Peritumoral Brain Zone in Astrocytoma: Morphology, Molecular Aspects, and Clinical Manifestations (Review)

A peritumoral brain zone is an area between a tumor and nontumorous brain tissue with tumor cell infiltration. The identification of this area is sufficiently difficult due to the lack of clear morphological or some other criteria. Besides, its dimensions may vary considerably. In the present review, we have analyzed the available data on the morphological structure and metabolism of peritumoral zone in astrocytomes, and considered the main molecular and genetic aspects and clinical manifestations.

Exploration of the peritumoral zone is of great importance for determining the extent of resection to prevent recurrence and to reveal the causes and mechanisms of continued tumor growth.

1. Stadlbauer A., Zimmermann M., Heinz G., Oberndorfer S., Doerfler A., Buchfelder M., Rössler K. Magnetic resonance imaging biomarkers for clinical routine assessment of microvascular architecture in glioma. J Cereb Blood Flow Metab 2017; 37(2): 632–643, https://doi.org/10.1177/0271678X16655549.
2. Ly K.I., Wen P.Y., Huang R.Y. Imaging of central nervous system tumors based on the 2016 World Health Organization Classification. Neurol Clin 2020; 38(1): 95–113, https://doi.org/10.1016/j.ncl.2019.08.004.
3. Rasmussen B.K., Hansen S., Laursen R.J., Kosteljanetz M., Schultz H., Nørgård B.M., Guldberg R., Gradel K.O. Epidemiology of glioma: clinical characteristics, symptoms, and predictors of glioma patients grade I–IV in the Danish Neuro-Oncology Registry. J Neurooncol 2017; 135(3): 571–579, https://doi.org/10.1007/s11060-017-2607-5.
4. Jiang B., Chaichana K., Veeravagu A., Chang S.D., Black K.L., Patil C.G. Biopsy versus resection for the management of low-grade gliomas. Cochrane Database Syst Rev 2017; 4(4): CD009319, https://doi.org/10.1002/14651858.CD009319.pub3.
5. Soni N., Priya S., Bathla G. Texture analysis in cerebral gliomas: a review of the literature. AJNR Am J Neuroradiol 2019; 40(6): 928–934, https://doi.org/10.3174/ajnr.A6075.
6. Bien-Möller S., Balz E., Herzog S., Plantera L., Vogelgesang S., Weitmann K., Seifert C., Fink M.A., Marx S., Bialke A., Venugopal C., Singh S.K., Hoffmann W., Rauch B.H., Schroeder H.W.S. Association of glioblastoma multiforme stem cell characteristics, differentiation, and microglia marker genes with patient survival. Stem Cells Int 2018; 2018: 9628289, https://doi.org/10.1155/2018/9628289.
7. Lemée J.M., Clavreul A., Menei P. Intratumoral heterogeneity in glioblastoma: don’t forget the peritumoral brain zone. Neuro Oncol 2015; 17(10): 1322–1332, https://doi.org/10.1093/neuonc/nov119.
8. Cui Y., Zeng W., Jiang H., Ren X., Lin S., Fan Y., Liu Y., Zhao J. Higher Cho/NAA ratio in postoperative peritumoral edema zone is associated with earlier recurrence of glioblastoma. Front Neurol 2020; 11: 592155, https://doi.org/10.3389/fneur.2020.592155.
9. Gill B.J., Pisapia D.J., Malone H.R., Goldstein H., Lei L., Sonabend A., Yun J., Samanamud J., Sims J.S., Banu M., Dovas A., Teich A.F., Sheth S.A., McKhann G.M., Sisti M.B., Bruce J.N., Sims P.A., Canoll P. MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc Natl Acad Sci U S A 2014; 111(34): 12550–12555, https://doi.org/10.1073/pnas.1405839111.
10. Fazi B., Felsani A., Grassi L., Moles A., D’Andrea D., Toschi N., Sicari D., De Bonis P., Anile C., Guerrisi M.G., Luca E., Farace M.G., Maira G., Ciafré S.A., Mangiola A. The transcriptome and miRNome profiling of glioblastoma tissues and peritumoral regions highlights molecular pathways shared by tumors and surrounding areas and reveals differences between short-term and long-term survivors. Oncotarget 2015; 6(26): 22526–22552, https://doi.org/10.18632/oncotarget.4151.
11. Tamura R., Ohara K., Sasaki H., Morimoto Y., Yoshida K., Toda M. Histopathological vascular investigation of the peritumoral brain zone of glioblastomas. J Neurooncol 2018; 136(2): 233–241, https://doi.org/10.1007/s11060-017-2648-9.
12. Zinn P.O., Mahajan B., Sathyan P., Singh S.K., Majumder S., Jolesz F.A., Colen R.R. Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS One 2011; 6(10): e25451, https://doi.org/10.1371/journal.pone.0025451.
13. Cubillos S., Obregón F., Vargas M.F., Salazar L.A., Lima L. Taurine concentration in human gliomas and meningiomas: tumoral, peritumoral, and extratumoral tissue. Adv Exp Med Biol 2006; 583: 419–422, https://doi.org/10.1007/978-0-387-33504-9_47.
14. Luo X., Xu S., Zhong Y., Tu T., Xu Y., Li X., Wang B., Yang F. High gene expression levels of VEGFA and CXCL8 in the peritumoral brain zone are associated with the recurrence of glioblastoma: a bioinformatics analysis. Oncol Lett 2019; 18(6): 6171–6179, https://doi.org/10.3892/ol.2019.10988.
15. Trusheim J., Dunbar E., Battiste J., Iwamoto F., Mohile N., Damek D., Bota D.A., Connelly J. A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. CNS Oncol 2017; 6(1): 29–43, https://doi.org/10.2217/cns-2016-0032.
16. Glas M., Rath B.H., Simon M., Reinartz R., Schramme A., Trageser D., Eisenreich R., Leinhaas A., Keller M., Schildhaus H.U., Garbe S., Steinfarz B., Pietsch T., Steindler D.A., Schramm J., Herrlinger U., Brüstle O., Scheffler B. Residual tumor cells are unique cellular targets in glioblastoma. Ann Neurol 2010; 68(2): 264–269, https://doi.org/10.1002/ana.22036.
17. Aubry M., de Tayrac M., Etcheverry A., Clavreul A., Saikali S., Menei P., Mosser J. From the core to beyond the margin: a genomic picture of glioblastoma intratumor heterogeneity. Oncotarget 2015; 6(14): 12094–12109, https://doi.org/10.18632/oncotarget.3297.
18. Csutak C., Ştefan P.A., Lenghel L.M., Moroşanu C.O., Lupean R.A., Şimonca L., Mihu C.M., Lebovici A. Differentiating high-grade gliomas from brain metastases at magnetic resonance: the role of texture analysis of the peritumoral zone. Brain Sci 2020; 10(9): 638, https://doi.org/10.3390/brainsci10090638.
19. Turkin A.M., Pogosbekyan E.L., Tonoyan A.C., Shults E.I., Maximov I.I., Dolgushin M.B., Khachanova N.V., Fadeeva L.M., Melnikova-Pitskhelauri T.V., Pitskhelauri D.I., Pronin I.N., Kornienko V.N. Diffusion kurtosis imaging in the assessment of peritumoral brain edema in glioblastomas and brain metastases. Meditsinskaya vizualizatsiya 2017; 4: 97–112, https://doi.org/10.24835/1607-0763-2017-4-97-112.
20. Sternberg E.J., Lipton M.L., Burns J. Utility of diffusion tensor imaging in evaluation of the peritumoral region in patients with primary and metastatic brain tumors. AJNR Am J Neuroradiol 2014; 35(3): 439–444, https://doi.org/10.3174/ajnr.A3702.
21. Latysheva A., Geier O.M., Hope T.R., Brunetti M., Micci F., Vik-Mo E.O., Emblem K.E., Server A. Diagnostic utility of restriction spectrum imaging in the characterization of the peritumoral brain zone in glioblastoma: analysis of overall and progression-free survival. Eur J Radiol 2020; 132: 109289, https://doi.org/10.1016/j.ejrad.2020.109289.
22. D’Alessio A., Proietti G., Sica G., Scicchitano B.M. pathological and molecular features of glioblastoma and its peritumoral tissue. Cancers (Basel) 2019; 11(4): 469, https://doi.org/10.3390/cancers11040469.
23. Lemée J.M., Clavreul A., Aubry M., Com E., de Tayrac M., Mosser J., Menei P. Integration of transcriptome and proteome profiles in glioblastoma: looking for the missing link. BMC Mol Biol 2018; 19(1): 13, https://doi.org/10.1186/s12867-018-0115-6.
24. Lama G., Mangiola A., Proietti G., Colabianchi A., Angelucci C., D’ Alessio A., De Bonis P., Geloso M.C., Lauriola L., Binda E., Biamonte F., Giuffrida M.G., Vescovi A., Sica G. Progenitor/stem cell markers in brain adjacent to glioblastoma: GD3 ganglioside and NG2 proteoglycan expression. J Neuropathol Exp Neurol 2016; 75(2): 134–147, https://doi.org/10.1093/jnen/nlv012.
25. Engelhorn T., Savaskan N.E., Schwarz M.A., Kreutzer J., Meyer E.P., Hahnen E., Ganslandt O., Dörfler A., Nimsky C., Buchfelder M., Eyüpoglu I.Y. Cellular characterization of the peritumoral edema zone in malignant brain tumors. Cancer Sci 2009; 100(10): 1856–1862, https://doi.org/10.1111/j.1349-7006.2009.01259.x.
26. Giambra M., Di Cristofori A., Valtorta S., Manfrellotti R., Bigiogera V., Basso G., Moresco R.M., Giussani C., Bentivegna A. The peritumoral brain zone in glioblastoma: where we are and where we are going. J Neurosci Res 2023; 101(2): 199–216, https://doi.org/10.1002/jnr.25134.
27. Rath B.H., Fair J.M., Jamal M., Camphausen K., Tofilon P.J. Astrocytes enhance the invasion potential of glioblastoma stem-like cells. PLoS One 2013; 8(1): e54752, https://doi.org/10.1371/journal.pone.0054752.
28. Kim J.K., Jin X., Sohn Y.W., Jin X., Jeon H.Y., Kim E.J., Ham S.W., Jeon H.M., Chang S.Y., Oh S.Y., Yin J., Kim S.H., Park J.B., Nakano I., Kim H. Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling. Cancer Lett 2014; 353(2): 194–200, https://doi.org/10.1016/j.canlet.2014.07.034.
29. Nagashima G., Suzuki R., Asai J., Fujimoto T. Immunohistochemical analysis of reactive astrocytes around glioblastoma: an immunohistochemical study of postmortem glioblastoma cases. Clin Neurol Neurosurg 2002; 104(2): 125–131, https://doi.org/10.1016/s0303-8467(01)00197-4.
30. Komohara Y., Ohnishi K., Kuratsu J., Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 2008; 216(1): 15–24, https://doi.org/10.1002/path.2370.
31. Engler J.R., Robinson A.E., Smirnov I., Hodgson J.G., Berger M.S., Gupta N., James C.D., Molinaro A., Phillips J.J. Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. PLoS One 2012; 7(8): e43339, https://doi.org/10.1371/journal.pone.0043339.
32. Pyonteck S.M., Akkari L., Schuhmacher A.J., Bowman R.L., Sevenich L., Quail D.F., Olson O.C., Quick M.L., Huse J.T., Teijeiro V., Setty M., Leslie C.S., Oei Y., Pedraza A., Zhang J., Brennan C.W., Sutton J.C., Holland E.C., Daniel D., Joyce J.A. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013; 19(10): 1264–1272, https://doi.org/10.1038/nm.3337.
33. Piccirillo S.G., Dietz S., Madhu B., Griffiths J., Price S.J., Collins V.P., Watts C. Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin. Br J Cancer 2012; 107(3): 462–468, https://doi.org/10.1038/bjc.2012.271.
34. Ruiz-Ontañon P., Orgaz J.L., Aldaz B., Elosegui-Artola A., Martino J., Berciano M.T., Montero J.A., Grande L., Nogueira L., Diaz-Moralli S., Esparís-Ogando A., Vazquez-Barquero A., Lafarga M., Pandiella A., Cascante M., Segura V., Martinez-Climent J.A., Sanz-Moreno V., Fernandez-Luna J.L. Cellular plasticity confers migratory and invasive advantages to a population of glioblastoma-initiating cells that infiltrate peritumoral tissue. Stem Cells 2013; 31(6): 1075–1085, https://doi.org/10.1002/stem.1349.
35. Toussaint L.G. 3rd, Nilson A.E., Goble J.M., Ballman K.V., James C.D., Lefranc F., Kiss R., Uhm J.H. Galectin-1, a gene preferentially expressed at the tumor margin, promotes glioblastoma cell invasion. Mol Cancer 2012; 11: 32, https://doi.org/10.1186/1476-4598-11-32.
36. Winkler F., Kienast Y., Fuhrmann M., Von Baumgarten L., Burgold S., Mitteregger G., Kretzschmar H., Herms J. Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis. Glia 2009; 57(12): 1306–1315, https://doi.org/10.1002/glia.20850.
37. Cuddapah V.A., Robel S., Watkins S., Sontheimer H. A neurocentric perspective on glioma invasion. Nat Rev Neurosci 2014; 15(7): 455–465, https://doi.org/10.1038/nrn3765.
38. Preusser M., Haberler C., Hainfellner J.A. Malignant glioma: neuropathology and neurobiology. Wien Med Wochenschr 2006; 156(11–12): 332–337, https://doi.org/10.1007/s10354-006-0304-7.
39. Mentlein R., Hattermann K., Held-Feindt J. Lost in disruption: role of proteases in glioma invasion and progression. Biochim Biophys Acta 2012; 1825(2): 178–185, https://doi.org/10.1016/j.bbcan.2011.12.001.
40. Giese A., Kluwe L., Laube B., Meissner H., Berens M.E., Westphal M. Migration of human glioma cells on myelin. Neurosurgery 1996; 38(4): 755–764, https://doi.org/10.1227/00006123-199604000-00026.
41. Scherer H.J. Structural development in gliomas. The American Journal of Cancer 1938; 34(3): 333–351.
42. Xu G.F., Xie W.F. Effect of ERBB2 expression on invasiveness of glioma TJ905 cells. Asian Pac J Trop Med 2013; 6(12): 964–967, https://doi.org/10.1016/S1995-7645(13)60172-8.
43. Weiss N., Miller F., Cazaubon S., Couraud P.O. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta 2009; 1788(4): 842–857, https://doi.org/10.1016/j.bbamem.2008.10.022.
44. Price S.J., Burnet N.G., Donovan T., Green H.A., Peña A., Antoun N.M., Pickard J.D., Carpenter T.A., Gillard J.H. Diffusion tensor imaging of brain tumours at 3T: a potential tool for assessing white matter tract invasion? Clin Radiol 2003; 58(6): 455–462, https://doi.org/10.1016/s0009-9260(03)00115-6.
45. Ferrer V.P., Moura Neto V., Mentlein R. Glioma infiltration and extracellular matrix: key players and modulators. Glia 2018; 66(8): 1542–1565, https://doi.org/10.1002/glia.23309.
46. Rauch U. Brain matrix: structure, turnover and necessity. Biochem Soc Trans 2007; 35(Pt 4): 656–660, https://doi.org/10.1042/BST0350656.
47. Karousou E., Misra S., Ghatak S., Dobra K., Götte M., Vigetti D., Passi A., Karamanos N.K., Skandalis S.S. Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer. Matrix Biol 2017; 59: 3–22, https://doi.org/10.1016/j.matbio.2016.10.001.
48. Park J.B., Kwak H.J., Lee S.H. Role of hyaluronan in glioma invasion. Cell Adh Migr 2008; 2(3): 202–207, https://doi.org/10.4161/cam.2.3.6320.
49. Sherman L.S., Struve J.N., Rangwala R., Wallingford N.M., Tuohy T.M., Kuntz C. 4th. Hyaluronate-based extracellular matrix: keeping glia in their place. Glia 2002; 38(2): 93–102, https://doi.org/10.1002/glia.10053.
50. Boregowda R.K., Appaiah H.N., Siddaiah M., Kumarswamy S.B., Sunila S., Thimmaiah K.N., Mortha K., Toole B., Banerjee S.D. Expression of hyaluronan in human tumor progression. J Carcinog 2006; 5: 2, https://doi.org/10.1186/1477-3163-5-2.
51. Stuhlmeier K.M. Aspects of the biology of hyaluronan, a largely neglected but extremely versatile molecule. Wien Med Wochenschr 2006; 156(21–22): 563–568, https://doi.org/10.1007/s10354-006-0351-0.
52. Ivkovic S., Beadle C., Noticewala S., Massey S.C., Swanson K.R., Toro L.N., Bresnick A.R., Canoll P., Rosenfeld S.S. Direct inhibition of myosin II effectively blocks glioma invasion in the presence of multiple motogens. Mol Biol Cell 2012; 23(4): 533–542, https://doi.org/10.1091/mbc.E11-01-0039.
53. Manini I., Caponnetto F., Bartolini A., Ius T., Mariuzzi L., Di Loreto C., Beltrami A.P., Cesselli D. Role of microenvironment in glioma invasion: what we learned from in vitro models. Int J Mol Sci 2018; 19(1): 147, https://doi.org/10.3390/ijms19010147.
54. Amberger V.R., Paganetti P.A., Seulberger H., Eldering J.A., Schwab M.E. Characterization of a membrane-bound metalloendoprotease of rat C6 glioblastoma cells. Cancer Res 1994; 54(15): 4017–4025.
55. Amberger V.R., Hensel T., Ogata N., Schwab M.E. Spreading and migration of human glioma and rat C6 cells on central nervous system myelin in vitro is correlated with tumor malignancy and involves a metalloproteolytic activity. Cancer Res 1998; 58(1): 149–1258.
56. Gritsenko P.G., Ilina O., Friedl P. Interstitial guidance of cancer invasion. J Pathol 2012; 226(2): 185–199, https://doi.org/10.1002/path.3031.
57. Wang J., Xu S.L., Duan J.J., Yi L., Guo Y.F., Shi Y., Li L., Yang Z.Y., Liao X.M., Cai J., Zhang Y.Q., Xiao H.L., Yin L., Wu H., Zhang J.N., Lv S.Q., Yang Q.K., Yang X.J., Jiang T., Zhang X., Bian X.W., Yu S.C. Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop. Nat Neurosci 2019; 22(1): 91–105, https://doi.org/10.1038/s41593-018-0285-z.
58. van Kessel E., Baumfalk A.E., van Zandvoort M.J.E., Robe P.A., Snijders T.J. Tumor-related neurocognitive dysfunction in patients with diffuse glioma: a systematic review of neurocognitive functioning prior to anti-tumor treatment. J Neurooncol 2017; 134(1): 9–18, https://doi.org/10.1007/s11060-017-2503-z.
59. Parmigiani E., Scalera M., Mori E., Tantillo E., Vannini E. Old stars and new players in the brain tumor microenvironment. Front Cell Neurosci 2021; 15: 709917, https://doi.org/10.3389/fncel.2021.709917.
60. Juhász C., Mittal S. Molecular imaging of brain tumor-associated epilepsy. Diagnostics (Basel) 2020; 10(12): 1049, https://doi.org/10.3390/diagnostics10121049.
61. Pallud J., McKhann G.M. Diffuse low-grade glioma-related epilepsy. Neurosurg Clin N Am 2019; 30(1): 43–54, https://doi.org/10.1016/j.nec.2018.09.001.
62. Politsky J.M. Brain tumor-related epilepsy: a current review of the etiologic basis and diagnostic and treatment approaches. Curr Neurol Neurosci Rep 2017; 17(9): 70, https://doi.org/10.1007/s11910-017-0777-3.
63. Parent E.E., Benayoun M., Ibeanu I., Olson J.J., Hadjipanayis C.G., Brat D.J., Adhikarla V., Nye J., Schuster D.M., Goodman M.M. [18F]Fluciclovine PET discrimination between high- and low-grade gliomas. EJNMMI Res 2018; 8(1): 67, https://doi.org/10.1186/s13550-018-0415-3.
64. Niesen C.E., Xu J., Fan X., Li X., Wheeler C.J., Mamelak A.N., Wang C. Transcriptomic profiling of human peritumoral neocortex tissues revealed genes possibly involved in tumor-induced epilepsy. PLoS One 2013; 8(2):e56077, https://doi.org/10.1371/journal.pone.0056077.
65. Korbecki J., Kojder K., Jeżewski D., Simińska D., Tarnowski M., Kopytko P., Safranow K., Gutowska I., Goschorska M., Kolasa-Wołosiuk A., Wiszniewska B., Chlubek D., Baranowska-Bosiacka I. Expression of SCD and FADS2 is lower in the necrotic core and growing tumor area than in the peritumoral area of glioblastoma multiforme. Biomolecules 2020; 10(5): 727, https://doi.org/10.3390/biom10050727.
66. Liubinas S.V., O’Brien T.J., Moffat B.M., Drummond K.J., Morokoff A.P., Kaye A.H. Tumour associated epilepsy and glutamate excitotoxicity in patients with gliomas. J Clin Neurosci 2014; 21(6): 899–908, https://doi.org/10.1016/j.jocn.2014.02.012.
67. Armstrong T.S., Grant R., Gilbert M.R., Lee J.W., Norden A.D. Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy. Neuro Oncol 2016; 18(6): 779–789, https://doi.org/10.1093/neuonc/nov269.
68. Guo J., Yao C., Chen H., Zhuang D., Tang W., Ren G., Wang Y., Wu J., Huang F., Zhou L. The relationship between Cho/NAA and glioma metabolism: implementation for margin delineation of cerebral gliomas. Acta Neurochir (Wien) 2012; 154(8): 1361–1370, https://doi.org/10.1007/s00701-012-1418-x.
69. Lemée J.M., Clavreul A., Aubry M., Com E., de Tayrac M., Eliat P.A., Henry C., Rousseau A., Mosser J., Menei P. Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis. J Neurooncol 2015; 122(1): 53–61, https://doi.org/10.1007/s11060-014-1695-8.
70. Mangiola A., Saulnier N., De Bonis P., Orteschi D., Sica G., Lama G., Pettorini B.L., Sabatino G., Zollino M., Lauriola L., Colabianchi A., Proietti G., Kovacs G., Maira G., Anile C. Gene expression profile of glioblastoma peritumoral tissue: an ex vivo study. PLoS One 2013; 8(3): e57145, https://doi.org/10.1371/journal.pone.0057145.
71. Nawashiro H., Otani N., Uozumi Y., Ooigawa H., Toyooka T., Suzuki T., Katoh H., Tsuzuki N., Ohnuki A., Shima K., Shinomiya N., Matsuo H., Kanai Y. High expression of L-type amino acid transporter 1 in infiltrating glioma cells. Brain Tumor Pathol 2005; 22(2): 89–91, https://doi.org/10.1007/s10014-005-0188-z.
72. Kruthika B.S., Jain R., Arivazhagan A., Bharath R.D., Yasha T.C., Kondaiah P., Santosh V. Transcriptome profiling reveals PDZ binding kinase as a novel biomarker in peritumoral brain zone of glioblastoma. J Neurooncol 2019; 141(2): 315–325, https://doi.org/10.1007/s11060-018-03051-5.
73. Liu H., Zhao Q., Tan L., Wu X., Huang R., Zuo Y., Chen L., Yang J., Zhang Z.X., Ruan W., Wu J., He F., Fang Y., Mao F., Zhang P., Zhang X., Yin P., Yan Z., Xu W., Lu H., Li Q., Liang M., Jia Y., Chen C., Xu S., Shi Y., Ping Y.F., Duan G.J., Yao X.H., Han Z., Pang T., Cui Y., Zhang X., Zhu B., Qi C., Wang Y., Lv S.Q., Bian X.W., Liu X. Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma. Cancer Cell 2023; 41(4): 693–710.e8, https://doi.org/10.1016/j.ccell.2023.03.004.
74. Yang Y., Chu L., Zeng Z., Xu S., Yang H., Zhang X., Jia J., Long N., Hu Y., Liu J. Four specific biomarkers associated with the progression of glioblastoma multiforme in older adults identified using weighted gene co-expression network analysis. Bioengineered 2021; 12(1): 6643–6654, https://doi.org/10.1080/21655979.2021.1975980.
75. Zhang M., Ye G., Li J., Wang Y. Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy. Brain Tumor Pathol 2015; 32(4): 229–236, https://doi.org/10.1007/s10014-015-0233-5.
76. Lemée J.M., Com E., Clavreul A., Avril T., Quillien V., de Tayrac M., Pineau C., Menei P. Proteomic analysis of glioblastomas: what is the best brain control sample? J Proteomics 2013; 85: 165–173, https://doi.org/10.1016/j.jprot.2013.04.031.
77. Piwecka M., Rolle K., Belter A., Barciszewska A.M., Żywicki M., Michalak M., Nowak S., Naskręt-Barciszewska M.Z., Barciszewski J. Comprehensive analysis of microRNA expression profile in malignant glioma tissues. Mol Oncol 2015; 9(7): 1324–1340, https://doi.org/10.1016/j.molonc.2015.03.007.
78. Virga J., Bognár L., Hortobágyi T., Zahuczky G., Csősz É., Kalló G., Tóth J., Hutóczki G., Reményi-Puskár J., Steiner L., Klekner A. Tumor grade versus expression of invasion-related molecules in astrocytoma. Pathol Oncol Res 2018; 24(1): 35–43, https://doi.org/10.1007/s12253-017-0194-6.
79. Nimbalkar V.P., Kruthika B.S., Sravya P., Rao S., Sugur H.S., Verma B.K., Chickabasaviah Y.T., Arivazhagan A., Kondaiah P., Santosh V. Differential gene expression in peritumoral brain zone of glioblastoma: role of SERPINA3 in promoting invasion, stemness and radioresistance of glioma cells and association with poor patient prognosis and recurrence. J Neurooncol 2021; 152(1): 55–65, https://doi.org/10.1007/s11060-020-03685-4.
80. Geribaldi-Doldán N., Fernández-Ponce C., Quiroz R.N., Sánchez-Gomar I., Escorcia L.G., Velásquez E.P., Quiroz E.N. The role of microglia in glioblastoma. Front Oncol 2021; 10: 603495, https://doi.org/10.3389/fonc.2020.603495.
81. Raja S., Byakod G., Pudakalkatti P. Growth factors in periodontal regeneration. Int J Dent Hyg 2009; 7(2): 82–89, https://doi.org/10.1111/j.1601-5037.2009.00380.x.
82. Danieli-Betto D., Peron S., Germinario E., Zanin M., Sorci G., Franzoso S., Sandonà D., Betto R. Sphingosine 1-phosphate signaling is involved in skeletal muscle regeneration. Am J Physiol Cell Physiol 2010; 298(3): C550–C558, https://doi.org/10.1152/ajpcell.00072.2009.
83. Duarte Azevedo M., Sander S., Tenenbaum L. GDNF, a neuron-derived factor upregulated in glial cells during disease. J Clin Med 2020; 9(2): 456, https://doi.org/10.3390/jcm9020456.
84. Giambra M., Messuti E., Di Cristofori A., Cavandoli C., Bruno R., Buonanno R., Marzorati M., Zambuto M., Rodriguez-Menendez V., Redaelli S., Giussani C., Bentivegna A. Characterizing the genomic profile in high-grade gliomas: from tumor core to peritumoral brain zone, passing through glioma-derived tumorspheres. Biology (Basel) 2021; 10(11): 1157, https://doi.org/10.3390/biology10111157.
85. Slegers R.J., Blumcke I. Low-grade developmental and epilepsy associated brain tumors: a critical update 2020. Acta Neuropathol Commun 2020; 8(1): 27, https://doi.org/10.1186/s40478-020-00904-x.
86. Cowie C.J., Cunningham M.O. Peritumoral epilepsy: relating form and function for surgical success. Epilepsy Behav 2014; 38: 53–61, https://doi.org/10.1016/j.yebeh.2014.05.009.
87. Pallud J., Audureau E., Blonski M., Sanai N., Bauchet L., Fontaine D., Mandonnet E., Dezamis E., Psimaras D., Guyotat J., Peruzzi P., Page P., Gal B., Párraga E., Baron M.H., Vlaicu M., Guillevin R., Devaux B., Duffau H., Taillandier L., Capelle L., Huberfeld G. Epileptic seizures in diffuse low-grade gliomas in adults. Brain 2014; 137(Pt 2): 449–462, https://doi.org/10.1093/brain/awt345.
88. van Breemen M.S., Wilms E.B., Vecht C.J. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 2007; 6(5): 421–430, https://doi.org/10.1016/S1474-4422(07)70103-5.
89. de Groot M., Reijneveld J.C., Aronica E., Heimans J.J. Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment. Brain 2012; 135(Pt 4): 1002–1016, https://doi.org/10.1093/brain/awr310.
90. Buckingham S.C., Campbell S.L., Haas B.R., Montana V., Robel S., Ogunrinu T., Sontheimer H. Glutamate release by primary brain tumors induces epileptic activity. Nat Med 2011; 17(10): 1269–1274, https://doi.org/10.1038/nm.2453.
91. Yuen T.I., Morokoff A.P., Bjorksten A., D’Abaco G., Paradiso L., Finch S., Wong D., Reid C.A., Powell K.L., Drummond K.J., Rosenthal M.A., Kaye A.H., O’Brien T.J. Glutamate is associated with a higher risk of seizures in patients with gliomas. Neurology 2012; 79(9): 883–889, https://doi.org/10.1212/WNL.0b013e318266fa89.
92. Pallud J., Le Van Quyen M., Bielle F., Pellegrino C., Varlet P., Cresto N., Baulac M., Duyckaerts C., Kourdougli N., Chazal G., Devaux B., Rivera C., Miles R., Capelle L., Huberfeld G. Cortical GABAergic excitation contributes to epileptic activities around human glioma. Sci Transl Med 2014; 6(244): 244ra89, https://doi.org/10.1126/scitranslmed.3008065.
93. Radin D.P., Tsirka S.E. Interactions between tumor cells, neurons, and microglia in the glioma microenvironment. Int J Mol Sci 2020; 21(22): 8476, https://doi.org/10.3390/ijms21228476.
94. Conti L., Palma E., Roseti C., Lauro C., Cipriani R., de Groot M., Aronica E., Limatola C. Anomalous levels of Cl-transporters cause a decrease of GABAergic inhibition in human peritumoral epileptic cortex. Epilepsia 2011; 52(9): 1635–1644, https://doi.org/10.1111/j.1528-1167.2011.03111.x.
95. Chen D.Y., Chen C.C., Crawford J.R., Wang S.G. Tumor-related epilepsy: epidemiology, pathogenesis and management. J Neurooncol 2018; 139(1): 13–21, https://doi.org/10.1007/s11060-018-2862-0.

Grishin A.S., Achkasova K.A., Kukhnina L.S., Sharova V.A., Ostapyuk M.V., Yashin K.S. Peritumoral Brain Zone in Astrocytoma: Morphology, Molecular Aspects, and Clinical Manifestations (Review). Sovremennye tehnologii v medicine 2024; 16(2): 79, https://doi.org/10.17691/stm2024.16.2.08