Exploring the Vital Link Between Glioma, Neuron, and Neural Activity in the Context of Invasion

Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas. Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas. Most primary malignant brain tumors and approximately 30% of all primary brain tumors are gliomas.1Ostrom Q.T. Gittleman H. Fulop J. Liu M. Blanda R. Kromer C. Wolinsky Y. Kruchko C. Barnholtz-Sloan J.S. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.Neuro Oncol. 2015; 17: iv1-iv62Google Scholar Glioma growth pattern is characterized by diffuse infiltration into normal brain parenchyma. In 1938, the German pathologist Hans Joachim Scherer (1906 to 1945) characterized four glioma infiltration patterns in humans (namely; perineuronal satellitosis, perivascular satellitosis, infiltration along white matter tracts, and subpial spread), which are currently known as Scherer secondary structures.2Scherer H.J. Structural development in gliomas.Am J Cancer. 1938; 34: 333-351Google Scholar Infiltration along the white matter tracts and subpial spread are common in patients with late-stage glioma,3Sahm F. Capper D. Jeibmann A. Habel A. Paulus W. Troost D. Von Deimling A. Addressing diffuse glioma as a systemic brain disease with single-cell analysis.Arch Neurol. 2012; 69: 523-526Google Scholar whereas perineuronal and perivascular satellitosis are seen in early- to late-stage glioma. Although the role of perivascular satellitosis in nutrition and hypoxia has been studied,4Mahase S. Rattenni R.N. Wesseling P. Leenders W. Baldotto C. Jain R. Zagzag D. Hypoxia-mediated mechanisms associated with antiangiogenic treatment resistance in glioblastomas.Am J Pathol. 2017; 187: 940-953Google Scholar the effects and mechanisms of perineuronal satellitosis remain largely unknown. Specifically, determining whether gliomas reach the nerve by random stochastic coincidence, the infiltrating glioma cells interact with preexisting neurons, and perineuronal satellitosis contributes to glioma-treatment resistance, remain to determined. Glial cells perform various functions in the central nervous system (CNS) and aid in the nourishment and metabolism of neurons, which originate from glioma cells.5DeBerardinis R.J. Lum J.J. Hatzivassiliou G. Thompson C.B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation.Cell Metab. 2008; 7: 11-20Google Scholar Gliomas with astrocytic-like properties, such as anaplastic gliomas and glioblastomas, are highly malignant, with total resection of the affected area as the most effective available treatment strategy.6Ribas G.C. Yasuda A. Ribas E.C. Nishikuni K. Rodrigues A.J. Surgical anatomy of microneurosurgical sulcal key points.Neurosurgery. 2006; 59: ONS177-ONS210Google Scholar However, most gliomas, independent of malignancy level, exhibit Scherer secondary structures, making total resection impossible. A few invisible, infiltrating glioma cells linger, leading to local relapse.7Jakola A.S. Myrmel K.S. Kloster R. Torp S.H. Lindal S. Unsgård G. Solheim O. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas.JAMA. 2012; 308: 1881-1888Google Scholar Although resection of the extra parenchyma surrounding the tumor has been performed, it remains controversial, especially in elderly patients.8Molinaro A.M. Hervey-Jumper S. Morshed R.A. Young J. Han S.J. Chunduru P. et al.Association of maximal extent of resection of contrast-enhanced and non-contrast-enhanced tumor with survival within molecular subgroups of patients with newly diagnosed glioblastoma.JAMA Oncol. 2020; 6: 495-503Google Scholar Alterations in tumor metabolism are a characteristic feature of glioblastoma. Invasive glioma cells can generate the energy required for colonization nearby brain tissue and adapt to novel microenvironments with varying energy and oxygen availability through metabolic reprogramming.9Garcia J.H. Jain S. Aghi M.K. Metabolic drivers of invasion in glioblastoma.Front Cell Dev Biol. 2021; 9: 683276Google Scholar The recent Go and Grow hypothesis suggests a phenotypic switching between the go (migration) and grow state (proliferation), depending on the oxygen level and nutrients in the glioma microenvironment.10Giese A. Loo M.A. Tran N. Haskett D. Coons S.W. Berens M.E. Dichotomy of astrocytoma migration and proliferation.Int J Cancer. 1996; 67: 275-282Google Scholar,11Hara A. Kanayama T. Noguchi K. Niwa A. Miyai M. Kawaguchi M. Ishida K. Hatano Y. Niwa M. Tomita H. Treatment strategies based on histological targets against invasive and resistant glioblastoma.J Oncol. 2019; 2019: 2964783Google Scholar This hypothesis suggests that aerobic glycolysis from glucose to lactate serves as the energy source during migration and invasion into the glioma microenvironment, whereas the pentose phosphate pathway is mostly utilized during proliferation.12Kathagen-Buhmann A. Schulte A. Weller J. Holz M. Herold-Mende C. Glass R. Lamszus K. Glycolysis and the pentose phosphate pathway are differentially associated with the dichotomous regulation of glioblastoma cell migration versus proliferation.Neuro Oncol. 2016; 18: 1219-1229Google Scholar Recent studies using optogenetic techniques and mouse xenograft glioma models have described the unique role of synaptogenesis in the proliferation of gliomas and identified potential targets for therapeutic involvement.13Venkatesh H.S. Morishita W. Geraghty A.C. Silverbush D. Gillespie S.M. Arzt M. Tam L.T. Espenel C. Ponnuswami A. Ni L. Woo P.J. Taylor K.R. Agarwal A. Regev A. Brang D. Vogel H. Hervey-Jumper S. Malenka R.C. Monje M. Electrical and synaptic integration of glioma into neural circuits.Nature. 2019; 573: 539-545Google Scholar,14Venkataramani V. Tanev D.I. Strahle C. Studier-Fischer A. Fankhauser L. Kessler T. Körber C. Kardorff M. Ratliff M. Xie R. Horstmann H. Messer M. Paik S.P. Knabbe J. Sahm F. Kurz F.T. Acikgöz A.A. Herrmannsdörfer F. Agarwal A. Bergles D.E. Chalmers A. Miletic H. Turcan S. Mawrin C. Hänggi D. Liu H.K. Wick W. Winkler F. Kuner T. Glutamatergic synaptic input to glioma cells drives brain tumour progression.Nature. 2019; 573: 532-538Google Scholar Recently, a mouse model that recapitulates the invasion of diffuse gliomas by perineuronal satellitosis has been established.15Miyai M. Kanayama T. Hyodo F. Kinoshita T. Ishihara T. Okada H. Suzuki H. Takashima S. Wu Z. Hatano Y. Egashira Y. Enomoto Y. Nakayama N. Soeda A. Yano H. Hirata A. Niwa M. Sugie S. Mori T. Maekawa Y. Iwama T. Matsuo M. Hara A. Tomita H. Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.Neuro-oncology Adv. 2021; 3: vdaa150Google Scholar Although a model with a diffuse tumor infiltration into normal brain is reported,16Claes A. Schuuring J. Boots-Sprenger S. Hendriks-Cornelissen S. Dekkers M. Van Der Kogel A.J. Leenders W.P. Wesseling P. Jeuken J.W. Phenotypic and genotypic characterization of orthotopic human glioma models and its relevance for the study of anti-glioma therapy.Brain Pathol. 2008; 18: 423-433Google Scholar,17Hashizume R. Gupta N. Patient-derived tumor models for diffuse intrinsic pontine gliomas.Curr Neuropharmacol. 2016; 15: 98-103Google Scholar histopathologic analysis revealed that this model is specifically tailored to perineuronal satellitosis. This review discusses the state of knowledge on the mechanism of perineuronal satellitosis and the interaction between glioma cells and neurons during tumor development and growth. Scherer was the first to define perineuronal satellitosis and glioma growth patterns in his influential study titled “Structural Development in Gliomas.”2Scherer H.J. Structural development in gliomas.Am J Cancer. 1938; 34: 333-351Google Scholar His work was based on the microscopic examination of 100 gliomas, including the entire tumor and surrounding structures, from the autopsy specimens of human patients. The term secondary structures is used to indicate all structures formed by glioma cells around preexisting tissue elements.2Scherer H.J. Structural development in gliomas.Am J Cancer. 1938; 34: 333-351Google Scholar Some of these structural characteristics become more obvious after a complete disruption of the tissue elements by glioma cells. Scherer described eight categories of secondary structures—perineural and neuronophagic, surface, perivascular, perifascicular, intrafascicular, interfibrillar, white and gray matter growth, and combinations of secondary structures. Perineural infiltration, including perineuronal satellitosis, is observed in perineural and neuronophagic, perifascicular, and interfibrillar growth. Neoplastic cells that spread around neurons and dendrites are known as perineuronal satellitosis. Glioma cells gather to replace the destroyed nerve cells via a process known as neuronophagic proliferation. Presently, perineuronal satellitosis, perivascular satellitosis, subpial spread, and invasion along the white matter tracts are the four basic histologic categories that may be used to categorize the formations (Figure 1).11Hara A. Kanayama T. Noguchi K. Niwa A. Miyai M. Kawaguchi M. Ishida K. Hatano Y. Niwa M. Tomita H. Treatment strategies based on histological targets against invasive and resistant glioblastoma.J Oncol. 2019; 2019: 2964783Google Scholar Scherer secondary structures in the mouse brain can be reproduced and recapitulated using a rare glioma cell line known as IG27 cells,15Miyai M. Kanayama T. Hyodo F. Kinoshita T. Ishihara T. Okada H. Suzuki H. Takashima S. Wu Z. Hatano Y. Egashira Y. Enomoto Y. Nakayama N. Soeda A. Yano H. Hirata A. Niwa M. Sugie S. Mori T. Maekawa Y. Iwama T. Matsuo M. Hara A. Tomita H. Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.Neuro-oncology Adv. 2021; 3: vdaa150Google Scholar a model of diffuse glioma with H3.3K27M mutation. The IG27-diffuse glioma displays perineuronal and perivascular satellitosis as well as extensive infiltration into normal tissue; IG27-diffuse glioma cells along nerve axons are also seen in the white matter pathways. Scherer characterized the primary structures of gliomas as morphologic patterns resulting from the intrinsic biology of tumors, which appear independently of previous tissue. Whorls, papillary structures, canaliculi, glandular formations, rosettes, and pseudorosettes are some examples of primary structures.18Peiffer J. Hans-Joachim Scherer (1906-1945), pioneer in glioma research.Brain Pathol. 1999; 9: 241-245Google Scholar Development of new blood vessels is essential for the growth of glioblastoma tumors, which are highly vascularized. Vascular endothelial cells proliferate, migrate, and differentiate throughout the complicated process of angiogenesis, which is triggered by certain signals.19Ahir B.K. Engelhard H.H. Lakka S.S. Tumor development and angiogenesis in adult brain tumor: glioblastoma.Mol Neurobiol. 2020; 57: 2461-2478Google Scholar Scherer secondary structures is the term given to patterns of glioma cell invasion.2Scherer H.J. Structural development in gliomas.Am J Cancer. 1938; 34: 333-351Google Scholar Scherer secondary structures are histopathologically classified on the basis of glioma distribution, development, and biological potential. The microenvironment significantly influences the migration of glioma cells, as observed via careful examination of histomorphology. Moreover, invasive glioma cells that exhibit Scherer secondary structures imitate crucial intracellular processes of both proliferation and migration in neural stem cells (NSCs) or glial progenitor cells in the CNS.20Mehta S. Lo Cascio C. Developmentally regulated signaling pathways in glioma invasion.Cell Mol Life Sci. 2018; 75: 385-402Google Scholar The term satellitosis refers to both reactive and neoplastic processes and describes an increase in the number of cells around a neuron. Typically associated with diffuse astrocytic neoplasms, neoplastic satellitosis is observed more frequently than reactive satellitosis. Intrafascicular growth occurs when cells preferentially infiltrate along myelinated fibers in white matter tracts, along with subpial, perivascular, and perineuronal accumulation of glioma cells.21Claes A. Idema A.J. Wesseling P. Diffuse glioma growth: a guerilla war.Acta Neuropathol. 2007; 114: 443-458Google Scholar Reactive satellitosis is characterized by neuronal degeneration, with little changes where the satellite cells are represented by nonneoplastic glial cells.22Civita P. Valerio O. Naccarato A.G. Gumbleton M. Pilkington G.J. Satellitosis, a crosstalk between neurons, vascular structures and neoplastic cells in brain tumours; early manifestation of invasive behaviour.Cancers. 2020; 12: 3720Google Scholar The structure of perineuronal satellitosis was determined using two-dimensional microscope. A recent study used three-dimensional images obtained using scanning electron microscopy to demonstrate that the histone H3K27M mutated IG27 cells are tightly connected to neurons in diffuse gliomas in mouse brain (Figure 2).15Miyai M. Kanayama T. Hyodo F. Kinoshita T. Ishihara T. Okada H. Suzuki H. Takashima S. Wu Z. Hatano Y. Egashira Y. Enomoto Y. Nakayama N. Soeda A. Yano H. Hirata A. Niwa M. Sugie S. Mori T. Maekawa Y. Iwama T. Matsuo M. Hara A. Tomita H. Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.Neuro-oncology Adv. 2021; 3: vdaa150Google Scholar The role of neural activity in glioma infiltration and proliferation has been previously elucidated.13Venkatesh H.S. Morishita W. Geraghty A.C. Silverbush D. Gillespie S.M. Arzt M. Tam L.T. Espenel C. Ponnuswami A. Ni L. Woo P.J. Taylor K.R. Agarwal A. Regev A. Brang D. Vogel H. Hervey-Jumper S. Malenka R.C. Monje M. Electrical and synaptic integration of glioma into neural circuits.Nature. 2019; 573: 539-545Google Scholar,14Venkataramani V. Tanev D.I. Strahle C. Studier-Fischer A. Fankhauser L. Kessler T. Körber C. Kardorff M. Ratliff M. Xie R. Horstmann H. Messer M. Paik S.P. Knabbe J. Sahm F. Kurz F.T. Acikgöz A.A. Herrmannsdörfer F. Agarwal A. Bergles D.E. Chalmers A. Miletic H. Turcan S. Mawrin C. Hänggi D. Liu H.K. Wick W. Winkler F. Kuner T. 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Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain.Science. 2014; 344: 1252304Google Scholar demonstrated that normal neural and oligodendroglial precursor cells in juvenile and adult mammalian brains have a significant mitogenic impact, indicating that neuronal activity may encourage proliferation in high-grade glioma (HGG). The subgranular zone of the dentate gyrus during hippocampus formation and the subventricular zone (SVZ) of the lateral ventricles are primary neurogenic zones in the adult mammalian brain. Glial fibrillary acidic protein–positive adult NSCs are quiescent cells with unrestricted capacity for self-renewal and multipotency. Proliferative progenitor cells derived from NSCs have a low capacity for self-renewal and are destined to develop into various cell types.28Alcantara Llaguno S.R. Parada L.F. Cell of origin of glioma: biological and clinical implications.Br J Cancer. 2016; 115: 1445-1450Google Scholar New neurons are produced by neuronal progenitor cells, which develop from NSCs in the SVZ and move along the rostral migratory stream and into the olfactory bulb, whereas migration of neurons into the granular cell layer occurs in the subgranular zone.28Alcantara Llaguno S.R. Parada L.F. Cell of origin of glioma: biological and clinical implications.Br J Cancer. 2016; 115: 1445-1450Google Scholar The activity of cholinergic neurons that branch out into the postnatal SVZ controls neurogenesis in that region.36Paez-Gonzalez P. Asrican B. Rodriguez E. Kuo C.T. Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis.Nat Neurosci. 2014; 17: 934-942Google Scholar Similarities between glioma stem cells and NSCs of the SVZ include high cell migration, variability of genetic material, strong proliferative potential, affiliation with blood vessels, and bilateral interaction with niche components, such as endothelial cells, pericytes, astrocytes, or extracellular matrix.37Matarredona E.R. Pastor A.M. Neural stem cells of the subventricular zone as the origin of human glioblastoma stem cells: therapeutic implications.Front Oncol. 2019; 9: 779Google Scholar In addition, recent studies have shown that the SVZ may potentially be a source of brain tumor stem cells, which resemble neurons, astrocytes, and oligodendrocytes that produce NSCs in terms of morphology and physiology.37Matarredona E.R. Pastor A.M. 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Its database contains information regarding the expression of genes associated with several structural characteristics frequently observed in glioblastoma tumors that have undergone laser capture microdissection (LCM) (Table 1).42Prabhu A. Kesarwani P. Kant S. Graham S.F. Chinnaiyan P. Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis.Neuro Oncol. 2017; 19: 1599-1606Google Scholar, 43Civita P. Franceschi S. Aretini P. Ortenzi V. Menicagli M. Lessi F. Pasqualetti F. Naccarato A.G. Mazzanti C.M. Laser capture microdissection and RNA-Seq analysis: high sensitivity approaches to explain histopathological heterogeneity in human glioblastoma FFPE archived tissues.Front Oncol. 2019; 9: 482Google Scholar, 44Daubon T. Guyon J. Raymond A.A. Dartigues B. Rudewicz J. Ezzoukhry Z. Dupuy J.W. Herbert J.M.J. Saltel F. Bjerkvig R. Nikolski M. Bikfalvi A. 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Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis.Neuro Oncol. 2017; 19: 1599-1606Google Scholar observed that glioblastoma subtype heterogeneity and its distinct tumor microenvironment are related, as are invading cells with a proneural hallmark.41Puchalski R.B. Shah N. Miller J. Dalley R. Nomura S.R. Yoon J.-G. et al.An anatomic transcriptional atlas of human glioblastoma.Science. 2018; 360: 660-663Google ScholarTable 1Articles with a Focus on Glioma Cell Infiltration Using Laser Capture MicrodissectionArticle no.StudySamplesGenes/pathway related to glioma infiltrationImplications of the genes/pathway1Prabhu et al (2017)42Prabhu A. Kesarwani P. Kant S. Graham S.F. Chinnaiyan P. Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis.Neuro Oncol. 2017; 19: 1599-1606Google ScholarHuman glioma tissue 37 caseAutophagy.Fatty acid metabolism unique to early stages of gliomagenesis.Neuronal receptor signaling.Comparison of central tumor and infiltrating tumor in glioma. Infiltrating tumor showed amplification of genes regulating neuronal receptor signaling and autophagy involved in the regulation of neurotransmitter release.2Civita et al (2019)43Civita P. Franceschi S. Aretini P. Ortenzi V. Menicagli M. Lessi F. Pasqualetti F. Naccarato A.G. Mazzanti C.M. Laser capture microdissection and RNA-Seq analysis: high sensitivity approaches to explain histopathological heterogeneity in human glioblastoma FFPE archived tissues.Front Oncol. 2019; 9: 482Google ScholarHuman glioblastoma tissue 3 caseForma