Reactive astrocytes and glioblastoma: are there new targets for more effective antitumor therapy?

Introduction. Astrocytes in the brain of a healthy person perform a number of protective functions, contribute to maintaining the functional activity of neurons and their synapses. However, in some pathological conditions, they change their phenotype to a reactive one and can both remodel damaged areas and contribute to increased aggression and invasiveness of gliomas.

Aim. To comprehensively study the features of reactive astrocytes and the chemo- and radioresistance of gliomas associated with reactive astrocytes.

Materials and methods. The authors analyzed articles from the databases Elsevier, pubmed, Scopus, google Scholar, Embase, web of Science, The Cochrane Library, global Health, CyberLeninka and RSCI. when selecting articles, the indexing systems of journals and the citation of articles, the scientific novelty of research, the statistical significance of the results obtained in them were taken into account, publications with duplication of the results of previous studies were excluded. In the course of the study, data on the mutual influence of reactive astrocytes and glioma cells were systematized.

Results. Astrocytes of the brain of healthy people are highly variable and heterogeneous, which further complicates the interpretation of published studies. At the same time, reactive astrocytes contribute to an increase in the chemoresistance and radioresistance of gliomas of different degrees of malignancy. At the same time, the exact mechanisms for controlling the interaction between reactive astrocytes and glioma cells, which contributed to less progression and invasion of the tumor or its regression, have not yet been established. However, this direction is now actively developing and is promising due to the possibility of additional effects on gliomas.

Conclusion. At the moment, there is no effective treatment that can cope with gliomas, all existing treatment methods are aimed only at increasing the life expectancy of patients with gliomas. The results of recent studies suggest that, probably, the current insufficient effectiveness of chemo- and radiotherapy may be associated with a very close relationship between tumor cells and tumor-associated reactive astrocytes due to their mutual supportive effect. Therefore, the solution to the problem of incurable patients with gliomas may lie in a complex effect on both tumor cells and their microenvironment.

1. Brotchi J., Bonnal J., Gerebtzoff M.A. Astroblaste tumoral et astrocyte réactionnel: distinction histochimique par l’activité de la déshydrogénase du glutamate. Neurochirurgie 1972;18(2):150–4.

2. Brotchi J. Astrocytes réactionnels et épilepsie. Acta Neurol Belg 1972;72(3):137–45.

3. Van Meir E.G., Hadjipanayis C.G., Norden A.D. et al. Exciting new advances in neuro-oncology. CA Cancer J Clin 2010;60(3):166–93. DOI: 10.3322/caac.20069

4. Tyagunova E.E., Zakharov A.S., Glukhov A.I. et al. Features of epileptiform activity in patients with diagnosed glioblastoma: from genetic and biochemical mechanisms to clinical aspects. Opukholi golovy i shei = Head and Neck Tumors 2022;12(3):102–13. (In Russ.). DOI: 10.17650/2222-1468-2022-12-3-102-113

5. Darmanis S., Sloan S.A., Croote D. et al. Single-cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep 2017;21(5):1399–410. DOI: 10.1016/j.celrep.2017.10.030

6. Zhang L., Zhang Y. Tunneling nanotubes between rat primary astrocytes and C6 glioma cells alter proliferation potential of glioma cells. Neurosci Bull 2015;31(3):371–8. DOI: 10.1007/s12264-014-1522-4

7. Umare M.D., Wankhede N.L., Bajaj K.K. et al. Interweaving of reactive oxygen species and major neurological and psychiatric disorders. Ann Pharm Fr 2022;80(4):409–25. DOI: 10.1016/j.pharma.2021.11.004

8. Liddelow S.A., Barres B.A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 2017;46(6):957–67. DOI: 10.1016/j.immuni.2017.06.006

9. Heiland H.D., Ravi V.M., Behringer S.P. et al. Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nat Commun 2019;10(1):2541. DOI: 10.1038/s41467-019-10493-6

10. Shlapakova T.I., Kostin R.K., Tyagunova E.E. Reactive oxygen species: participation in cellular processes and progression of pathology. Russian Journal of Bioorganic Chemistry 2020;46(5):657–74. DOI: 10.1134/s1068162020050222

11. Zhang Y., Chen K., Sloan S.A. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci 2014;34(36):11929–47. DOI: 10.1523/JNEUROSCI.1860-14.2014

12. Zhang Y., Sloan S.A., Clarke L.E. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 2016;89(1):37–53. DOI: 10.1016/j.neuron.2015.11.013

13. Liddelow S.A., Guttenplan K.A., Clarke L.E. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017;541(7638):481–7. DOI: 10.1038/nature21029

14. Zamanian J.L., Xu L., Foo L.C. et al. Genomic analysis of reactive astrogliosis. J Neurosci 2012;32(18):6391–410. DOI: 10.1523/JNEUROSCI.6221-11.2012

15. Guan X., Hasan M.N., Maniar S. et al. Reactive astrocytes in glioblastoma multiforme. Mol Neurobiol 2018;55(8):6927–38. DOI:10.1007/s12035-018-0880-8

16. Herculano-Houzel S. The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. Glia 2014;62(9):1377–91. DOI: 10.1002/glia.22683

17. Butt A.M., Fern R.F., Matute C. Neurotransmitter signaling in white matter. Glia 2014;62(11):1762–79. DOI: 10.1002/glia.22674

18. Haroutunian V., Katsel P., Roussos P. et al. Myelination, oligodendrocytes, and serious mental illness. Glia 2014;62(11):1856–77. DOI: 10.1002/glia.22716

19. Banker G.A. Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 1980;209(4458):809–10. DOI: 10.1126/science.7403847

20. Ullian E.M., Sapperstein S.K., Christopherson K.S. et al. Control of synapse number by glia. Science 2001;291(5504):657–61. DOI: 10.1126/science.291.5504.657

21. Christopherson K.S., Ullian E.M., Stokes C.C. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 2005;120(3):421–33. DOI: 10.1016/j.cell.2004.12.020

22. Kucukdereli H., Allen N.J., Lee A.T. et al. Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc Natl Acad Sci USA 2011;108(32):E440–9. DOI: 10.1073/pnas.1104977108

23. Allen N.J., Bennett M.L., Foo L.C. et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 2012;486(7403):410–4. DOI: 10.1038/nature11059

24. Singh S.K., Stogsdill J.A., Pulimood N.S. et al. Astrocytes assemble thalamocortical synapses by bridging NRX1alpha and NL1 via Hevin. Cell 2016;164(1–2):183–96. DOI: 10.1016/j.cell.2015.11.034

25. Farhy-Tselnicker I., van Casteren A.C., Lee A. et al. Astrocytesecreted glypican 4 regulates release of neuronal pentraxin 1 from axons to induce functional synapse formation. Neuron 2017;96(2):428–45.e413. DOI: 10.1016/j.neuron.2017.09.053

26. Krencik R., Seo K., van Asperen J.V. et al. Systematic three-dimensional coculture rapidly recapitulates interactions between human neurons and astrocytes. Stem Cell Rep 2017;9(6):1745–53. DOI: 10.1016/j.stemcr.2017.10.026

27. Stogsdill J.A., Ramirez J., Liu D. et al. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 2017;551(7679):192–7. DOI: 10.1038/nature24638

28. Blanco-Suarez E., Liu T.F., Kopelevich A. et al. Astrocyte-secreted chordin-like 1 drives synapse maturation and limits plasticity by increasing synaptic GluA2 AMPA receptors. Neuron 2018;100(5):1116–32.e1113. DOI: 10.1016/j.neuron.2018.09.043

29. Chung W.S., Clarke L.E., Wang G.X. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 2013;504(7480):394–400. DOI: 10.1038/nature12776

30. Tasdemir-Yilmaz O.E., Freeman M.R. Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Genes Dev 2014;28(1):20–33. DOI: 10.1101/gad.229518.113

31. Vainchtein I.D., Chin G., Cho F.S. et al. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 2018;359(6381):1269–73. DOI: 10.1126/science.aal3589

32. Lee J.H., Kim J.Y., Noh S. et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 2021;590(7847):612–7. DOI: 10.1038/s41586-020-03060-3

33. Kuffler S.W., Nicholls J.G., Orkand R.K. Physiological properties of glial cells in the central nervous system of amphibia. J Neurophysiol 1966;29(4):768–87. DOI: 10.1152/jn.1966.29.4.768

34. Olsen M.L., Sontheimer H. Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J Neurochem 2008;107(3):589–601. DOI: 10.1111/j.1471-4159.2008.05615.x

35. Kelley K.W., Ben Haim L., Schirmer L. et al. Kir4.1-dependent astrocyte-fast motor neuron interactions are required for peak strength. Neuron 2018;98(2):306–19.e307. DOI: 10.1016/j.neuron.2018.03.010

36. Bazargani N., Attwell D. Astrocyte calcium signaling: the third wave. Nat Neurosci 2016;19(2):182–9. DOI: 10.1038/nn.4201

37. Shlapakova T.I., Kostin R.K., Tyagunova E.E. Reactive oxygen species: participation in cellular processes and the development of pathology. Bioorganicheskaya khimiya = Bioorganic Chemistry 2020;46(5):466–85. (In Russ.). DOI: 10.31857/S013234232005022X

38. Yu X., Nagai J., Marti-Solano M. et al. Context-specific striatal astrocyte molecular responses are phenotypically exploitable. Neuron 2020;108(6):1146–62.e1110. DOI: 10.1016/j.neuron.2020.09.021

39. Placone A.L., Quinones-Hinojosa A., Searson P.C. The role of astrocytes in the progression of brain cancer: complicating the picture of the tumor microenvironment. Tumour Biol 2016;37(1):61–9. DOI: 10.1007/s13277-015-4242-0

40. Burda J.E., Bernstein A.M., Sofroniew M.V. Astrocyte roles in traumatic brain injury. Exp Neurol 2016;275(3):305–15. DOI: 10.1016/j.expneurol.2015.03.020

41. Heneka M.T., Carson M.J., El Khoury J. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015;14(4):388–405. DOI: 10.1016/s1474-4422(15)70016-5

42. Krawczyk M.C., Haney J.R., Pan L. et al. Human astrocytes exhibit tumor microenvironment-, age-, and sex-related transcriptomic signatures. J Neurosci 2022;42(8):1587–603. DOI: 10.1523/JNEUROSCI.0407-21.2021

43. Diaz-Castro B., Bernstein A.M., Coppola G. et al. Molecular and functional properties of cortical astrocytes during peripherally induced neuroinflammation. Cell Rep 2021;36(6):109508. DOI: 10.1016/j.celrep.2021.109508

44. Pinter A., Hevesi Z., Zahola P. et al. Chondroitin sulfate proteoglycan-5 forms perisynaptic matrix assemblies in the adult rat cortex. Cell Signal 2020;74:109710. DOI:10.1016/j.cellsig.2020.109710

45. Chen W., Wang D., Du X. et al. Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes. Med Oncol 2015;32(3):43. DOI: 10.1007/s12032-015-0487-0

46. Biasoli D., Sobrinho M.F., da Fonseca A.C. et al. Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy. Oncogene 2014;3(10):e123. DOI: 10.1038/oncsis.2014.36

47. Shlapakova T.I., Tyagunova E.E., Kostin R.K. et al. Targeted antitumor drug delivery to glioblastoma multiforme cells. Russ J Bioorg Chem 2021;47(2):376–9. DOI: 10.1134/S1068162021020254

48. Shlapakova T.I., Tyagunova E.E., Kostin R.K. et al. Targeted delivery of antitumor drugs to glioblastoma multiforme cells. Bioorganicheskaya khimiya = Bioorganic Chemistry 2021;47(3):299–303. (In Russ.). DOI: 10.31857/S0132342321020251

49. Bogoyavlenskaya T.A., Tyagunova E.E., Kostin R.K. et al. Glioblastoma break-in; try something new. Int J Cancer Manag 2021;14(1):e109054. DOI: 10.5812/ijcm.109054

50. Esteban F.J., Horcajadas A., El-Rubaidi O. et al. El monóxido de nitrógeno en los astrocitomas malignos. Rev Neurol 2005;40(7):437–40.

51. Campos J.C., Campos P.T., Bona N.P. et al. Synthesis and Biological Evaluation of Novel 2-imino-4-thiazolidinones as Potential Antitumor Agents for Glioblastoma. Med Chem 2022;18(4):452–62. DOI: 10.2174/1573406417666210806094543

52. Grant R., Ironside J.W. Glutathione S-transferases and cytochrome P450 detoxifying enzyme distribution in human cerebral glioma. J Neurooncol 1995;25(1):1–7. DOI: 10.1007/BF01054717

53. Han X., Yoon S.H., Ding Y. et al. Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells. Oncol Rep 2010;23(4):1053–62. DOI: 10.3892/or_00000732

54. Fletcher-Sananikone E., Kanji S., Tomimatsu N. et al. Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence. Cancer Res 2021;81(23):5935–47. DOI: 10.1158/0008-5472.CAN-21-0752

55. Nikolenko V.N., Gridin L.A., Oganesyan M.V. The posterior perforated substance: a brain mystery wrapped in an enigma. Curr Top Med Chem 2019;19(32):2991–8. DOI: 10.2174/1568026619666191127122452