Glioma‑neuronal interactions in tumor progression: Mechanism, therapeutic strategies and perspectives (Review)

Hua,Tianzhen; Shi,Huanxiao; Zhu,Mengmei; Chen,Chao; Su,Yandong; Wen,Shengjia; Zhang,Xu; Chen,Juxiang; Huang,Qilin; Wang,Hongxiang

doi:10.3892/ijo.2022.5394

Glioma‑neuronal interactions in tumor progression: Mechanism, therapeutic strategies and perspectives (Review)

Authors:
- Tianzhen Hua
- Huanxiao Shi
- Mengmei Zhu
- Chao Chen
- Yandong Su
- Shengjia Wen
- Xu Zhang
- Juxiang Chen
- Qilin Huang
- Hongxiang Wang
View Affiliations

Affiliations: Department of Neurosurgery, Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China, Department of Neurosurgery, General Hospital of Central Theater Command of Chinese People's Liberation Army, Wuhan, Hubei 430070, P.R. China
Published online on: July 11, 2022 https://doi.org/10.3892/ijo.2022.5394
Article Number: 104
Copyright: © Hua et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

An increasing body of evidence has become available to reveal the synaptic and functional integration of glioma into the brain network, facilitating tumor progression. The novel discovery of glioma‑neuronal interactions has fundamentally challenged our understanding of this refractory disease. The present review aimed to provide an overview of how the neuronal activities function through synapses, neurotransmitters, ion channels, gap junctions, tumor microtubes and neuronal molecules to establish communications with glioma, as well as a simplified explanation of the reciprocal effects of crosstalk on neuronal pathophysiology. In addition, the current state of therapeutic avenues targeting critical factors involved in glioma‑euronal interactions is discussed and an overview of clinical trial data for further investigation is provided. Finally, newly emerging technologies, including immunomodulation, a neural stem cell‑based delivery system, optogenetics techniques and co‑culture of neuron organoids and glioma, are proposed, which may pave a way towards gaining deeper insight into both the mechanisms associated with neuron‑ and glioma‑communicating networks and the development of therapeutic strategies to target this currently lethal brain tumor.

View Figures

View References

1	Lapointe S, Perry A and Butowski NA: Primary brain tumours in adults. Lancet. 392:432–446. 2018. View Article : Google Scholar : PubMed/NCBI
2	Rominiyi O, Vanderlinden A, Clenton SJ, Bridgewater C, Al-Tamimi Y and Collis SJ: Tumour treating fields therapy for glioblastoma: Current advances and future directions. Br J Cancer. 124:697–709. 2021. View Article : Google Scholar :
3	Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS and Khasraw M: Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 70:299–312. 2020. View Article : Google Scholar : PubMed/NCBI
4	Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, et al: The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol. 23:1231–1251. 2021. View Article : Google Scholar : PubMed/NCBI
5	Klemm F, Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S, Brouland JP, Iacobuzio-Donahue CA, Brennan C, Tabar V, et al: Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell. 181:1643–1660.e17. 2020. View Article : Google Scholar : PubMed/NCBI
6	Broekman ML, Maas SLN, Abels ER, Mempel TR, Krichevsky AM and Breakefield XO: Multidimensional communication in the microenvirons of glioblastoma. Nat Rev Neurol. 14:482–495. 2018. View Article : Google Scholar : PubMed/NCBI
7	Mohme M and Neidert MC: Tumor-specific T cell activation in malignant brain tumors. Front Immunol. 11:2052020. View Article : Google Scholar : PubMed/NCBI
8	Wei J, Chen P, Gupta P, Ott M, Zamler D, Kassab C, Bhat KP, Curran MA, de Groot JF and Heimberger AB: Immune biology of glioma-associated macrophages and microglia: Functional and therapeutic implications. Neuro Oncol. 22:180–194. 2020.
9	Venkatesh HS: The neural regulation of cancer. Science. 366:9652019. View Article : Google Scholar : PubMed/NCBI
10	De Luca C, Virtuoso A, Papa M, Certo F, Barbagallo GMV and Altieri R: Regional development of glioblastoma: The anatomical conundrum of cancer biology and its surgical implication. Cells. 11:13492022. View Article : Google Scholar : PubMed/NCBI
11	Parmigiani E, Scalera M, Mori E, Tantillo E and Vannini E: Old stars and new players in the brain tumor microenvironment. Front Cell Neurosci. 15:7099172021. View Article : Google Scholar : PubMed/NCBI
12	Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Körber C, Kardorff M, Ratliff M, Xie R, et al: Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 573:532–538. 2019. View Article : Google Scholar : PubMed/NCBI
13	Lim-Fat MJ and Wen PY: Glioma progression through synaptic activity. Nat Rev Neurol. 16:6–7. 2020. View Article : Google Scholar
14	Kirmse K and Zhang C: Principles of GABAergic signaling in developing cortical network dynamics. Cell Rep. 38:1105682022. View Article : Google Scholar : PubMed/NCBI
15	Tantillo E, Vannini E, Cerri C, Spalletti C, Colistra A, Mazzanti CM, Costa M and Caleo M: Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation. Neurobiol Dis. 141:1049422020. View Article : Google Scholar : PubMed/NCBI
16	Melgarejo da Rosa M: Communication of glioma cells with neuronal plasticity: What is the underlying mechanism? Neurochem Int. 141:1048792020. View Article : Google Scholar : PubMed/NCBI
17	Radin DP and Tsirka SE: Interactions between tumor cells, neurons, and microglia in the glioma microenvironment. Int J Mol Sci. 21:84762020. View Article : Google Scholar :
18	Jung E, Alfonso J, Osswald M, Monyer H, Wick W and Winkler F: Emerging intersections between neuroscience and glioma biology. Nat Neurosci. 22:1951–1960. 2019. View Article : Google Scholar : PubMed/NCBI
19	Hasselmo ME, Alexander AS, Hoyland A, Robinson JC, Bezaire MJ, Chapman GW, Saudargiene A, Carstensen LC and Dannenberg H: The unexplored territory of neural models: Potential guides for exploring the function of metabotropic neuromodulation. Neuroscience. 456:143–158. 2021. View Article : Google Scholar
20	Pei Z, Lee KC, Khan A, Erisnor G and Wang HY: Pathway analysis of glutamate-mediated, calcium-related signaling in glioma progression. Biochem Pharmacol. 176:1138142020. View Article : Google Scholar : PubMed/NCBI
21	Charsouei S, Jabalameli MR and Karimi-Moghadam A: Molecular insights into the role of AMPA receptors in the synaptic plasticity, pathogenesis and treatment of epilepsy: Therapeutic potentials of perampanel and antisense oligonucleotide (ASO) technology. Acta Neurol Belg. 120:531–544. 2020. View Article : Google Scholar : PubMed/NCBI
22	Cull-Candy SG and Farrant M: Ca²⁺ -permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease. J Physiol. 599:2655–2671. 2021. View Article : Google Scholar : PubMed/NCBI
23	Dohrke JN, Watson JF, Birchall K and Greger IH: Characterizing the binding and function of TARP γ8-selective AMPA receptor modulators. J Biol Chem. 295:14565–14577. 2020. View Article : Google Scholar : PubMed/NCBI
24	Müller-Längle A, Lutz H, Hehlgans S, Rödel F, Rau K and Laube B: NMDA receptor-mediated signaling pathways enhance radiation resistance, survival and migration in glioblastoma cells-A potential target for adjuvant radiotherapy. Cancers (Basel). 11:5032019. View Article : Google Scholar
25	Nepali K, Hsu TI, Hsieh CM, Lo WL, Lai MJ, Hsu KC, Lin TE, Chuang JY and Liou JP: Pragmatic recruitment of memantine as the capping group for the design of HDAC inhibitors: A preliminary attempt to unravel the enigma of glioblastoma. Eur J Med Chem. 217:1133382021. View Article : Google Scholar : PubMed/NCBI
26	Wan Z, Sun R, Liu YW, Li S, Sun J, Li J, Zhu J, Moharil P, Zhang B, Ren P, et al: Targeting metabotropic glutamate receptor 4 for cancer immunotherapy. Sci Adv. 7:eabj42262021. View Article : Google Scholar : PubMed/NCBI
27	Blyufer A, Lhamo S, Tam C, Tariq I, Thavornwatanayong T and Mahajan SS: Riluzole: A neuroprotective drug with potential as a novel anti-cancer agent (review). Int J Oncol. 59:952021. View Article : Google Scholar :
28	Mugge L, Mansour TR, Crippen M, Alam Y and Schroeder J: Depression and glioblastoma, complicated concomitant diseases: A systemic review of published literature. Neurosurg Rev. 43:497–511. 2020. View Article : Google Scholar
29	Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, Whetstone H, So M, Aviv T, Park N, et al: Inhibition of dopamine receptor D4 impedes autophagic flux, proliferation, and survival of glioblastoma stem cells. Cancer Cell. 29:859–873. 2016. View Article : Google Scholar : PubMed/NCBI
30	Caffino L, Mottarlini F, Targa G, Verheij MMM, Fumagalli F and Homberg JR: Responsivity of serotonin transporter knockout rats to short and long access to cocaine: Modulation of the glutamate signalling in the nucleus accumbens shell. Br J Pharmacol. 179:3727–3739. 2022. View Article : Google Scholar : PubMed/NCBI
31	Bi J, Khan A, Tang J, Armando AM, Wu S, Zhang W, Gimple RC, Reed A, Jing H, Koga T, et al: Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug. Cell Rep. 37:1099572021. View Article : Google Scholar : PubMed/NCBI
32	Tao F, Zhu J, Duan L, Wu J, Zhang J, Yao K, Bo J and Zu H: Anti-inflammatory effects of doxepin hydrochloride against LPS-induced C6-glioma cell inflammatory reaction by PI3K-mediated Akt signaling. J Biochem Mol Toxicol. 34:e224242020. View Article : Google Scholar
33	Otto-Meyer S, DeFaccio R, Dussold C, Ladomersky E, Zhai L, Lauing KL, Bollu LR, Amidei C, Lukas RV, Scholtens DM and Wainwright DA: A retrospective survival analysis of glioblastoma patients treated with selective serotonin reuptake inhibitors. Brain Behav Immun Health. 2:1000252020. View Article : Google Scholar : PubMed/NCBI
34	Takayasu T, Kurisu K, Esquenazi Y and Ballester LY: Ion channels and their role in the pathophysiology of gliomas. Mol Cancer Ther. 19:1959–1969. 2020. View Article : Google Scholar : PubMed/NCBI
35	He L, Sun Z, Li J, Zhu R, Niu B, Tam KL, Xiao Q, Li J, Wang W, Tsui CY, et al: Electrical stimulation at nanoscale topography boosts neural stem cell neurogenesis through the enhancement of autophagy signaling. Biomaterials. 268:1205852021. View Article : Google Scholar
36	Arvind R, Chandana SR, Borad MJ, Pennington D, Mody K and Babiker H: Tumor-treating fields: A fourth modality in cancer treatment, new practice updates. Crit Rev Oncol Hematol. 168:1035352021. View Article : Google Scholar : PubMed/NCBI
37	Tsai HF, IJspeert C and Shen AQ: Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice. APL Bioeng. 4:0361022020. View Article : Google Scholar : PubMed/NCBI
38	Nicoletti NF, Erig TC, Zanin RF, Roxo MR, Ferreira NP, Gomez MV, Morrone FB and Campos MM: Pre-clinical evaluation of voltage-gated calcium channel blockers derived from the spider P. nigriventer in glioma progression. Toxicon. 129:58–67. 2017. View Article : Google Scholar : PubMed/NCBI
39	Catacuzzeno L, Sforna L, Esposito V, Limatola C and Franciolini F: Ion channels in glioma malignancy. Rev Physiol Biochem Pharmacol. 181:223–267. 2021. View Article : Google Scholar
40	Vannini E, Mori E, Tantillo E, Schmidt G, Caleo M and Costa M: CTX-CNF1 recombinant protein selectively targets glioma cells in vivo. Toxins (Basel). 13:1942021. View Article : Google Scholar
41	Catacuzzeno L and Franciolini F: Role of KCa3.1 channels in modulating Ca²⁺ oscillations during glioblastoma cell migration and invasion. Int J Mol Sci. 19:29702018. View Article : Google Scholar
42	Rosa P, Catacuzzeno L, Sforna L, Mangino G, Carlomagno S, Mincione G, Petrozza V, Ragona G, Franciolini F and Calogero A: BK channels blockage inhibits hypoxia-induced migration and chemoresistance to cisplatin in human glioblastoma cells. J Cell Physiol. 233:6866–6877. 2018. View Article : Google Scholar : PubMed/NCBI
43	Ru Q, Li WL, Xiong Q, Chen L, Tian X and Li CY: Voltage-gated potassium channel blocker 4-aminopyridine induces glioma cell apoptosis by reducing expression of microRNA-10b-5p. Mol Biol Cell. 29:1125–1136. 2018. View Article : Google Scholar : PubMed/NCBI
44	Aissaoui D, Mlayah-Bellalouna S, Jebali J, Abdelkafi-Koubaa Z, Souid S, Moslah W, Othman H, Luis J, ElAyeb M, Marrakchi N, et al: Functional role of Kv1.1 and Kv1.3 channels in the neoplastic progression steps of three cancer cell lines, elucidated by scorpion peptides. Int J Biol Macromol. 111:1146–1155. 2018. View Article : Google Scholar : PubMed/NCBI
45	Hu L, Li LL, Lin ZG, Jiang ZC, Li HX, Zhao SG and Yang KB: Blockage of potassium channel inhibits proliferation of glioma cells via increasing reactive oxygen species. Oncol Res. 22:57–65. 2014. View Article : Google Scholar
46	Roehlecke C and Schmidt MHH: Tunneling nanotubes and tumor microtubes in cancer. Cancers (Basel). 12:8572020. View Article : Google Scholar
47	Portela M, Venkataramani V, Fahey-Lozano N, Seco E, Losada-Perez M, Winkler F and Casas-Tintó S: Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. PLoS Biol. 17:e30005452019. View Article : Google Scholar : PubMed/NCBI
48	Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, Tam LT, Espenel C, Ponnuswami A, Ni L, et al: Electrical and synaptic integration of glioma into neural circuits. Nature. 573:539–545. 2019. View Article : Google Scholar : PubMed/NCBI
49	Epifantseva I and Shaw RM: Intracellular trafficking pathways of Cx43 gap junction channels. Biochim Biophys Acta Biomembr. 1860:40–47. 2018. View Article : Google Scholar
50	Pinto G, Brou C and Zurzolo C: Tunneling nanotubes: The fuel of tumor progression? Trends Cancer. 6:874–888. 2020. View Article : Google Scholar : PubMed/NCBI
51	Osswald M, Jung E, Sahm F, Solecki G, Venkataramani V, Blaes J, Weil S, Horstmann H, Wiestler B, Syed M, et al: Brain tumour cells interconnect to a functional and resistant network. Nature. 528:93–98. 2015. View Article : Google Scholar : PubMed/NCBI
52	Jaraíz-Rodríguez M, Talaverón R, García-Vicente L, Pelaz SG, Domínguez-Prieto M, Aacute;lvarez-Vázquez A, Flores-Hernández R, Sin WC, Bechberger J, Medina JM, et al: Connexin43 peptide, TAT-Cx43266-283, selectively targets glioma cells, impairs malignant growth, and enhances survival in mouse models in vivo. Neuro Oncol. 22:493–504. 2020. View Article : Google Scholar
53	Pettee KM, Becker KN, Alberts AS, Reinard KA, Schroeder JL and Eisenmann KM: Targeting the mDia formin-assembled cytoskeleton is an effective anti-invasion strategy in adult high-grade glioma patient-derived neurospheres. Cancers (Basel). 11:3922019. View Article : Google Scholar
54	Sinyuk M, Mulkearns-Hubert EE, Reizes O and Lathia J: Cancer connectors: connexins, gap junctions, and communication. Front Oncol. 8:6462018. View Article : Google Scholar
55	Zhang C, Liu CF, Chen AB, Yao Z, Li WG, Xu SJ and Ma XY: Prognostic and clinic pathological value of Cx43 expression in glioma: A meta-analysis. Front Oncol. 9:12092019. View Article : Google Scholar : PubMed/NCBI
56	Filbin MG and Segal RA: How neuronal activity regulates glioma cell proliferation. Neuro Oncol. 17:1543–1544. 2015. View Article : Google Scholar : PubMed/NCBI
57	Yao M, Ventura PB, Jiang Y, Rodriguez FJ, Wang L, Perry JSA, Yang Y, Wahl K, Crittenden RB, Bennett ML, et al: Astrocytic trans-differentiation completes a multicellular paracrine feedback loop required for medulloblastoma tumor growth. Cell. 180:502–520.e19. 2020. View Article : Google Scholar : PubMed/NCBI
58	Griffin N, Faulkner S, Jobling P and Hondermarck H: Targeting neurotrophin signaling in cancer: The renaissance. Pharmacol Res. 135:12–17. 2018. View Article : Google Scholar : PubMed/NCBI
59	Rocco ML, Soligo M, Manni L and Aloe L: Nerve growth factor: Early studies and recent clinical trials. Curr Neuropharmacol. 16:1455–1465. 2018. View Article : Google Scholar : PubMed/NCBI
60	Franzese O, Di Francesco AM, Meco D, Graziani G, Cusano G, Levati L, Riccardi R and Ruggiero A: hTERT transduction extends the lifespan of primary pediatric low-grade glioma cells while preserving the biological response to NGF. Pathol Oncol Res. 27:6123752021. View Article : Google Scholar : PubMed/NCBI
61	Meco D, Di Francesco AM, Melotti L, Ruggiero A and Riccardi R: Ectopic nerve growth factor prevents proliferation in glioma cells by senescence induction. J Cell Physiol. 234:6820–6830. 2019. View Article : Google Scholar
62	Park JC, Chang IB, Ahn JH, Kim JH, Song JH, Moon SM and Park YH: Nerve growth factor stimulates glioblastoma proliferation through Notch1 receptor signaling. J Korean Neurosurg Soc. 61:441–449. 2018. View Article : Google Scholar : PubMed/NCBI
63	Barreda Tomás FJ, Turko P, Heilmann H, Trimbuch T, Yanagawa Y, Vida I and Münster-Wandowski A: BDNF expression in cortical GABAergic interneurons. Int J Mol Sci. 21:15672020. View Article : Google Scholar
64	Li YF: A hypothesis of monoamine (5-HT)-glutamate/GABA long neural circuit: Aiming for fast-onset antidepressant discovery. Pharmacol Ther. 208:1074942020. View Article : Google Scholar
65	Liu S, Jiang T, Zhong Y and Yu Y: miR-210 inhibits cell migration and invasion by targeting the brain-derived neurotrophic factor in glioblastoma. J Cell Biochem. Feb 11–2019.Epub ahead of print.
66	Wang J, Gao F, Cui S, Yang S, Gao F, Wang X and Zhu G: Utility of 7,8-dihydroxyflavone in preventing astrocytic and synaptic deficits in the hippocampus elicited by PTSD. Pharmacol Res. 176:1060792022. View Article : Google Scholar : PubMed/NCBI
67	Lange F, Hörnschemeyer J and Kirschstein T: Glutamatergic mechanisms in glioblastoma and tumor-associated epilepsy. Cells. 10:12262021. View Article : Google Scholar : PubMed/NCBI
68	Keifer J: Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease. J Neurosci Res. 100:979–991. 2022. View Article : Google Scholar : PubMed/NCBI
69	Gorick CM, Saucerman JJ and Price RJ: Computational model of brain endothelial cell signaling pathways predicts therapeutic targets for cerebral pathologies. J Mol Cell Cardiol. 164:17–28. 2022. View Article : Google Scholar
70	Jawhari S, Bessette B, Hombourger S, Durand K, Lacroix A, Labrousse F, Jauberteau MO, Ratinaud MH and Verdier M: Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival. Carcinogenesis. 38:592–603. 2017. View Article : Google Scholar : PubMed/NCBI
71	Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, Gibson EM, Mount CW, Polepalli J, Mitra SS, et al: Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell. 161:803–816. 2015. View Article : Google Scholar : PubMed/NCBI
72	Bemben MA, Nguyen TA, Li Y, Wang T, Nicoll RA and Roche KW: Isoform-specific cleavage of neuroligin-3 reduces synapse strength. Mol Psychiatry. 24:145–160. 2019. View Article : Google Scholar
73	Liu R, Qin XP, Zhuang Y, Zhang Y, Liao HB, Tang JC, Pan MX, Zeng FF, Lei Y, Lei RX, et al: Glioblastoma recurrence correlates with NLGN3 levels. Cancer Med. May 18–2018.Epub ahead of print.
74	Dang NN, Li XB, Zhang M, Han C, Fan XY and Huang SH: NLGN3 upregulates expression of ADAM10 to promote the cleavage of NLGN3 via activating the LYN pathway in human gliomas. Front Cell Dev Biol. 9:6627632021. View Article : Google Scholar :
75	Venkatesh HS, Tam LT, Woo PJ, Lennon J, Nagaraja S, Gillespie SM, Ni J, Duveau DY, Morris PJ, Zhao JJ, et al: Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature. 549:533–537. 2017. View Article : Google Scholar : PubMed/NCBI
76	Li Z, Gao W, Fei Y, Gao P, Xie Q, Xie J and Xu Z: NLGN3 promotes neuroblastoma cell proliferation and growth through activating PI3K/AKT pathway. Eur J Pharmacol. 857:1724232019. View Article : Google Scholar : PubMed/NCBI
77	Fumagalli A, Heuninck J, Pizzoccaro A, Moutin E, Koenen J, Séveno M, Durroux T, Junier MP, Schlecht-Louf G, Bachelerie F, et al: The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication. Nat Commun. 11:48552020. View Article : Google Scholar : PubMed/NCBI
78	Derks J, Wesseling P, Carbo EWS, Hillebrand A, van Dellen E, de Witt Hamer PC, Klein M, Schenk GJ, Geurts JJG, Reijneveld JC and Douw L: Oscillatory brain activity associates with neuroligin-3 expression and predicts progression free survival in patients with diffuse glioma. J Neurooncol. 140:403–412. 2018. View Article : Google Scholar : PubMed/NCBI
79	Gu J, Jin T, Li Z, Chen H, Xia H, Xu X and Gui Y: Exosomes expressing neuronal autoantigens induced immune response in antibody-positive autoimmune encephalitis. Mol Immunol. 131:164–170. 2021. View Article : Google Scholar : PubMed/NCBI
80	Kumari M and Anji A: Small but mighty-exosomes, novel inter-cellular messengers in neurodegeneration. Biology (Basel). 11:4132022.
81	Chivet M, Javalet C, Laulagnier K, Blot B, Hemming FJ and Sadoul R: Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons. J Extracell Vesicles. 3:247222014. View Article : Google Scholar : PubMed/NCBI
82	Sharma P, Mesci P, Carromeu C, McClatchy DR, Schiapparelli L, Yates JR III, Muotri AR and Cline HT: Exosomes regulate neurogenesis and circuit assembly. Proc Natl Acad Sci USA. 116:16086–16094. 2019. View Article : Google Scholar : PubMed/NCBI
83	Gao X, Zhang Z, Mashimo T, Shen B, Nyagilo J, Wang H, Wang Y, Liu Z, Mulgaonkar A, Hu XL, et al: Gliomas interact with non-glioma brain cells via extracellular vesicles. Cell Rep. 30:2489–2500.e5. 2020. View Article : Google Scholar : PubMed/NCBI
84	Yu K, Lin CJ, Hatcher A, Lozzi B, Kong K, Huang-Hobbs E, Cheng YT, Beechar VB, Zhu W, Zhang Y, et al: PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature. 578:166–171. 2020. View Article : Google Scholar : PubMed/NCBI
85	Wang J, Liu W, Xu W, Yang B, Cui M, Li Z, Zhang H, Jin C, Xue H and Zhang J: Comprehensive analysis of the oncogenic, genomic alteration, and immunological landscape of cation-chloride cotransporters in pan-cancer. Front Oncol. 12:8196882022. View Article : Google Scholar : PubMed/NCBI
86	Al Awabdh S, Donneger F, Goutierre M, Séveno M, Vigy O, Weinzettl P, Russeau M, Moutkine I, Lévi S, Marin P and Poncer JC: Gephyrin interacts with the K-Cl cotransporter KCC2 to regulate its surface expression and function in cortical neurons. J Neurosci. 42:166–182. 2022. View Article : Google Scholar :
87	Moreira Franco YE, Alves MJ, Uno M, Moretti IF, Trombetta-Lima M, de Siqueira Santos S, Dos Santos AF, Arini GS, Baptista MS, Lerario AM, et al: Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness. Cancer Metab. 9:182021. View Article : Google Scholar : PubMed/NCBI
88	Lisi L, Ciotti GMP, Chiavari M, Martire M and Navarra P: The effects of CHF6467, a new mutated form of NGF, on cell models of human glioblastoma. A comparison with wild-type NGF. Growth Factors. 40:37–45. 2022. View Article : Google Scholar : PubMed/NCBI
89	Rosso P, Fico E, Mesentier-Louro LA, Triaca V, Lambiase A, Rama P and Tirassa P: NGF eye administration recovers the TrkB and glutamate/GABA marker deficit in the adult visual cortex following optic nerve crush. Int J Mol Sci. 22:100142021. View Article : Google Scholar : PubMed/NCBI
90	Colucci-D'Amato L, Speranza L and Volpicelli F: Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int J Mol Sci. 21:77772020. View Article : Google Scholar :
91	Carniel BP and da Rocha NS: Brain-derived neurotrophic factor (BDNF) and inflammatory markers: Perspectives for the management of depression. Prog Neuropsychopharmacol Biol Psychiatry. 108:1101512021. View Article : Google Scholar
92	Caponegro MD, Oh K, Madeira MM, Radin D, Sterge N, Tayyab M, Moffitt RA and Tsirka SE: A distinct microglial subset at the tumor-stroma interface of glioma. Glia. 69:1767–1781. 2021. View Article : Google Scholar : PubMed/NCBI
93	Wei J, Song R, Sabbagh A, Marisetty A, Shukla N, Fang D, Najem H, Ott M, Long J, Zhai L, et al: Cell-directed aptamer therapeutic targeting for cancers including those within the central nervous system. Oncoimmunology. 11:20628272022. View Article : Google Scholar : PubMed/NCBI
94	Wegrzyn D, Freund N, Faissner A and Juckel G: Poly I:C activated microglia disrupt perineuronal nets and modulate synaptic balance in primary hippocampal neurons in vitro. Front Synaptic Neurosci. 13:6375492021. View Article : Google Scholar :
95	Szepesi Z, Manouchehrian O, Bachiller S and Deierborg T: Bidirectional microglia-neuron communication in health and disease. Front Cell Neurosci. 12:3232018. View Article : Google Scholar : PubMed/NCBI
96	Moraes CA, Zaverucha-do-Valle C, Fleurance R, Sharshar T, Bozza FA and d'Avila JC: Neuroinflammation in sepsis: Molecular pathways of microglia activation. Pharmaceuticals (Basel). 14:4162021. View Article : Google Scholar
97	Raffaele S, Lombardi M, Verderio C and Fumagalli M: TNF production and release from microglia via extracellular vesicles: Impact on brain functions. Cells. 9:21452020. View Article : Google Scholar :
98	Milanese M, Bonifacino T, Torazza C, Provenzano F, Kumar M, Ravera S, Zerbo AR, Frumento G, Balbi M, Nguyen TPN, et al: Blocking glutamate mGlu₅ receptors with the negative allosteric modulator CTEP improves disease course in SOD1^G93A mouse model of amyotrophic lateral sclerosis. Br J Pharmacol. 178:3747–3764. 2021. View Article : Google Scholar : PubMed/NCBI
99	Boakye PA, Tang SJ and Smith PA: Mediators of neuropathic pain; focus on spinal microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt ligands, and interleukin 1β. Front Pain Res (Lausanne). 2:6981572021. View Article : Google Scholar
100	Anagnostakis F and Piperi C: Targeting options of tumor-associated macrophages (TAM) activity in gliomas. Curr Neuropharmacol. Jan 20–2022.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
101	Barca C, Foray C, Hermann S, Herrlinger U, Remory I, Laoui D, Schäfers M, Grauer OM, Zinnhardt B and Jacobs AH: The colony stimulating factor-1 receptor (CSF-1R)-mediated regulation of microglia/macrophages as a target for neurological disorders (glioma, stroke). Front Immunol. 12:7873072021. View Article : Google Scholar : PubMed/NCBI
102	Qian M, Wang S, Guo X, Wang J, Zhang Z, Qiu W, Gao X, Chen Z, Xu J, Zhao R, et al: Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-κB pathways. Oncogene. 39:428–442. 2020. View Article : Google Scholar
103	Counil H and Krantic S: Synaptic activity and (neuro)inflammation in Alzheimer's disease: Could exosomes be an additional link? J Alzheimers Dis. 74:1029–1043. 2020. View Article : Google Scholar : PubMed/NCBI
104	Zhu C, Bilousova T, Focht S, Jun M, Elias CJ, Melnik M, Chandra S, Campagna J, Cohn W, Hatami A, et al: Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson's disease model. Mol Brain. 14:702021. View Article : Google Scholar
105	Blitz SE, Kappel AD, Gessler FA, Klinger NV, Arnaout O, Lu Y, Peruzzi PP, Smith TR, Chiocca EA, Friedman GK and Bernstock JD: Tumor-associated macrophages/microglia in glioblastoma oncolytic virotherapy: A double-edged sword. Int J Mol Sci. 23:18082022. View Article : Google Scholar : PubMed/NCBI
106	Adamus T, Hung CY, Yu C, Kang E, Hammad M, Flores L, Nechaev S, Zhang Q, Gonzaga JM, Muthaiyah K, et al: Glioma-targeted delivery of exosome-encapsulated antisense oligonucleotides using neural stem cells. Mol Ther Nucleic Acids. 27:611–620. 2021. View Article : Google Scholar
107	Ehtesham M, Kabos P, Gutierrez MA, Chung NH, Griffith TS, Black KL and Yu JS: Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 62:7170–7174. 2002.PubMed/NCBI
108	Benmelouka AY, Munir M, Sayed A, Attia MS, Ali MM, Negida A, Alghamdi BS, Kamal MA, Barreto GE, Ashraf GM, et al: Neural stem cell-based therapies and glioblastoma management: Current evidence and clinical challenges. Int J Mol Sci. 22:22582021. View Article : Google Scholar : PubMed/NCBI
109	Batalla-Covello J, Ngai HW, Flores L, McDonald M, Hyde C, Gonzaga J, Hammad M, Gutova M, Portnow J, Synold T, et al: Multiple treatment cycles of neural stem cell delivered oncolytic adenovirus for the treatment of glioblastoma. Cancers (Basel). 13:63202021. View Article : Google Scholar
110	van Solinge TS, Nieland L, Chiocca EA and Broekman MLD: Advances in local therapy for glioblastoma-taking the fight to the tumour. Nat Rev Neurol. 18:221–236. 2022. View Article : Google Scholar : PubMed/NCBI
111	Luzzi S, Giotta Lucifero A, Brambilla I, Trabatti C, Mosconi M, Savasta S and Foiadelli T: The impact of stem cells in neuro-oncology: Applications, evidence, limitations and challenges. Acta Biomed. 91(Suppl 7): S51–E60. 2020.
112	Leopold AV, Chernov KG, Shemetov AA and Verkhusha VV: Neurotrophin receptor tyrosine kinases regulated with near-infrared light. Nat Commun. 10:11292019. View Article : Google Scholar : PubMed/NCBI
113	Hwang JW, Loisel-Duwattez J, Desterke C, Latsis T, Pagliaro S, Griscelli F, Bennaceur-Griscelli A and Turhan AG: A novel neuronal organoid model mimicking glioblastoma (GBM) features from induced pluripotent stem cells (iPSC). Biochim Biophys Acta Gen Subj. 1864:1295402020. View Article : Google Scholar : PubMed/NCBI
114	Mariappan A, Goranci-Buzhala G, Ricci-Vitiani L, Pallini R and Gopalakrishnan J: Trends and challenges in modeling glioma using 3D human brain organoids. Cell Death Differ. 28:15–23. 2021. View Article : Google Scholar
115	Goranci-Buzhala G, Mariappan A, Gabriel E, Ramani A, Ricci-Vitiani L, Buccarelli M, D'Alessandris QG, Pallini R and Gopalakrishnan J: Rapid and efficient invasion assay of glioblastoma in human brain organoids. Cell Rep. 31:1077382020. View Article : Google Scholar : PubMed/NCBI
116	Krieger TG, Tirier SM, Park J, Jechow K, Eisemann T, Peterziel H, Angel P, Eils R and Conrad C: Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics. Neuro Oncol. 22:1138–1149. 2020. View Article : Google Scholar : PubMed/NCBI
117	Krishna S, Choudhury A, Seo K, Ni L, Kakaizada F, Lee A, Aabedi A, Cao C, Sudharshan R, Egladyous A, et al: Glioblastoma remodeling of neural circuits in the human brain decreases survival. bioRxiv. Feb 19–2021.