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Background: Gliomas differ from meningiomas in their margins, most of which are not separated from the surrounding tissue by a distinct interface. Purpose: To characterize the margins of gliomas quantitatively based on the margin sharpness coefficient (MSC) is significant for clinical judgment and invasive analysis of gliomas. Material and Methods: The data for this study used magnetic resonance image (MRI) data from 67 local patients and 15 open patients to quantify the intensity of changes in the glioma margins of the brain using MSC. The accuracy of MSC was assessed by consistency analysis and Bland–Altman test analysis, as well as invasive correlations using receiver operating characteristic (ROC) and Spearman correlation coefficients for subjects. Results: In grading the tumors, the mean MSC values were significantly lower for high-grade gliomas (HGG) than for low-grade gliomas (LGG). The concordance correlation between the measured gradient and the actual gradient was high (HGG: 0.981; LGG: 0.993), and the Bland–Altman mean difference at the 95% confidence interval (HGG: −0.576; LGG: 0.254) and the limits of concordance (HGG: 5.580; LGG: 5.436) indicated no statistical difference. The correlation between MSC and invasion based on the margins of gliomas showed an AUC of 0.903 and 0.911 for HGG and LGG, respectively. The mean Spearman correlation coefficient of the MSC versus the actual distance of invasion was −0.631 in gliomas. Conclusion: The relatively low MSC on the blurred margins and irregular shape of gliomas may help in benign-malignant differentiation and invasion prediction of gliomas and has potential application for clinical judgment. [ABSTRACT FROM AUTHOR]

Malignant gliomas are notoriously invasive, a major impediment against their successful treatment. This invasive growth has motivated the use of predictive partial differential equation models, formulated at varying levels of detail, and including (i) “proliferation-infiltration” models, (ii) “go-or-grow” models, and (iii) anisotropic diffusion models. Often, these models use macroscopic observations of a diffuse tumour interface to motivate a phenomenological description of invasion, rather than performing a detailed and mechanistic modelling of glioma cell invasion processes. Here we close this gap. Based on experiments that support an important role played by long cellular protrusions, termed tumour microtubes, we formulate a new model for microtube-driven glioma invasion. In particular, we model a population of tumour cells that extend tissue-infiltrating microtubes. Mitosis leads to new nuclei that migrate along the microtubes and settle elsewhere. A combination of steady state analysis and numerical simulation is employed to show that the model can predict an expanding tumour, with travelling wave solutions led by microtube dynamics. A sequence of scaling arguments allows us reduce the detailed model into simpler formulations, including models falling into each of the general classes (i), (ii), and (iii) above. This analysis allows us to clearly identify the assumptions under which these various models can be a posteriori justified in the context of microtube-driven glioma invasion. Numerical simulations are used to compare the various model classes and we discuss their advantages and disadvantages. [ABSTRACT FROM AUTHOR]

Gliomas are the most common and fatal brain tumors worldwide. Abnormal DNA promoter methylation is an important mechanism for gene loss of tumor suppressors. A long non-coding RNA colorectal adenocarcinoma hypermethylated (CAHM) has been reported to be nearly deleted in glioblastomas (GBMs). Nevertheless, the roles of CAHM in gliomas remain unknown up to now. In the present study, 969 glioma samples downloaded from the CGGA and Gravendeel databases were included. We found that CAHM expression was correlated with glioma grades, molecular subtype, IDH mutation status, and 1q/19p codel status. In glioma cells, CAHM is hypermethylated by DNA methyltransferase1 (DNMT1) and the loss of CAHM expression could be reversed by 5-Aza-2′-deoxycytidine (5-Aza), a specific inhibitor of DNA methyltransferases. Besides, the expression of CAHM was negatively associated with overall survival in both primary and recurrent gliomas. Moreover, the result of Gene Ontology (GO) analysis suggested that CAHM participated in negatively regulating cell development, nervous system development, neurogenesis, and integrin-mediated signaling pathway. Overexpression of CAHM inhibited glioma cell proliferation, clone formation, and invasion. Further exploring results showed that CAHM overexpression suppressed glioma migration and invasion through SPAK/MAPK pathway. Collectively, this study disclosed that CAHM might be a suppressor in gliomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Since the pioneering work of Damadian (1971), the longitudinal T1-relaxation of nuclear magnetic resonance (NMR) has been reported to generate significant contrast between cancer and healthy tissues at low magnetic fields. However, low NMR sensitivity was a substantial obstacle. Fast field cycling NMR (FFC-NMR) can overcome this problem and is commercially available for physics/chemistry research since around the years 2000s. Herein, using FFC-NMR in vivo, we show that T1-relaxation measured at very low fields is sensitive to transmembrane water exchange, thus allowing the discrimination between glioma invasion/migration and proliferation. Aquaporins 4 and 1 are found to be upregulated in invasion/migration, indicating that water exchange modulates T1-relaxations in glioma, via these aquaporins action. Overall, results suggest that, by blocking the aquaporin functions, the T1-relaxation should decrease in invasion/migration glioma. Results also stipulate that the entire invasion/migration volume could be visualized by FFC imaging, noninvasively. This may impact the medical community since invasion/migration delineation remains challenging by any medical imaging modality. This work shows that the longitudinal relaxation differences observed at very low magnetic fields between invasion/migration and proliferation processes on glioma mouse models in vivo are related to differences in the transmembrane water exchange basically linked to the aquaporin expression changes. Three glioma mouse models were used: Glio6 and Glio96 as invasion/migration models and U87 as cell proliferation model. In vivo proton longitudinal relaxation-rate constants (R1) at very low fields were measured by fast field cycling NMR (FFC-NMR). The tumor contribution to the observed proton relaxation rate, R1tum (U87: 12.26 ± 0.64 s−1; Glio6: 3.76 ± 0.88 s−1; Glio96: 6.90 ± 0.64 s−1 at 0.01 MHz), and the intracellular water lifetime, τin (U87: 826 ± 19 ms; Glio6: 516 ± 8 ms; Glio96: 596 ± 15 ms), were found to be good diagnostic hallmarks to distinguish invasion/migration from proliferation (p < 0.01 and 0.001). Overexpression of AQP4 and AQP1 were assessed in invasion/migration models, highlighting the pathophysiological role of these two aquaporins in water exchange that, in turn, determine the lower values in the observed R1 relaxation rate constant in glioma invasion/migration. Overall, our findings demonstrate that τin and R1 (measured at very low fields) are relevant biomarkers, discriminating invasion/migration from proliferation in vivo. These results highlight the use of FFC-NMR and FFC-imaging to assess the efficiency of drugs that could modulate aquaporin functions. [ABSTRACT FROM AUTHOR]

Background: Gliomas are highly invasive brain neoplasms. MRI is the most important tool to diagnose and monitor glioma but has shortcomings. In particular, the assessment of tumor cell invasion is insufficient. This is a clinical dilemma, as recurrence can arise from MRI-occult glioma cell invasion., Hypothesis: Tumor cell invasion, tumor growth and radiotherapy alter the brain parenchymal microstructure and thus are assessable by diffusion tensor imaging (DTI) and MR elastography (MRE)., Study Type: Experimental, animal model., Animal Model: Twenty-three male NMRI nude mice orthotopically implanted with S24 patient-derived glioma cells (experimental mice) and 9 NMRI nude mice stereotactically injected with 1 μL PBS (sham-injected mice)., Field Strength/sequence: 2D and 3D T2-weighted rapid acquisition with refocused echoes (RARE), 2D echo planar imaging (EPI) DTI, 2D multi-slice multi-echo (MSME) T2 relaxometry, 3D MSME MRE at 900 Hz acquired at 9.4 T (675 mT/m gradient strength)., Assessment: Longitudinal 4-weekly imaging was performed for up to 4 months. Tumor volume was assessed in experimental mice (n = 10 treatment-control, n = 13 radiotherapy). The radiotherapy subgroup and 5 sham-injected mice underwent irradiation (3 × 6 Gy) 9 weeks post-implantation/sham injection. MRI-/MRE-parameters were assessed in the corpus callosum and tumor core/injection tract. Imaging data were correlated to light sheet microscopy (LSM) and histology., Statistical Tests: Paired and unpaired t-tests, a P-value ≤0.05 was considered significant., Results: From week 4 to 8, a significant callosal stiffening (4.44 ± 0.22 vs. 5.31 ± 0.29 kPa) was detected correlating with LSM-proven tumor cell invasion. This was occult to all other imaging metrics. Histologically proven tissue destruction in the tumor core led to an increased T2 relaxation time (41.65 ± 0.34 vs. 44.83 ± 0.66 msec) and ADC (610.2 ± 12.27 vs. 711.2 ± 13.42 × 10 -6  mm 2 /s) and a softening (5.51 ± 0.30 vs. 4.24 ± 0.29 kPa) from week 8 to 12. Radiotherapy slowed tumor progression., Data Conclusion: MRE is promising for the assessment of key glioma characteristics., Evidence Level: NA TECHNICAL EFFICACY: Stage 2., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

We deduce a model for glioma invasion that accounts for the dynamics of brain tissue being actively degraded by tumor cells via excessive acidity production, but also according to the local orientation of tissue fibers. Our approach has a multiscale character: we start with a microscopic description of single cell dynamics including biochemical and/or biophysical effects of the tumor microenvironment, translated on the one hand into cell stress and corresponding forces and on the other hand into receptor binding dynamics. These lead on the mesoscopic level to kinetic equations involving transport terms with respect to all considered kinetic variables and eventually, by appropriate upscaling, to a macroscopic reaction–diffusion equation for glioma density with multiple taxis, coupled to (integro-)differential equations characterizing the evolution of acidity and macro- and mesoscopic tissue. Our approach also allows for a switch between fast and slower moving regimes, according to the local tissue anisotropy. We perform numerical simulations to assess the importance of each tactic term and investigate the influence of two models for tissue dynamics on the tumor shape. We also suggest how the model can be used to perform a numerical necrosis-based tumor grading or support radiotherapy planning by dose painting. Finally, we discuss alternative ways of including cell level environmental influences in such a multiscale modeling approach, ultimately leading in the macroscopic limit to (multiple) taxis. [ABSTRACT FROM AUTHOR]

Glioma is a broad class of brain and spinal cord tumors arising from glia cells, which are the main brain cells that can develop into neoplasms.They are highly invasive and lead to irregular tumor margins which are not precisely identifiable by medical imaging, thus rendering a precise enough resection very difficult.The understanding of glioma spread patterns is hence essential for both radiological therapy as well as surgical treatment.In this paper we propose a multiscale model for glioma growth including interactions of the cells with the underlying tissuenetwork, along with proliferative effects. Our current accounting for two subpopulations of cells to accomodate proliferation according to the go-or-grow dichtomotyis an extension of the setting in [16].As in that paper, we assume that cancer cells use neuronal fiber tracts as invasive pathways. Hence, the individualstructure of brain tissue seems to be decisive for the tumor spread. Diffusion tensor imaging (DTI) is able to provide suchinformation, thus opening the way for patient specificmodeling of glioma invasion. Starting from a multiscale model involving subcellular (microscopic) and individual (mesoscale)cell dynamics, we perform a parabolic scaling to obtain an approximating reaction-diffusion-transport equation on themacroscale of the tumor cell population. Numerical simulations based on DTI data are carried out in order to assess theperformance of our modeling approach.

Starting from a two-scale description involving receptor binding dynamics and a kinetic transport equation for the evolution of the cell density function under velocity reorientations, we deduce macroscopic models for glioma invasion featuring partial differential equations for the mass density and momentum of a population of glioma cells migrating through the anisotropic brain tissue. The proposed first and higher-order moment closure methods enable numerical simulations of the kinetic equation. Their performance is then compared to that of the diffusion limit. The approach allows for diffusion tensor imaging (DTI)-based, patient-specific predictions of the tumor extent and its dynamic behavior. [ABSTRACT FROM AUTHOR]

Abstract: Glioblastoma multiforme is the most common brain tumor in adults. Because of its highly invasive nature, it is not easy to treat, resulting in high mortality rates. Stromal interacting molecule 1 (Stim1) plays important roles in regulating store‐operated Ca2+ entry, and controls invasion by cancer cells. However, the mechanisms and functions of Stim1 in glioma progression are still unclear. In this study, we investigated the effects of targeting Stim1 expression on glioma cell invasion. By analyzing profiles of glioblastoma multiforme patients from RNA‐sequencing data in The Cancer Genome Atlas, higher expression levels of STIM1 were correlated with the poor survival. Furthermore, signaling pathways associated with tumor malignancy, including the epithelial‐to‐mesenchymal transition (EMT), were activated in patients with high STIM1 expression according to gene set enrichment analyses. Higher Stim1 levels were found in glioma cells compared to human astrocytes, and these higher levels enhanced glioma cell invasion. Xanthohumol (XN), a prenylated flavonoid extracted from the hop plant Humulus lupulus L. (Cannabaceae), significantly reduced cell invasion through inhibiting Stim1 expression. From an micro(mi)RNA array analysis, miR‐4725‐3p was up‐regulated by XN treatment. Over‐expression of miR‐4725‐3p inhibited glioma cell invasion via directly targeting the 3′‐untranslated region of STIM1. The extracellular signal‐regulated kinase/c‐Fos pathway was also validated to participate in XN‐up‐regulated miR‐4725‐3p expression according to promoter and chromatin immunoprecipitation assays. These results emphasize that miR‐4725‐3p‐inhibited STIM1 signaling is involved in XN‐attenuated glioma cell invasion. These findings may provide insights into novel therapeutic strategies for future glioblastoma therapy and drug development. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/ [ABSTRACT FROM AUTHOR]

Glioblastoma are notorious for their highly invasive growth, diffusely infiltrating adjacent brain structures that precludes complete resection, and is a major obstacle for cure. To characterize this “invisible” tumor part, we designed a high resolution multimodal imaging approach assessing in vivo the metabolism of invasively growing glioma xenografts in the mouse brain. Animals were subjected longitudinally to magnetic resonance imaging (MRI) and 1H spectroscopy (MRS) at ultra high field (14.1 Tesla) that allowed the measurement of 16 metabolic biomarkers to characterize the metabolic profiles. As expected, the neuronal functionality was progressively compromised as indicated by decreasing N‐acetyl aspartate, glutamate and gamma‐aminobutyric acid and reduced neuronal TCA cycle (−58%) and neurotransmission (−50%). The dynamic metabolic changes observed, captured differences in invasive growth that was modulated by re‐expression of the tumor suppressor gene WNT inhibitory factor 1 (WIF1) in the orthotopic xenografts that attenuates invasion. At late stage mice were subjected to 13C MRS with infusion of [1,6‐13C]glucose and 18FDG positron emission tomography (PET) to quantify cell‐specific metabolic fluxes involved in glucose metabolism. Most interestingly, this provided the first in vivo evidence for significant glucose oxidation in glioma cells. This suggests that the infiltrative front of glioma does not undergo the glycolytic switch per se, but that environmental triggers may induce metabolic reprograming of tumor cells. [ABSTRACT FROM AUTHOR]

Abstract: Malignant gliomas are primary tumors of the central nervous system characterized by diffuse infiltration into the brain and a high recurrence rate. Advances in comprehensive genomic studies have provided unprecedented insight into the genetic and molecular heterogeneity of these tumors and refined our understanding of their evolution from low to high grade. However, similar levels of phenotypic characterization are indispensable to understanding the complexity of malignant gliomas. Experimental glioma models have also achieved great progress in recent years. Advances in transgenic technologies and cell culture have allowed the establishment of mouse models that mirror the human disease with increasing fidelity and which support single‐cell resolution for phenotypic analyses. Here we review the major types of preclinical glioma models, with an emphasis on how recent developments in experimental modeling have shed new light on two fundamental aspects of glioma phenotype, their cell of origin and their invasive potential. [ABSTRACT FROM AUTHOR]

Diffuse invasion of glioma cells into the brain parenchyma leads to nonresectable brain tumors and poor prognosis of glioma disease. In vivo, glioma cells can adopt a range of invasion strategies and routes, by moving as single cells, collective strands and multicellular networks along perivascular, perineuronal and interstitial guidance cues. Current in vitro assays to probe glioma cell invasion, however, are limited in recapitulating the modes and adaptability of glioma invasion observed in brain parenchyma, including collective behaviours. To mimic in vivo-like glioma cell invasion in vitro, we here applied three tissue-inspired 3D environments combining multicellular glioma spheroids and reconstituted microanatomic features of vascular and interstitial brain structures. Radial migration from multicellular glioma spheroids of human cell lines and patient-derived xenograft cells was monitored using (1) reconstituted basement membrane/hyaluronan interfaces representing the space along brain vessels; (2) 3D scaffolds generated by multi-layered mouse astrocytes to reflect brain interstitium; and (3) freshly isolated mouse brain slice culture ex vivo. The invasion patterns in vitro were validated using histological analysis of brain sections from glioblastoma patients and glioma xenografts infiltrating the mouse brain. Each 3D assay recapitulated distinct aspects of major glioma invasion patterns identified in mouse xenografts and patient brain samples, including individually migrating cells, collective strands extending along blood vessels, and multicellular networks of interconnected glioma cells infiltrating the neuropil. In conjunction, these organotypic assays enable a range of invasion modes used by glioma cells and will be applicable for mechanistic analysis and targeting of glioma cell dissemination. [ABSTRACT FROM AUTHOR]

Glioma is a common type of primary brain tumour, with a strongly invasive potential, often exhibiting non-uniform, highly irregular growth. This makes it difficult to assess the degree of extent of the tumour, hence bringing about a supplementary challenge for the treatment. It is therefore necessary to understand the migratory behaviour of glioma in greater detail. In this paper, we propose a multiscale model for glioma growth and migration. Our model couples the microscale dynamics (reduced to the binding of surface receptors to the surrounding tissue) with a kinetic transport equation for the cell density on the mesoscopic level of individual cells. On the latter scale, we also include the proliferation of tumour cells via effects of interaction with the tissue. An adequate parabolic scaling yields a convection-diffusion- reaction equation, for which the coefficients can be explicitly determined from the information about the tissue obtained by diffusion tensor imaging (DTI). Numerical simulations relying on DTI measurements confirm the biological findings that glioma spread along white matter tracts. [ABSTRACT FROM AUTHOR]

In recent years, tissue clearing has revolutionized the way we view biological materials. This has resulted in considerable advances in neuropathology and brain imaging. Its application to gliomas has the potential to increase understanding of tumor architecture, reveal mechanisms of tumor invasion, and provide valuable insights into diagnostics and treatments. This review outlines numerous tissue-clearing applications and recent developments in glioma research and delineates the limitations of existing technology and potential applications in experimental and clinical oncology., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy [ABSTRACT FROM AUTHOR]

Abstract: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which play a key role in invasion, migration, and angiogenesis of astrogliomas and other malignant tumors. Thus, controlling MMPs has been considered an important therapeutic strategy for prevention and/or treatment of gliomas. However, most MMP inhibitors developed so far are broad spectrum inhibitors; thus, it is necessary to develop a selective MMP inhibitor to minimize potential side effects. In the present study, we found that mangiferin, a glucosylxanthone isolated from Anemarrhena asphodeloides, specifically inhibited MMP-9 gene expression in phorbol myristate acetate (PMA)-stimulated human astroglioma U87MG, U373MG, and CRT-MG cells. However, it did not affect other MMPs, such as MMP-1, -2, -3, and -14. Mangiferin suppressed MMP-9 expression at the promoter, mRNA, and protein levels and additionally inhibited MMP-9 enzymatic activity. The Matrigel-invasion assay showed that mangiferin suppresses the in vitro invasiveness of glioma cells, which appears to be correlated with mangiferin-mediated MMP-9 inhibition. Further mechanistic studies demonstrated that mangiferin inhibits the binding of NF-κB and AP-1 to the MMP-9 promoter and suppresses the PMA-induced phosphorylation of Akt and MAP kinases, which are upstream signaling molecules in MMP-9 expression. Thus, the specific inhibition of MMP-9 by mangiferin may provide a valuable pharmacological tool for treatment of gliomas. [Copyright &y& Elsevier]

Abstract: Invasion of malignant glioma is a highly complex phenomenon involving molecular and cellular processes at various spatio-temporal scales, whose precise interplay is still not fully understood. In order to identify the intrinsic cellular mechanisms of glioma invasion, we study an in vitro culture of glioma cells. By means of a computational approach, based on a cellular automaton model, we compare simulation results to the experimental data and deduce cellular mechanisms from microscopic and macroscopic observables (experimental data). For the first time, it is shown that the migration/proliferation dichotomy plays a central role in the invasion of glioma cells. Interestingly, we conclude that a diverging invasive zone is a consequence of this dichotomy. Additionally, we observe that radial persistence of glioma cells in the vicinity of dense areas accelerates the invasion process. We argue that this persistence results from a cell-cell repulsion mechanism. If glioma cell behavior is regulated through a migration/proliferation dichotomy and a self-repellent mechanism, our simulations faithfully reproduce all the experimental observations. [Copyright &y& Elsevier]

To identify molecular therapeutic targets for glioma, we performed gene expression profiling by using a complementary DNA (cDNA) microarray method and identified the urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) as a gene expressed highly in glioma tissue compared with the normal brain tissue. The uPARAP is an endocytic receptor for collagen. In certain cell types, uPARAP occurs in a complex with the urokinase plasminogen activator receptor (uPAR) where it fulfills other functions in addition to collagenolysis. Quantitative PCR analysis using a cDNA panel revealed higher expression levels of uPARAP in glioma tissue compared with normal brain tissue. Western blot analysis revealed that the uPARAP protein was expressed in glioma samples and two glioma cell lines, KNS42 and KNS81, but not expressed in control tissue from the normal brain. Introduction of small interfering RNA-targeted uPARAP into the two different glioma cell lines, KNS42 and KNS81, resulted in downregulation of uPARAP expression, and it significantly suppressed glioma cell migration and invasion in vitro. Control glioma cells showed small cell bodies, whereas uPARAP siRNA-treated glioma cells exhibited large and flat morphology. Most of the polymeric actin in the control glioma cells was concentrated in the lamellipodia that are observed in mobile cells. In contrast, in the uPARAP siRNA-treated glioma cells, polymeric actin became organized in stress fibers and the lamellipodia disappeared, characteristic of immobile cells. Our present study suggests that uPARAP may be involved in glioma cell invasiveness through actin cytoskeletal rearrangement. downregulation of uPARAP may be a novel anti-invasion therapeutic strategy for malignant gliomas. [ABSTRACT FROM AUTHOR]

The natural morphological growth and invasion of World Health Organization (WHO) grade II glioma has not been well documented in previous literature. This study retrospectively analysed the morphological invasive characteristics of adult. Data from 20 patients (15 men, 5 women; mean age, 38 years; age range, 22–64 years), who had supratentorial WHO grade II gliomas and consecutively underwent serial preoperative conventional MR examinations were retrospectively analysed, for change in location, and evidence of haemorrhage, enhancement, necrosis, peri-tumoural oedema and mass effect. Seven tumours, initially located in the grey matter (3, insula; 4, frontal cortices), expanded without definite invasion along fibres. Thirteen tumours, originated from the junction of grey and white matter, invaded in different orientations (4, contralateral invasion; 1, ipsilateral remote dissemination; 8, ipsilateral invasion via the surrounding fibres). The increased proportion of haemorrhage, enhancement, necrosis, peri-tumoural oedema and mass effect in the first and last pre-operative examinations were 14% (1/7), 29% (2/7), 43% (3/7), 43% (3/7) and 29% (2/7), respectively, for the 7 tumours initially located in grey matter, and 15% (2/13), 38% (5/13), 31% (4/13), 15% (2/13) and 38% (5/13) respectively for the 13 tumours initially located at the junction of grey and white matter. The growth of supratentorial WHO grade II glioma is a complicated process. The growth directionality may be determined by initial tumour location. [ABSTRACT FROM AUTHOR]

Abstract: Matrix metalloproteinases (MMPs) play an important role in glioma infiltration, facilitating cell migration and tumor invasion through their ability to degrade the extracellular matrix. Therefore, the inhibition of MMPs has been suggested to be a promising therapeutic strategy for brain tumors. This study examined the effect of ginsenoside Rh2 on the expression of MMPs in human astroglioma cells. Rh2 inhibited the PMA-induced mRNA expression of MMP-1, -3, -9, and -14, suggesting that Rh2 has a broad-spectrum inhibitory effect on MMPs. The molecular mechanism underlying MMP-9 inhibition was further investigated because MMP-9 plays a major role in the invasiveness of glioma. It was found that Rh2 inhibited the secretion and protein expression of MMP-9 induced by PMA in human astroglioma cells. The Rh2-mediated inhibition of MMP-9 gene expression appears to occur through NF-κB and AP-1 because their DNA binding and transcriptional activities were suppressed by the agent. Furthermore, Rh2 significantly repressed the PMA-mediated activation of p38 MAPK, ERK and JNK, which are upstream modulators of NF-κB and AP-1. Finally, Rh2 inhibited the in vitro invasiveness of glioma cells, which might be attributed to the broad-spectrum inhibition of MMPs by Rh2. Overall, the strong inhibition of MMP expression by Rh2 might provide a potential therapeutic modality for brain tumors. [Copyright &y& Elsevier]

Diffuse invasion of brain tissue is a major reason for the poor prognosis of patients with glioblastoma. Annexin 2, a member of the large annexin family of Ca2+ and membrane-binding proteins, is expressed at high protein levels in human gliomas and has been proposed as a marker of glioma malignancy, while its functional role in these tumours is unknown so far. The ability of annexin 2 to interact with the actin cytoskeleton, as well as its potential to bind invasion-associated proteases, suggests that it could participate in invasion-associated processes in human gliomas. Therefore, we analysed here functional consequences of RNA interference-mediated silencing of annexin 2 in U87MG and U373MG human glioma cell lines. While no impact of annexin 2 downregulation on proliferation and adhesion was observed, our analyses revealed that migration of U87MG and U373MG cells was significantly inhibited following annexin 2 depletion. This effect was not related to a compensatory increase of the related annexins 1 or 6. Our findings identify annexin 2 as a potential candidate involved in glioma invasion and support the potential of RNA interference as powerful tool in the decryption of glioma invasion mechanisms. [ABSTRACT FROM AUTHOR]

The current understanding of glioma biology reveals targets for anti-invasive therapy which include manipulations of extracellular matrix and receptors, growth factors and cytokines, proteases, cytoskeletal components, oncogenes and tumor suppressor genes. A better understanding of the complex regulation and the signalling molecules involved in glioma invasion is still needed in order to design new and effective treatment modalities towards invasive tumor cells. Representative and valid in vitro experimental systems and animal models of gliomas are necessary for the characterization of the invasive phenotype and further development of anti-invasive therapy. In the future, it will probably be important to move from comparative genomic modelling through protein characterization based on advanced proteomic techniques to analyse tissue samples, where the aim for gliomas should be to compare invaded and non-invaded tissue. This will hopefully render promising new therapeutic targets for gliomas. [ABSTRACT FROM AUTHOR]

Experimental investigation of glioma biology and therapy requires a representative model and a convenient technique for regulating gene expression. We have established an in vivo model in which genetically modified rat C6 glioma cells (C6TL cells) are transplanted into nude mice brain, followed by specific transcriptional control of a transgene. Histologically, the tumors exhibit an astrocytic phenotype and closely resemble human malignant gliomas including diffuse brain invasion. Due to a stably integrated lacZ gene, individual tumor cells can be unequivocally identified in tissue sections by histochemistry for β-galactosidase. Since C6TL cells carry the tet transactivator (tTA) gene, any additional gene under control of a tetracycline/tTA-responsive promoter can be transcriptionally regulated by the concentration of tetracycline. C6TL cells stably transfected with a tetracycline/tTA-responsive luciferase reporter gene showed 23-fold regulation of luciferase activity in vitro. After intracerebral transplantation a regulation of 4.5- to 8.3-fold was obtained, dependent on the concentration and the type of tetracycline in the drinking water. This model should be useful for studying the functional role of candidate genes in tumor biology as well as for experimental gene therapy studies. [ABSTRACT FROM AUTHOR]

Background: Tumor invasion, a hallmark of malignant gliomas, involves reorganization of cell polarity and changes in the expression and distribution of scaffolding proteins associated with polarity complexes. The scaffolding proteins of the DLG family are usually downregulated in invasive tumors and regarded as tumor suppressors. Despite their important role in regulating neurodevelopmental signaling, the expression and functions of DLG proteins have remained almost entirely unexplored in malignant gliomas., Methods: Western blot, immunohistochemistry, and analysis of gene expression were used to quantify DLG members in glioma specimens and cancer datasets. Over-expression and knockdown of DLG5, the highest-expressed DLG member in glioblastoma, were used to investigate its effects on tumor stem cells and tumor growth. qRT-PCR, Western blotting, and co-precipitation assays were used to investigate DLG5 signaling mechanisms., Results: DLG5 was upregulated in malignant gliomas compared to other solid tumors, being the predominant DLG member in all glioblastoma molecular subtypes. DLG5 promoted glioblastoma stem cell invasion, viability, and self-renewal. Knockdown of this protein in vivo disrupted tumor formation and extended survival. At the molecular level, DLG5 regulated Sonic Hedgehog (Shh) signaling, making DLG5-deficient cells insensitive to Shh ligand. Loss of DLG5 increased the proteasomal degradation of Gli1, underlying the loss of Shh signaling and tumor stem cell sensitization., Conclusions: The high expression and pro-tumoral functions of DLG5 in glioblastoma, including its dominant regulation of Shh signaling in tumor stem cells, reveal a novel role for this protein that is strikingly different from its proposed tumor-suppressor role in other solid tumors., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We present a 59-year-old woman who noted an enlarging lump on her forehead 6 months after a left frontotemporal craniotomy for tumor resection and chemoradiation of her primary glioblastoma multiforme (GBM). GBM is a highly aggressive intracranial neoplasm associated with the shortest survival time of any primary central nervous system malignancy. Extracranial metastasis is rare, especially without previous surgical disruption of the dura and calvarium, which has been postulated to cause seeding of the extracranial space with tumor cells. This patient’s MRI revealed tumor recurrence for which she underwent repeat resection. Histopathology confirmed GBM with unmethylated O-6-methylguanine-DNA methyltransferase and wildtype isocitrate dehydrogenase 1 status, as well as tumor invasion through the bone and subdermal space. The genetic and molecular factors that predict extracranial invasion remain unclear and require further investigation. Emerging data on circulating tumor cells in GBM patients indicate that extraaxial metastasis may be part of the disease course in some, particularly in long term survivors. Furthermore, the proximity of calvarial and scalp lesions to previous surgical sites and the time course in which they emerge after surgery suggests that iatrogenic seeding may also play a role in metastasis. With heightened awareness of the phenomenon, surgical strategies such as watertight approximation of the dura, bone flap replacement, or changing surgical instruments once the intradural component is complete may prove useful to prevent seeding. Prophylactic craniospinal irradiation may also be an appropriate tool in patients at high risk for metastasis, although this population is difficult to identify. [ABSTRACT FROM AUTHOR]

In order to investigate the biological role of fibronectin in glioma cell invasion, we studied the relation between migratory responses or adhesiveness of glioma cells to fibronectin and the in vitro invasion in three human malignant glioma cell lines, A172, T98G and U373MG. All these cell lines chemotactically migrated in a dose-dependent manner to fibronectin in concentrations ranging from 0.5 to 10 µg/ml, with A172 cells showing the strongest migration and U373 cells the weakest. Checkerboard analyses demonstrated that A172 and T98G cells showed much stronger chemokinetic responses to fibronectin than U373MG cells. In contrast to the migratory responses, A172 and U373MG cells showed an almost equally high adhesion to fibronectin and T98G cells a low adhesion. The degree of expression of the integrin α5 subunit correlated well with the strength of glioma cell adhesion to fibronectin rather than that of migration to the molecule. Furthermore, the cell adhesion to fibronectin was almost completely inhibited by arginine-glycine-aspartic acid (RGD)-containing peptides, but the fibronectin-stimulated cell migration was only partially inhibited. An in vitro invasion assay disclosed that U373MG cells invaded the artificial basement membrane barrier the most and A172 cells the least. However, addition of fibronectin to the glioma cells markedly enhanced the invasive activity of A172 and T98G cells but had little effect on that of U373MG cells. These results indicate that fibronectin-stimulated migration can be one of the factors promoting invasiveness of glioma cells and that the chemokinetic activity of fibronectin may play a crucial role in glioma invasion through conferring motor-driving force on the glioma cells. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) possesses glioma stem cells (GSCs) that exhibit aggressive invasion behavior in the brain. Current preclinical GBM invasion assays using mouse brain xenografts are time consuming and less efficient. Here, we demonstrate an array of methods that allow rapid and efficient assaying of GSCs invasion in human brain organoids. The assays are versatile to characterize various aspects of GSCs, such as invasion, integration, and interaction with mature neurons of brain organoids. Tissue clearing and quantitative 3D imaging of GSCs in host organoids reveal that invasiveness is inversely correlated with the organoids' age. Importantly, the described invasion assays can distinguish the invasive behaviors of primary and recurrent GSCs. The assays are also amenable to test pharmacological agents. As an example, we show that GI254023X, an inhibitor of ADAM10, could prevent the integration of GSCs into the organoids. • Controlled and efficient assays characterize GSCs invasions in human brain organoids • GSCs interact with mature neurons and establish hemisynapses in human brain organoids • Assay 2 resembles the invasion behavior of GSCs in clinical samples of brain tissues • Assay 3 is preferentially suitable for drug screening For an improved versatility and reliability of 3D human brain organoids in modeling GBM, Goranci-Buzhala et al. established an array of methods that allow rapid and efficient assaying of glioma stem cell (GSC) invasion. Readouts described here can be used to study GSC invasion, integration, interaction with mature neurons, and drug screening. [ABSTRACT FROM AUTHOR]

Widespread tumor cell invasion is a fundamental property of diffuse gliomas and is ultimately responsible for their poor prognosis. A greater understanding of basic mechanisms underlying glioma invasion is needed to provide insights into therapies that could potentially counteract them. While none of the currently available in vitro models can fully recapitulate the complex interactions of glioma cells within the brain tumor microenvironment, if chosen and developed appropriately, these models can provide controlled experimental settings to study molecular and cellular phenomena that are challenging or impossible to model in vivo. Therefore, selecting the most appropriate in vitro model, together with its inherent advantages and limitations, for specific hypotheses and experimental questions achieves primary significance. In this review, we describe and discuss commonly used methods for modeling and studying glioma invasion in vitro, including platforms, matrices, cell culture, and visualization techniques, so that choices for experimental approach are informed and optimal., (© 2020 Wiley Periodicals, Inc.)

Diffuse brain invasion by glioma cells prevents effective surgical or molecular-targeted therapy and underlies a detrimental outcome. Migrating glioma cells are guided by complex anatomical brain structures but the exact mechanisms remain poorly defined. To identify adhesion receptor systems and matrix structures supporting glioma cell invasion into brain-like environments we used 2D and 3D organotypic invasion assays in combination with antibody-, peptide- and RNA-based interference. Combined interference with β1 and αV integrins abolished the migration of U-251 and E-98 glioma cells on reconstituted basement membrane; however, invasion into primary brain slices or 3D astrocyte-based scaffolds and migration on astrocyte-deposited matrix was only partly inhibited. Any residual invasion was supported by vascular structures, as well as laminin 511, a central constituent of basement membrane of brain blood vessels. Multi-targeted interference against β1, αV and α6 integrins expressed by U-251 and E-98 cells proved insufficient to achieve complete migration arrest. These data suggest that mechanocoupling by integrins is relatively resistant to antibody- or peptide-based targeting, and cooperates with additional, as yet unidentified adhesion systems in mediating glioma cell invasion in complex brain stroma., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Glioblastoma are notorious for their highly invasive growth, diffusely infiltrating adjacent brain structures that precludes complete resection, and is a major obstacle for cure. To characterize this "invisible" tumor part, we designed a high resolution multimodal imaging approach assessing in vivo the metabolism of invasively growing glioma xenografts in the mouse brain. Animals were subjected longitudinally to magnetic resonance imaging (MRI) and 1 H spectroscopy (MRS) at ultra high field (14.1 Tesla) that allowed the measurement of 16 metabolic biomarkers to characterize the metabolic profiles. As expected, the neuronal functionality was progressively compromised as indicated by decreasing N-acetyl aspartate, glutamate and gamma-aminobutyric acid and reduced neuronal TCA cycle (-58%) and neurotransmission (-50%). The dynamic metabolic changes observed, captured differences in invasive growth that was modulated by re-expression of the tumor suppressor gene WNT inhibitory factor 1 (WIF1) in the orthotopic xenografts that attenuates invasion. At late stage mice were subjected to 13 C MRS with infusion of [1,6- 13 C]glucose and 18 FDG positron emission tomography (PET) to quantify cell-specific metabolic fluxes involved in glucose metabolism. Most interestingly, this provided the first in vivo evidence for significant glucose oxidation in glioma cells. This suggests that the infiltrative front of glioma does not undergo the glycolytic switch per se, but that environmental triggers may induce metabolic reprograming of tumor cells., (© 2018 UICC.)

Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion., (© 2017 The Author(s).)

The p75 neurotrophin receptor (p75 NTR , a.k.a. CD271), a transmembrane glycoprotein and a member of the tumor necrosis family (TNF) of receptors, was originally identified as a nerve growth factor receptor in the mid-1980s. While p75 NTR is recognized to have important roles during neural development, its presence in both neural and nonneural tissues clearly supports the potential to mediate a broad range of functions depending on cellular context. Using an unbiased in vivo selection paradigm for genes underlying the invasive behavior of glioma, a critical characteristic that contributes to poor clinical outcome for glioma patients, we identified p75 NTR as a central regulator of glioma invasion. Herein we review the expanding role that p75 NTR plays in glioma progression with an emphasis on how p75 NTR may contribute to the treatment refractory nature of glioma. Based on the observation that p75 NTR is expressed and functional in two critical glioma disease reservoirs, namely, the highly infiltrative cells that evade surgical resection, and the radiation- and chemotherapy-resistant brain tumor-initiating cells (also referred to as brain tumor stem cells), we propose that p75 NTR and its myriad of downstream signaling effectors represent rationale therapeutic targets for this devastating disease. Lastly, we provide the provocative hypothesis that, in addition to the well-documented cell autonomous signaling functions, the neurotrophins, and their respective receptors, contribute in a cell nonautonomous manner to drive the complex cellular and molecular composition of the brain tumor microenvironment, an environment that fuels tumorigenesis., (© 2017 Elsevier Inc. All rights reserved.)