough CK et al (2015) Temperatures achieved in human and canine neocortex during intraoperative passive or active focal cooling. Ther Hypothermia Temp Manag 5:95–103. doi:10.1089/ther.2014.0025

    Article  PubMed  PubMed Central  Google Scholar 

  58. Bakken HE, Kawasaki H, Oya H et al (2003) A device for cooling localized regions of human cerebral cortex. Technical note. J Neurosurg 99:604–608. doi:10.3171/jns.2003.99.3.0604

    Article  PubMed  Google Scholar 

  59. Lyubynskaya T, Osorio I, Kochemasov G et al (2007) Implantable brain microcooler for the closed-loop system of epileptic seizure prevention. In: 11th Mediterranean Conference on Medical Biomedical Engineering and Computing 2007. Springer Berlin Heidelberg, pp 911–914

  60. Tanaka N, Fujii M, Imoto H et al (2008) Effective suppression of hippocampal seizures in rats by direct hippocampal cooling with a Peltier chip. J Neurosurg 108:791–797. doi:10.3171/JNS/2008/108/4/0791

    Article  PubMed  Google Scholar 

  61. Rothman SM (2009) The therapeutic potential of focal cooling for neocortical epilepsy. Neurotherapeutics 6:251–257. doi:10.1016/j.nurt.2008.12.002

    Article  PubMed  PubMed Central  Google Scholar 

  62. Benabid AL, Chabardes S, Mitrofanis J, Pollak P (2009) Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 8:67–81. doi:10.1016/S1474-4422(08)70291-6

    Article  PubMed  Google Scholar 

  63. Osorio I, Chang F-C, Gopalsami N (2009) Seizure control with thermal energy? Modeling of heat diffusivity in brain tissue and computer-based design of a prototype mini-cooler. Epilepsy Behav 16:203–211. doi:10.1016/j.yebeh.2009.08.014

    Article  PubMed  Google Scholar 

  64. Hilderbrand JK, Peterson GP, Rothman SM (2007) Development of phase change heat spreader for treatment of intractable neocortical epilepsy. Heat Transf Eng 28: 282–291. doi:10.1080/01457630601117872

    Article  CAS  Google Scholar 

  65. Rothman SM, Smyth MD, Yang X-F, Peterson GP (2005) Focal cooling for epilepsy: an alternative therapy that might actually work. Epilepsy Behav 7:214–221. doi:10.1016/j.yebeh.2005.05.021

    Article  PubMed  Google Scholar 

  66. Truettner JS, Alonso OF, Bramlett HM, Dietrich WD (2011) Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats. J Cereb Blood Flow Metab 31:1897–1907. doi:10.1038/jcbfm.2011.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank Drs Boudewijn van der Sanden, Wafaa Jabbour, François Berger, and Nelly Wion-Barbot for their helpful discussions, comments and critical reading of the manuscript.

Author information

Authors and Affiliations

  1. BrainTech Lab, INSERM U1205, CEA, Grenoble, France

    Didier Wion

Authors
  1. Didier Wion
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Didier Wion.

Ethics declarations

Conflict of interest

The author declares he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wion, D. Therapeutic dormancy to delay postsurgical glioma recurrence: the past, present and promise of focal hypothermia. J Neurooncol 133, 447–454 (2017). https://doi.org/10.1007/s11060-017-2471-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-017-2471-3

Keywords

Search

Navigation