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Journal articles on the topic 'Glioma brain tumor'
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1
Berg, Tracy, Carolina Marques, Vasiliki Pantazopoulou, et al. "TAMI-05. THE IRRADIATED BRAIN MICROENVIRONMENT SUPPORTS GLIOMA STEMNESS AND SURVIVAL VIA ASTROCYTE-DERIVED TRANSGLUTAMINASE 2." Neuro-Oncology 22, Supplement_2 (2020): ii213—ii214. http://dx.doi.org/10.1093/neuonc/noaa215.894.
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Abstract The highest-grade gliomas invariably recur as incurable tumors following standard of care comprising surgery, radiotherapy, and chemotherapy. The majority of the recurrent tumors form within the area of the brain receiving high-dose irradiation during treatment of the primary tumor, indicating that the recurrent tumor forms in an irradiated microenvironment. The tumor microenvironment has been demonstrated to influence the therapeutic response and stemness characteristics of tumor cells, but the influence of radiation on the microenvironment and its subsequent consequences for tumor cells are incompletely understood. Here, we used genetically engineered glioma mouse models and human glioma samples to characterize the impact of standard of care radiotherapy on the brain tumor microenvironment. We found that tumor-associated astrocytes subjected to radiation in vitro could enhance tumor cell stemness and survival of co-cultured glioma cells. More aggressive gliomas formed in vivo when mouse brains were irradiated prior to tumor cell implantation, suggesting that the irradiated brain microenvironment supports tumor growth. We isolated the effect of irradiated astrocytes to extracellular matrix secreted by these cells, and specifically found that astrocyte-derived transglutaminase 2 (TGM2) is a stromal promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in glioma mouse models. Recombinant TGM2 enhanced, and TGM2 inhibitors blocked, glioma cell stemness. In human GBM tissue, TGM2 levels were increased in recurrent vs. primary tumors. In summary, in addition to supporting TGM2 as a potential therapeutic target in glioma, our data indicate that radiotherapy results in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
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Rao, Rohit, Feng Zhang, Ravinder Verma, Jincheng Wang, Dazhuan Xin, and Richard Lu. "TMIC-55. CHARACTERIZATION OF TUMOR-MICROENVIRONMENT INTERACTIONS IN GLIOBLASTOMAS AT THE SINGLE-CELL LEVEL." Neuro-Oncology 21, Supplement_6 (2019): vi259—vi260. http://dx.doi.org/10.1093/neuonc/noz175.1089.
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Abstract Glioblastomas are malignant brain tumors that carry a poor prognosis. The tumor microenvironment has been identified as an important regulator of tumor growth and may represent a novel target for therapy. Transcriptional subtypes of glioma are a major source of heterogeneity of expression in gliomas. Gliomas are highly heterogeneous diseases and can be classified into different subtypes including proneural, classical and mesenchymal tumors. We hypothesized that different subtypes of glioma will have different microenvironmental composition and exhibit distinct responses to therapies. To understand whether gliomas induced by different oncogenic drivers affect microenvironment composition, we induced mouse gliomas using a PDGFB and dnp53 driver to model proneural glioma and HRasV12 and dnp53 to model mesenchymal glioma, respectively. We performed single cell transcriptomic profiling to characterize the tumor microenvironment in these glioma models. We found that in the PDGFB/dnp53 glioma model had a large microglia contribution with about 30% tumor-associated microglia. In contrast, the HRasV12/dnp53 glioma model had only sparse microenvironmental cells. In addition, microglia in each model displayed subtype-specific gene expression programs, with microglia in the HRasV12/dnp53 tumor model expressing increased antigen presenting genes while increased levels of osteopontin in the PDGFB/dnp53 tumor model. To determine the tumor-microenvironment interactions, we performed receptor-ligand analysis using CellPhoneDb to identify secretory ligands that support tumor cell growth in microenvironmental cells. We found that tumor-associated pericytes are an important source of growth factor ligands in both PDGFB/dnp53 and HRasV12/dnp53 glioma models. We are investigating the contribution of microglia and pericytes to tumor growth and survival through cell depletion and pharmacological inhibition and determining whether the differences in tumor microglia between the models affects sensitivity to therapies including immunotherapy. Understanding how tumor-intrinsic signaling modulates microenvironment niches and tumor-microenvironment communications aids rational design of combinations targeting the malignant brain tumors.
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Langhnoja, Jaldeep, Xin Wei, Phonepasong Arounleut, Ipsita Kundu, and Timothy Phoenix. "CNSC-30. DETERMINING THE REGULATION AND FUNCTION OF ANGPT1 HIGH-GRADE GLIOMAS." Neuro-Oncology 26, Supplement_8 (2024): viii47. http://dx.doi.org/10.1093/neuonc/noae165.0186.
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Abstract Angiopoietin-1 (Angpt1) is a secreted protein that promotes angiogenesis and vascular stability in development and certain disease states through activation of the Tie2 receptor. However, little is known about its regulation and function in brain tumors. Angpt1 is upregulated in glial brain tumors, including high-grade gliomas and ependymomas. We find Angpt1 is expressed by specific cell populations within gliomas, along with non-tumor reactive astrocytes and perivascular mural cells. Leveraging an in vivo brain tumor modeling system we have generated glioma models to investigate how tumor cell state impacts Angpt1 expression, along with creating Angpt1 knock-out models. We find that Angpt1 expression is increased when glioma models are biased towards a more astrocytic and/or mesenchymal state, mirroring developmental expression patterns. Ongoing studies utilizing these models are being used to determine the mechanisms that regulate the dynamic expression of Angpt1 and its function in glioma pathogenesis, including tumor angiogenesis and blood-brain barrier function.
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Frantsiyants, Elena M., Eduard E. Rostorguev, and Elena A. Sheiko. "Certain aspects of brain tumor angiogenesis." Annals of Clinical and Experimental Neurology 15, no. 2 (2021): 50–58. https://doi.org/10.25692/acen.2021.2.7.
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Neuroepithelial tumors are one of the most common conditions with a high mortality rate. Despite the growing body of knowledge about the underlying biology of these tumors, their treatment has not changed significantly over the past decade. Angiogenesis is a key component of the neoplastic process. Neoangiogenesis activity has a significant effect on tumor development and its metastatic potential. Studying how the growth and progression of gliomas are dependent on the degree of vascularisation has allowed the development of a new way of fighting tumors with antiangiogenesis therapy. Unfortunately, currently, antiangiogenesis therapy cannot cure a patient with glioma. The use of antiangiogenesis drugs to suppress tumor growth by inhibiting angiogenesis in gliomas is still limited despite being a promising direction. Information about molecular and genetic features of glial brain tumors, proangiogenic signalling pathways, mechanisms of angiogenesis, prognostic factors, etc., is essential to develop a new and effective therapy. A recent literature review revealed quite contradictory data. On the one hand, neoangiogenesis of malignant brain tumors is considered to be an independent prognostic factor for glioma progression. However, some publications deny that angiogenesis in gliomas is a predictor of tumor development. All of the above underline the need for continued study into the relationship between angiogenesis and tumor growth.
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Hashemi, Melika, Durgadevi Selvam, Reid J. Hale, Katelynn Shockley, Ailin Zhyrgalbekovna, and Andrea Comba. "CNSC-55. UNCOVERING THE ROLE OF COLLAGEN EXTRACELLULAR MATRIX IN GLIOBLASTOMA BRAIN MICROENVIRONMENT TRANSFORMATION." Neuro-Oncology 26, Supplement_8 (2024): viii53. http://dx.doi.org/10.1093/neuonc/noae165.0211.
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Abstract Glioblastoma (GBM) is a highly malignant brain tumor characterized by diffuse infiltration and significant heterogeneity, without effective treatment. Mesenchymal-like (MES) glioma cells drive tumor aggression by promoting brain invasion and tumor microenvironment remodeling. Previous spatial transcriptomic analyses identified Collagen, particularly COL1A, as a key extracellular matrix (ECM) component, enriched in MES areas termed oncostreams. Depletion of COL1A1 disrupted oncostreams, influencing the tumor microenvironment to support cell survival, and migration. Reactive astrocytes and macrophages, essential components of the brain microenvironment, impact glioma progression. However, the interplay between glioma-secreted collagen and the brain microenvironment remains poorly understood. To elucidate this, we generated orthotopic mouse glioma models with high-collagen (NPD) and low-collagen (NPDshCol1A1). Our data revealed that downregulation of COL1A1 in glioma cells alters the abundance and spatial distribution of reactive astrocytes and macrophages/microglia. Immunofluorescence and flow cytometry analysis showed that tumors with low-collagen had decreased GFAP+ reactive astrocyte cells at the invasive edge and perivascular niche compared to high-collagen gliomas. Moreover, our results shows that high collagen levels may activate astrocytes through distant communication, as evidenced by the higher presence of reactive astrocytes in the contralateral cortex of NPD tumors. However, low-collagen tumors exhibited an increase in astrocytes (GFAP+) in the tumor core. Furthermore, high-collagen gliomas demonstrated increased macrophage infiltration, promoting an immunosuppressive environment. Using multiplex immunohistochemistry assays, we observed that reactive astrocytes along the invasive tumor edge were associated with glioma cells expressing elevated levels of COL1A1 and TGF-β ligand. In summary, our results show that glioma cell-expressed COL1A1 promotes the activation of peritumoral and perivascular brain-resident astrocytes and macrophages. The interactions of reactive astrocyte with glioma cells enriched in collagen form a feedback loop that enhances tumor invasion and vascular proliferation, suggesting that targeting the ECM-astrocyte interactions could disrupt these processes and offer a therapeutic avenue for GBM.
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Venkataramani, Varun, Yvonne Yang, Marc Schubert, et al. "TAMI-52. NEURONAL MECHANISMS OF BRAIN TUMOR INVASION." Neuro-Oncology 23, Supplement_6 (2021): vi209. http://dx.doi.org/10.1093/neuonc/noab196.835.
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Abstract Incurable gliomas are characterized by their infiltration into the whole brain. Recently, we described tumor microtubes as a novel structure contributing to glioma cell invasion and uncovered synaptic contacts on glioma cells that drive brain tumour progression. However, the exact effects of neuronal activity on glioma cell motility are yet unclear. Here, we show how a recently described neuronal-like cellular transcription state of glioblastoma cells is correlated to glioma cell invasion in vivo. To unravel the details of neuronal features of glioma invasion in space and time, we established a novel approach of intravital imaging for brain tumor cells with a membrane-bound GFP combined with deep learning algorithms that are used to track glioma cell processes with a high temporal resolution over several hours. This approach uncovers how invading tumor microtubes use Levy-like movement patterns indicative of efficient search patterns often employed by animal predators searching for scarce resources such as food. Neuronal activity is able to accelerate the tumor microtube dynamics, accelerate the Levy-like movement patterns and increase the overall invasion speed of glioma cells. These processes are mediated by local calcium transients in glioma cell somata and tumor microtubes. In accordance, genetic manipulation and pharmacological perturbation of AMPA receptors reduces tumor microtube length, number and branching points by interfering with intracellular calcium transients. All in all, the work here uncovers novel neuronal activity-mediated mechanisms of glioma cell invasion, a hallmark of this yet fatal disease.
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Wang, Y. "P02.06.B CROSSTALK BETWEEN GLIOMA AND MYELOID SHAPES DISTINCT TUMOR MICROENVIRONMENT IN SPINAL CORD, BRAIN STEM AND CEREBRUM." Neuro-Oncology 26, Supplement_5 (2024): v35. http://dx.doi.org/10.1093/neuonc/noae144.109.
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Abstract BACKGROUND Occurring in the cerebrum, brainstem, and spinal cord, glioma are the most common primary malignant tumors in the central nervous system. Currently, there is a increasing understanding of the microenvironment of cerebral gliomas and brainstem gliomas, and clinical trials of immunotherapy for them are also ongoing. However, research on the microenvironment of spinal cord glioma is still lacking, Their immunotherapy potential deserve further exploration. MATERIAL AND METHODS We performed single-cell sequencing of fresh tissues from 8 cases of spinal cord DMG. Through integrating public scRNA data from 19 brain glioblastoma cases and 9 cases of DIPG samples, we did an integrated analysis of 199,696 human glioma, immune, and other stromal cells at the single cell level. Further analysis of cell communication revealed the distinct interaction between glioma cells and different cells in the microenvironment, especially tumor infiltrating macrophages. RESULTS Single cell analysis indicates that the main participants in the glioma microenvironment are tumor cells and tumor infiltrating macrophages; In addition, compared to midline gliomas, brain gliomas contain a higher proportion of lymphocytes. Interaction analysis revealed that spinal cord gliomas can regulate the infiltration of macrophages in spinal cord gliomas through the THY1-ADGR5 axis and higher expression of IGF1 by macrophages, promoting the proliferation and invasion of gliomas with IGF1R. CONCLUSION This study provides insights into molecular, spatial, and functional heterogeneity of glioma and glioma-associated immune cells in GBM, DIPG and spinal cord DMG, suggesting that selectively modulating tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating glioma.
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Merickel, Joshua L., G. Elizabeth Pluhar, Aaron Rendahl, and M. Gerard O’Sullivan. "Prognostic histopathologic features of canine glial tumors." Veterinary Pathology 58, no. 5 (2021): 945–51. http://dx.doi.org/10.1177/03009858211025795.
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Gliomas are relatively common tumors in aged dogs (especially brachycephalic breeds), and the dog is proving to be useful as a translational model for humans with brain tumors. Hitherto, there is relatively little prognostic data for canine gliomas and none on outcome related to specific histological features. Histologic sections of tumor biopsies from 33 dogs with glioma treated with surgical resection and immunotherapy and 21 whole brains obtained postmortem were reviewed. Tumors were diagnosed as astrocytic, oligodendroglial, or undefined glioma using Comparative Brain Tumor Consortium criteria. Putative features of malignancy were evaluated, namely, mitotic counts, glomeruloid vascularization, and necrosis. For biopsies, dogs with astrocytic tumors lived longer than those with oligodendroglial or undefined tumor types (median survival 743, 205, and 144 days, respectively). Dogs with low-grade gliomas lived longer than those with high-grade gliomas (median survival 734 and 194 days, respectively). Based on analysis of tumor biopsies, low mitotic counts, absence of glomeruloid vascularization, and absence of necrosis correlated with increased survival (median 293, 223, and 220 days, respectively), whereas high mitotic counts, glomeruloid vascularization, and necrosis correlated with poor survival (median 190, 170, and 154 days, respectively). Mitotic count was the only histological feature in biopsy samples that significantly correlated with survival ( P < .05). Whole-brain analyses for those same histologic features had similar and more robust correlations, and were statistically significant for all features ( P < .05). The small size of biopsy samples may explain differences between biopsy and whole-brain tumor data. These findings will allow more accurate prognosis for gliomas.
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Winkler, Frank. "INSP-13. Malignant networks in brain tumors: from basic discoveries to clinical implications." Neuro-Oncology 24, Supplement_1 (2022): i188—i189. http://dx.doi.org/10.1093/neuonc/noac079.709.
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Abstract Integration into communicating tumor cell networks is a way how the entire brain tumor organism can progress in the brain, and resist therapies. It started with our discovery of ultra-long membrane protrusions, tumor microtube (TM), in tumor cells from glioblastomas and other incurable adult and pediatric glioma entities (Osswald et al., Nature 2015). These TMs are used for early brain invasion, and later interconnect single tumor cells to communicating and resistant multicellular networks, but also glioma cells to neurons in the brain, with neuron-glioma synapses stimulating glioma progression (Venkataramani et al., Nature 2019). Increasing formation of these homotypic and heterotypic networks is seen with increasing glioma malignancy: lowest in low-grade oligodendrogliomas, and highest in glioblastomas and K27M mutated gliomas. The genetic reduction of GAP-43, a crucial neurodevelopmental factor that drives TM formation and function, not only deprived glioblastoma cells from the ability to form functional tumor networks, but also made radiotherapy much more effective, by and large eradicating experimental tumors from the mouse brain, which is typically not possible with radiotherapy alone. Consistent with the concept of tumor cell resilience by network integration, radiotherapy and also chemotherapy (Weil et al., Neuro-Oncology 2017) preferentially killed the unconnected glioblastoma cells, leaving the tumor cell networks largely intact. Damage to the tumor network by surgical measures induced a self-healing response. Taken together, integration into multicellular, highly functional, communicating and resilient networks is not only a feature of the nervous system, but also of incurable, most aggressive brain tumors. In this talk, clinical concepts that originate from these discoveries are presented, including a network disconnection strategy currently tested in the German MecMeth trial (EudraCT2021-000708-39), and the AMPAR inhibitor perampanel as a potential inhibitor of neuron-glioma synapses. Furthermore, new basic and translational developments in the field of brain tumor networks are presented and discussed.
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Van Houdt, Winan J., Yosef S. Haviv, Baogen Lu, et al. "The human survivin promoter: a novel transcriptional targeting strategy for treatment of glioma." Journal of Neurosurgery 104, no. 4 (2006): 583–92. http://dx.doi.org/10.3171/jns.2006.104.4.583.
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Object Malignant brain tumors have been proved to be resistant to standard treatments and therefore require new therapeutic strategies. Survivin, a recently described member of the inhibitor of apoptosis protein family, is overexpressed in several human brain tumors, primarily gliomas, but is downregulated in normal tissues. The authors hypothesized that the expression of tumor-specific survivin could be exploited for treatment of gliomas by targeting the tumors with gene therapy vectors. Methods Following confirmation of survivin expression in glioma cell lines, an adenoviral vector containing the survivin promoter and the reporter gene luciferase was tested in established and primary glioma cells, normal astrocytic cells, and normal human brain tissues. High levels of reporter gene expression were observed in established tumor and primary tumor cell lines and low levels of expression in astrocytes and normal human brain tissue. To test oncolytic potency, the authors constructed survivin promoter–based conditionally replicative adenoviruses (CRAds), composed of survivin promoter–regulated E1 gene expression and an RGD-4C capsid modification. These CRAds could efficiently replicate within and kill a variety of established glioma tumor cells, but were inactive in a normal human liver organ culture. Finally, survivin promoter–based CRAds significantly inhibited the growth of glioma xenografts in vivo. Conclusions Together these data indicate that the survivin promoter is a promising tumor-specific promoter for transcriptional targeting of adenovirus-based vectors and CRAds for malignant gliomas. The strategy of using survivin–CRAds may thus translate into an experimental therapeutic approach that can be used in human clinical trials.
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Shkiryak, A., S. Khanenko, S. Ziablitsev, and V. Andruschenko. "ASSOCIATION OF GLIOBLASTOMA WITH MENTAL STRESS." POLISH JOURNAL OF SCIENCE, no. 77 (August 17, 2024): 8–12. https://doi.org/10.5281/zenodo.13336799.
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Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system. Compared with patients with other cancers, glioma patients often suffer from increased levels of psychological stress, such as anxiety and fear. Chronic stress is thought to impact glioma profoundly. However, because of the complex mechanisms underlying CS and variability in individual tolerance, the role of CS in glioma remains unclear[2]. This review suggests to study deeper potential role of chronic mental stress in gliomas, particularly glioblastoma, etiology, pathogenesis. Mental stress management among population may lead to better results in gliomas prevention and treatment. After diagnosis, glioblastoma [GBM] patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression. However, systematic study about the relationship between depression and GBM progression is still lacking [1]. Given the negative impact of maladaptive psychosocial and biobehavioral factors on normal immune system functions, the question remains as to how psychological conditions potentially affect the brain tumor patient anti-tumor immune response [3]. Since immunotherapy has yet to show efficacy at increasing malignant glioma patient survival in all randomized, phase III clinical trials to-date, this review provides new insights into the potential negative effects of chronic distress on brain tumor patient immune functions and outcomes [3]. Central nervous system [CNS] tumors account for 1.6% of all newly diagnosed cancers worldwide according to Global Cancer Statistics 2020 [4], with gliomas being the most common primary CNS tumors, accounting for approximately 75%. from all detected [5]. In this article we will talk about gliomas and what them belong to chronic stress. How to decrease risk factors of initiation of brain oncology.
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Syed Ali Nawaz, Makhdoom Syed Muhammad Ali, Malik Mubasher Hussain, Muhammad Saif Ullah, Tariq Hussain, and Tanveer Aslam. "A COMPUTER-AIDED BRAIN GLIOMA IDENTIFICATION USING MRI BASED TEXTURE ANALYSIS." Agricultural Sciences Journal, no. 1 (June 30, 2024): 213–22. http://dx.doi.org/10.56520/asj.24.357.
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Brain gliomas are deadly tumors that are discovered after a stressful, lengthy, and difficult procedure. Radiology is a broad and varied field that detects brain tumors, but interpreting radiological pictures of the brain needs advanced training, experience, and subject-matter expertise. The endeavor is challenging due to the wide variation in brain tumor tissues among individuals and similar cases within normal tissues. Magnetic resonance imaging (MRI)-based computer-aided biomedical image processing solves the challenges associated with brain tumor localization and identification while simultaneously addressing the shortage of qualified radiologists. This study proposes a computer-aided brain glioma identification (CABGD) model for brain glioma identification using the texture analysis of brain MRIs. The proposed model makes use of machine learning classifiers and brain MRI data. There were 200 MRIs of both normal and glioma brains in the experimental dataset. Firstly, the MRI dataset was pre-processed to crop the MRIs, size equalization, and gray-level conversion. Next, noises were removed by applying filters. Two ROIs of the sizes (10 ×10) were taken on each MRI after the tumor region was segmented. After extracting COM texture features from each ROI, thirty optimal features were obtained through a compound supervised feature selection, blend of Fisher (FSHR), probabilistic model of error (POE), average correlation (AVC), and mutual information (MUI). The optimal feature brain MRI dataset was classified into glioma and normal brain by applying machine learning classifiers named Bayas Net (BN), logistic model tree (LMT), and partial decision tree (PART); the classification results of the NB, LMT, and PART classifiers were 79.75%, 82.75, and 85%, respectively.
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Raphael, Itay, Michael Graner, Christopher Moertel, Gary Kohanbash, and Michael Olin. "EXTH-42. GLIOMA-DERIVED CD200 PROMOTES TUMOR GROWTH AND SUPPRESSES NK CELL AND CD8 T CELL ANTI-GLIOMA ACTIVITY." Neuro-Oncology 26, Supplement_8 (2024): viii246. http://dx.doi.org/10.1093/neuonc/noae165.0973.
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Abstract Immune-checkpoint inhibitors, such as anti-PD1 and anti-CTLA4, have emerged as promising therapeutic options for several malignancies yet show little efficacy against malignant brain cancers. CD200 is a newly recognized immune-checkpoint which is expressed by a marid of cell types, modulating immune homeostasis through multiple receptors. There is currently limited information regarding CD200 effects in brain tumors. Furthermore, while it is well accepted that CD200 binding to its inhibitory receptor induces a pro-tumorigenic environment through its ability to suppress immune responses, there are increasing evidence that CD200 could also have anti-tumor characteristics. Here we evaluated the role of tumor-derived CD200 on anti-glioma immunity. We demonstrate that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in serum of patients undergoing immunotherapy. Transcriptomic analysis of CD200 knockout (KO) glioma models reveals that glioma-derived CD200 significantly modifies the glioma tumor microenvironment (TME), not only through immune regulation but also through immune-independent pathways, such as tumor metabolism. Furthermore, we show that CD200 KO gliomas have reduced proliferation and are rejected by their hosts. Downstream analysis revealed that rejection of CD200 KO gliomas relied on a functional adoptive immune system, while decreased proliferation was linked to reduced CXCL10 production by the CD200 KO gliomas. Additionally, we demonstrate that glioma-mediated CD200 strongly suppresses anti-glioma NK cell function within the tumor microenvironment (TME), while secreted CD200 inhibits the priming of antigen-specific CD8 T cells in the lymphatic. Notably, NK cells were essential for the initial rejection of CD200 KO gliomas, while CD8 T cells played a critical role in establishing durable anti-tumor responses. Our work provides new mechanistic insights on glioma-derived CD200-mediated immunosuppression and an untapped potential for targeting CD200 by immunotherapies for malignant gliomas.
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Morrone, Fernanda Bueno, Pedro Vargas, Liliana Rockenbach, and Thamiris Becker Scheffel. "P2Y12 Purinergic Receptor and Brain Tumors: Implications on Glioma Microenvironment." Molecules 26, no. 20 (2021): 6146. http://dx.doi.org/10.3390/molecules26206146.
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Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor’s aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides’ interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy.
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Riviere-Cazaux, C., L. Carlstrom, K. Rajani, et al. "OS09.5.A BREAKING DOWN BARRIERS: THE IMPACT OF BLOOD-BRAIN BARRIER DISRUPTION ON THE GLIOMA METABOLIC MICROENVIRONMENT, IN SITU." Neuro-Oncology 25, Supplement_2 (2023): ii21. http://dx.doi.org/10.1093/neuonc/noad137.062.
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Abstract BACKGROUND The microenvironment of glioblastoma is complex and defined in part by protumorigenic metabolic changes. Within this microenvironment, blood-brain barrier disruption is often associated with the most aggressive portions of the tumor. To date, the metabolic tumor microenvironments of enhancing, blood-brain barrier (BBB) disrupted portions of gliomas, as compared to BBB-intact tumor, remain poorly understood. Specifically, it is unclear if the associated blood-brain barrier disruption merely reflects or functionally supports tumor aggressiveness. METHODS Intra-operative high-molecular weight microdialysis was utilized under an investigational device exemption (NCT NCT04047264) to sample the extracellular metabolome of radiographically diverse regions during fifteen neurosurgical resections. The global extracellular metabolome of recovered microdialysate from contrast-enhancing and non-enhancing tumor, as well as brain adjacent to tumor, was evaluated via ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) on the Metabolon platform and assessed using enrichment and correlation analyses. RESULTS Among 162 named metabolites identified via ultra-performance liquid chromatography tandem mass spectrometry, a novel glioma-associated metabolite, guanidinoacetate (GAA), was 126.32x higher in enhancing tumor than in adjacent brain and 13.63x higher in non-enhancing tumor than brain. Forty-eight additional metabolites were 2.05-10.18x more abundant in enhancing tumor than brain, including carnitine family members and all nine large neutral amino acids. Except for GAA and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumor and brain microdialysate were comparatively modest and less consistent, suggesting heterogeneity in the glioma metabolic microenvironment of blood-brain barrier (BBB) intact areas as compared to BBB-disrupted portions of gliomas. Interestingly, the enhancing but not the non-enhancing glioma metabolome was significantly enriched for plasma-associated metabolites, largely comprising amino acids and carnitines. CONCLUSION Our patient-derived data suggest that the BBB-disrupted metabolome of high-grade gliomas is characterized by metabolite diffusion from circulation into the tumor microenvironment. Further studies are ongoing to determine how this alteration in the glioma extracellular metabolome impacts glioma behavior and how it could be therapeutically targeted via BBB-modulating drugs.
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Byvaltsev, Vadim, Ivan Stepanov, Yevgeniy Belykh, and Anna Yarullina. "MOLECULAR ASPECTS OF ANGIOGENESIS IN BRAIN GLIOBLASTOMAS." Problems in oncology 63, no. 1 (2017): 19–27. http://dx.doi.org/10.37469/0507-3758-2017-63-1-19-27.
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It is known that angiogenesis plays a critical role in the growth and progression of brain gliomas. Inducing factor in neoangiogenesis are changes primarily occur within the intra-tumoral events: changing the structure of the microvasculature of tumor tissue, increased hypoxia adaptation of tumor cells and the synthesis of angiogenic factors, cell growth. Due to the location of abnormal blood vessels in the tumor tissue generated chaotic flow of blood, which leads to severe hypoxia - as a key factor in inducing the angiogenesis process. Hypoxia-inducible factor 1 (HIF-1) is the main molecule that regulates the growth and progression of glial tumors. Glioma cells, with their inherent properties of stem cells actively synthesized HIF-1. This population of cells called - “glioma stem cells” inducing synthesis of vascular endothelial growth factor (VEGF). It VEGF is central to the process of angiogenesis. A promising area of targeted therapy of brain gliomas is the anti-angiogenic therapy. Applications, both direct and indirect angiogenesis inhibitors, significantly improved the prognosis of patients with glial brain tumors. Undoubtedly an integrated approach to the study of microvascular disturbances, hypoxia, biology and cell behavior of “glioma stem cells” and the role of various factors of cell growth in the tumorigenesis of brain gliomas of the brain allows us to develop new and effective methods of diagnosis and treatment of this disease in the near future.
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Lowenstein, Pedro, Syed M. Faisal, Anna Argento, et al. "PATH-60. BRAIN TUMORS: FROM ONCOSTREAMS TO LIQUID CRYSTALS." Neuro-Oncology 25, Supplement_5 (2023): v182. http://dx.doi.org/10.1093/neuonc/noad179.0689.
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Abstract High grade gliomas (HGG) are the most common, destructive, and varied of all malignant brain tumors. HGG are heterogeneous at the histological, cellular, and molecular level, which makes them hard to study and treat. One particular tumor pathological differentiation is mesenchymal differentiation, containing oblong, motile cells. We recently noted distinct fascicles of elongated, aligned, mesenchymal-like cells in mouse and human gliomas, which we denote as oncostreams. Time-lapse confocal microscopy in ex vivo slices, and in in vivo two photon imaging, indicated that cells in oncostreams are motile. Oncostream motility was classified based on cellular orientation. The molecular characteristics of oncostreams were determined by laser capture microdissection, RNA-sequencing, and bioinformatics. 43 genes were differentially expressed; COL1A1 was overexpressed in oncostreams. Inhibition of COL1A1 in mouse gliomas, using the Sleeping Beauty transposon model, reduced oncostreams, tumor aggressiveness, proliferation, tumor vasculature, and collective glioma invasion. More recently, we elucidated that glioma cell growth in vitro, and potentially in vivo displays domains of nematic orientation (oncostreams) and topological defects, suggesting that gliomas are organized as liquid crystals. Topological defects are singularities of local orientation, and characteristic of liquid crystals. Further, studies of gliomas in vivo, suggest the presence of ±1/2 topological defects. Thus, nematic orientation and topological defects are present in brain tumors in vitro and in vivo. This provides support for our hypothesis that brain tumors are organized as active liquid crystals. As topological defects have been exploited to alter liquid crystal behavior, we hypothesize that manipulating brain tumor liquid crystalline behavior will be of therapeutic importance. Comba et al. (2022) Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression. Nature Communications: Wood et al. (2023) Scale-free correlations and potential criticality in weakly ordered populations of brain cancer cells. Science Advances (in press).
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Costa, Amanda De Andrade, and David H. Gutmann. "Brain tumors in neurofibromatosis type 1." Neuro-Oncology Advances 2, Supplement_1 (2019): i85—i97. http://dx.doi.org/10.1093/noajnl/vdz040.
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Abstract AbstractAs a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been significantly advanced through the use of genetically engineered mice, yielding new targets for therapeutic drug design and evaluation. In addition, Nf1 murine glioma models have served as instructive platforms for defining the cell of origin of these tumors, elucidating the critical role of the tumor microenvironment in determining tumor growth and vision loss, and determining how cancer risk factors (sex, germline NF1 mutation) impact on glioma formation and progression. Moreover, these preclinical models have permitted early phase analysis of promising drugs that reduce tumor growth and attenuate vision loss, as an initial step prior to translation to human clinical trials.
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Winkler, Frank. "Abstract IA005: Brain tumors hijack neuronal mechanisms to thrive." Cancer Research 84, no. 5_Supplement_1 (2024): IA005. http://dx.doi.org/10.1158/1538-7445.brain23-ia005.
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Abstract Our nervous system is involved in the inititation, growth, dissemination, and therapy resistance of many cancer types throughout the body. In this talk I will present this emerging field of “Cancer Neuroscience”, with the example of our work on brain tumors: how incurable gliomas hijack neurodevelopmental pathways to build tumor cell networks and to colonize the brain; how neurons form synapses to tumor cells that stimulate tumor growth; and how neuro-cancer disconnection strategies are developed. A special focus will lie on the question how these discoveries can be optimally translated into the clinic. Integration into communicating tumor cell networks is a way how the entire brain tumor organism can progress in the brain, and resist therapies. It started with our discovery of ultra-long membrane protrusions, tumor microtube (TM), in tumor cells from glioblastomas and other incurable adult and pediatric glioma entities (Osswald et al., Nature 2015). These TMs are used for very effective brain invasion, and later interconnect single tumor cells to communicating and resistant multicellular networks, but also glioma cells to neurons in the brain, with neuron-glioma synapses stimulating glioma growth (Venkataramani et al., Nature 2019) and invasion (Venkataramani et al., Cell 2022). Increasing formation of these homotypic and heterotypic networks is seen with increasing glioma malignancy: lowest in low-grade oligodendrogliomas, and highest in glioblastomas and K27M mutated gliomas. The genetic reduction of GAP-43, a crucial neurodevelopmental factor that drives TM formation and function, not only deprived glioblastoma cells from the ability to form functional tumor networks, but also made radiotherapy much more effective, by and large eradicating experimental tumors from the mouse brain, which is typically not possible with radiotherapy alone. Recently, we also discovered that brain tumor networks are constantly activated by pacemaker-like glioblastoma cells residing in network hubs that generate a periodic rhythmic activity that stimulates tumor growth and resilience (Hausmann et al., Nature 2023). Consistent with the concept of tumor cell resilience by network integration, radiotherapy and also chemotherapy (Weil et al., Neuro-Oncology 2017) preferentially killed the unconnected glioblastoma cells, leaving the tumor cell networks largely intact. Damage to the tumor network by surgical measures induced a self-healing response. Taken together, integration into multicellular, highly functional, communicating, and resilient networks is not only a feature of the nervous system, but also of incurable, most aggressive brain tumors. In this talk, clinical concepts that originate from these discoveries are presented, including a network disconnection strategy currently tested in the German MecMeth trial (EudraCT2021-000708-39), and the AMPAR inhibitor perampanel as a potential inhibitor of neuron-glioma synapses. Furthermore, new basic and translational developments in the field of brain tumor networks are presented and discussed. Citation Format: Frank Winkler. Brain tumors hijack neuronal mechanisms to thrive [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA005.
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Winkler, Frank. "IL-3 DISCONNECTING BRAIN TUMOR NETWORKS FOR IMPROVED THERAPIES." Neuro-Oncology Advances 4, Supplement_3 (2022): iii28. http://dx.doi.org/10.1093/noajnl/vdac167.112.
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Abstract Integration into communicating tumor cell networks is a way how the entire brain tumor organism can progress in the brain, and resist therapies. It started with our discovery of ultra-long membrane protrusions, tumor microtube (TM), in tumor cells from glioblastomas and other incurable adult and pediatric glioma entities (Osswald et al., Nature 2015). These TMs are used for very effective brain invasion, and later interconnect single tumor cells to communicating and resistant multicellular networks, but also glioma cells to neurons in the brain, with neuron-glioma synapses stimulating glioma growth(Venkataramani et al., Nature 2019) and invasion (Venkataramani et al., Cell 2022). Increasing formation of these homotypic and heterotypic networks is seen with increasing glioma malignancy: lowest in low-grade oligodendrogliomas, and highest in glioblastomas and K27M mutated gliomas. The genetic reduction of GAP-43, a crucial neurodevelopmental factor that drives TM formation and function, not only deprived glioblastoma cells from the ability to form functional tumor networks, but also made radiotherapy much more effective, by and large eradicating experimental tumors from the mouse brain, which is typically not possible with radiotherapy alone. Consistent with the concept of tumor cell resilience by network integration, radiotherapy and also chemotherapy (Weil et al., Neuro-Oncology 2017) preferentially killed the unconnected glioblastoma cells, leaving the tumor cell networks largely intact. Damage to the tumor network by surgical measures induced a self-healing response. Taken together, integration into multicellular, highly functional, communicating and resilient networks is not only a feature of the nervous system, but also of incurable, most aggressive brain tumors. In this talk, clinical concepts that originate from these discoveries are presented, including a network disconnection strategy currently tested in the German MecMeth trial (EudraCT2021-000708-39), and the AMPAR inhibitor perampanel as a potential inhibitor of neuron-glioma synapses. Furthermore, new basic and translational developments in the field of brain tumor networks are presented and discussed.
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Singh Pendro, Varun, Jyothish LS, Darpan Kaur, and Saurabh Sharma. "Comparison of MRS imaging tumor index among high and low grade intra axial brain tumor with histology." Romanian Journal of Neurology 21, no. 3 (2022): 213–18. http://dx.doi.org/10.37897/rjn.2022.3.3.
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Aim. The aim of this study was to compare the MRS imaging tumor index among high-grade and low-grade intra axial brain tumor with histology. Patients and methods. This prospective observational study consisted of 30 patients who underwent surgery for intra-axial brain glioma in the Department of Neurosurgery, Government Medical College, Thiruvananthapuram in a 1 year duration. Inferences were drawn based on MRI scans of brain (plain + contrast) with MRS and a histological examination. Results. The normalized area values of 3 metabolite resonances, namely N-Acetyl Aspartate (NAA), Choline (Cho) and Creatinine (Cr), between low grade glioma and high-grade glioma were found to be statistically significant (p<0.05). Significant difference was also present among Cho/NAA and Cho/Cr in differentiating low-grade from high-grade glioma. Conclusion. This study has shown that Cho/NAA and Cho/Cr ratios are reliable determinants of the tumor grade with good sensitivity and specificity. Thus, Cho/NAA and Cho/Cr ratios of MRS maybe used as a diagnostic tool in differentiating low grade gliomas from high grade gliomas.
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XI, Guifa, Ashorne Mahenthiran, Benjamin Best, et al. "EXTH-18. PEPTIDE NANO-STRUCTURES ENHANCE PEDIATRIC BRAIN TUMOR CHEMOTHERAPEUTIC EFFICACY." Neuro-Oncology 21, Supplement_6 (2019): vi86. http://dx.doi.org/10.1093/neuonc/noz175.352.
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Abstract Pediatric gliomas, particularly high-grade gliomas, which include diffuse intrinsic pontine gliomas (DIPGs), are among the most formidable and devastating cancers in children. These tumors remain incurable, despite many treatment approaches. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance. Bone morphogenetic protein 4 (BMP4), essential for CNS development, increases GSC therapeutic sensitivity and is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated, as this can lead to identification of additional treatment targets and delivery systems for BMP4 administration in a clinical setting. Additionally, extension of BMP4 short half-life would enhance its’ clinical application. Here we show that BMP4 increases chemosensitivity by decreasing H3K4me3 at the promoter of multidrug resistant gene 1 (MDR1), resulting in decreased MDR1 expression. BMP4 appears to bring about this effect by decreasing hSETD1A, an H3K4me3 methyltransferase. Our work also demonstrates the first use of a novel sulfated glycopeptide (glyco-PA) nanostructure as a vector for BMP4 delivery. Glyco-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, this work illuminates BMP4 effects on pediatric glioma therapeutic sensitivity through epigenetic mechanisms, and demonstrates the potential of bioactive glyco-PA nanostructures as a delivery mechanism for treating pediatric malignant gliomas and other tumors.
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Hutagalung, Tommy Rizky, and Ridha Dharmajaya. "Recent Updates on Experience, Treatment and Prevalence of Adult Brain Tumor : Single Center Study." Asian Australasian Neuro and Health Science Journal (AANHS-J) 3, no. 2 (2021): 4–10. http://dx.doi.org/10.32734/aanhsj.v3i2.6218.
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Introduction : Brain tumor is a disease with high morbidity and mortality rates. Treating brain tumors requiring medical providers to have basic understanding of brain tumor diagnosis and management. The most common brain tumors are meningiomas, gliomas, pituitary adenomas and brain metastasis. The treatment of each type of brain tumor is different and multidisciplinary involving other scientific fields besides neurosurgery.
 Case Series : We reported 131 cases of brain tumors at the Haji Adam Malik Hospital in the period January 2018-December 2019, consisting of 52 cases (40%) of meningioma, 34 cases (26%) of Glioma , 12 cases (9%) of pituitary adenomas and 33 cases (25%) of brain metastasis. Meningiomas were mostly treated with surgery alone in 38% of cases, gliomas with surgery followed by chemo-radiation in 41% of cases, all of pituitary adenomas were treated with endonasal transfenoid surgery, while brain metastasis in 70% of cases required whole brain radiation with controlled primary tumors.
 Discussion : The modalities for treating brain tumor patients has been increasing recently. Meningiomas are mostly benign and managed by surgical resection only, chemo-radiation reserved for high risk or refractory case of meningiomas. Glioblastoma is the most common glioma and aggressive malignant primary brain tumor, limited response to gross surgical tumor and chemo-radiation. Pituitary adenomas mostly treated with endonasal transfenoid surgery, radiotherapy use in recurrent case. Brain metastasis may require complex multidisciplinary care with neurosurgery, radiation oncology, and medical oncology.
 Conclusion: The treatment of brain tumors is influenced by various considerations such as age, patient condition,neurological deficits, location of the tumor, comorbidities, experience of the neurosurgeon and available modalities. Treatment methods for brain tumors continue to evolve.
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Ikeno, Yuji. "Ethylnitrosourea-induced gliomas: a song in the attic?" Aging Pathobiology and Therapeutics 5, no. 2 (2023): 48–51. http://dx.doi.org/10.31491/apt.2023.06.111.
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It is essential to seek the underlying molecular mechanisms of glioma development, and critical to discover interventions that reduce the incidence and attenuate the growth of gliomas using a well-established in vivo experimental model because glioma is clinically one of the most difficult malignant tumors to treat. Ethylnitrosourea (ENU)-induced glioma in the rat has been extensively utilized as an experimental brain tumor model since the mid-1960s, however, the scientific value of ENU-induced glioma has been underappreciated mainly due to the recent development of transgenic mouse glioma models. Because of the pathophysiological characteristics, which are similar to the high grade human malignant gliomas, ENU-induced glioma is an excellent in vivo model to: a) examine the cell origin, development, and pathophysiology of gliomas; b) investigate anti-tumor effects of calorie restriction (CR) and its underlying mechanisms; and c) discover new preventive and/or therapeutic interventions of glioma. Further exploration of genetic changes during initiation, malignant transformation of glial cells, and progression of glioma as well as CR’s anti-tumor effects on cellular processes using cutting edge technology, e.g., spatial transcriptomics, could provide more insight and a deeper understanding of the pathophysiology of gliomas.
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De Fazio, Emerson, Matilde Pittarello, Alessandro Gans, et al. "Intrinsic and Microenvironmental Drivers of Glioblastoma Invasion." International Journal of Molecular Sciences 25, no. 5 (2024): 2563. http://dx.doi.org/10.3390/ijms25052563.
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Gliomas are diffusely infiltrating brain tumors whose prognosis is strongly influenced by their extent of invasion into the surrounding brain tissue. While lower-grade gliomas present more circumscribed borders, high-grade gliomas are aggressive tumors with widespread brain infiltration and dissemination. Glioblastoma (GBM) is known for its high invasiveness and association with poor prognosis. Its low survival rate is due to the certainty of its recurrence, caused by microscopic brain infiltration which makes surgical eradication unattainable. New insights into GBM biology at the single-cell level have enabled the identification of mechanisms exploited by glioma cells for brain invasion. In this review, we explore the current understanding of several molecular pathways and mechanisms used by tumor cells to invade normal brain tissue. We address the intrinsic biological drivers of tumor cell invasion, by tackling how tumor cells interact with each other and with the tumor microenvironment (TME). We focus on the recently discovered neuronal niche in the TME, including local as well as distant neurons, contributing to glioma growth and invasion. We then address the mechanisms of invasion promoted by astrocytes and immune cells. Finally, we review the current literature on the therapeutic targeting of the molecular mechanisms of invasion.
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Jang, Hyun Ji, and Jong-Whi Park. "Microenvironmental Drivers of Glioma Progression." International Journal of Molecular Sciences 26, no. 5 (2025): 2108. https://doi.org/10.3390/ijms26052108.
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Gliomas, particularly glioblastoma (GBM), are among the most challenging brain tumors due to their complex and dynamic tumor microenvironment (TME). The TME plays a pivotal role in tumor progression, immune evasion, and resistance to therapy through intricate interactions among glioma cells, immune components, neurons, astrocytes, the extracellular matrix, and the blood-brain barrier. Targeting the TME has demonstrated potential, with immunotherapies such as checkpoint inhibitors and neoadjuvant therapies enhancing immune responses. Nonetheless, overcoming the immunosuppressive landscape and metabolic adaptations continues to pose significant challenges. This review explores the diverse cellular and molecular mechanisms that shape the glioma TME. A deeper understanding of these mechanisms holds promise for providing novel therapeutic opportunities to improve glioma treatment outcomes.
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Varela, Maria Luisa, Andrea Comba, Mohammad Faisal Syed, et al. "CNSC-14. ROLE OF A COLLAGEN RECEPTOR, LAIR-1, IN GLIOMA CELLS: A POTENTIAL THERAPEUTIC TARGET." Neuro-Oncology 24, Supplement_7 (2022): vii24—vii25. http://dx.doi.org/10.1093/neuonc/noac209.095.
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Abstract Most primary brain tumors are gliomas, among which Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. GBM has a median survival of 15-18 months, and despite extensive research remains incurable. Previous work in our lab has shown the importance of Collagen I, expressed by glioma cells, in glioma growth. Employing genetically engineered mouse models (GEMM) of glioma, NPA (NRas, shP53, shATRX), we identified that Collagen 1α1 (Col1A1) plays a key role in tumor malignancy. Molecular ablation of Col1A1 extends median survival, with a reduction in migration and proliferation. However, the mechanisms underlining these changes in survival, and the receptors mediating these effects remain unknown. Several collagen receptors are present in glioma cells. LAIR-1 is a collagen receptor that was originally described as an inhibitory receptor in hematopoietic cells. Since then, it has been demonstrated that LAIR-1 plays critical roles in the immune imbalance of autoimmune diseases and cancers. There have been several studies postulating the expression of LAIR-1 in tumor cells, including non-hematopoietic tumors. These studies suggest that LAIR-1 may constitute a novel receptor that tumor cells exploit to promote tumor growth and achieve immune evasion, yet its role in glioma remains unclear. Here we describe that glioma cells express LAIR-1, and that its molecular ablation in vitro showed reduced cell proliferation. In addition, GEMM lacking LAIR-1 (NRas, shP53, shATRX, shLAIR-1) exhibit improved median survival. Our preliminary data suggest that LAIR-1 expressed in glioma cells has a role in glioma aggressiveness. Currently we are further characterizing the role of LAIR-1 in high grade gliomas, as well as its potential as a therapeutic target. We hypothesize that blocking the interaction between LAIR-1 and collagen in the tumor microenvironment may improve median survival by reducing tumor proliferation.
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Bolleboom, A., B. L. J. Bouwen, C. M. F. Dirven, A. J. P. E. Vincent, and Z. Gao. "P19.05.A THE NEURONAL CORRELATES OF BRAIN TUMOR ASSOCIATED SEIZURES IN HUMAN AND MOUSE PERITUMORAL CORTEX." Neuro-Oncology 25, Supplement_2 (2023): ii125. http://dx.doi.org/10.1093/neuonc/noad137.423.
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Abstract BACKGROUND The occurrence of seizures is the most common comorbidity in malignant brain tumors. Recent advancements in the field of cancer neuroscience indicate that seizures can potentially influence brain tumor progression through intricate neuron-glioma interactions in the peritumoral infiltrated cortex of glioma patients. Therefore, understanding not only the tumor processes but also the neuronal properties in the tumor microenvironment could provide key insights into the relationship between epilepsy and tumor progression. To investigate this, we conducted a study to characterize neuronal alterations in glioma infiltrated neocortex of both patients and a glioma mouse model. MATERIAL AND METHODS Infiltrated peritumoral cortex was obtained from both epileptic and non-epileptic patients undergoing brain tumor surgery. Ex vivo brain slices were prepared and single-cell electrophysiology was performed on peritumoral neurons. High grade gliomas were induced into compound LoxP-conditional mice via stereotactic viral injection in combination with serial electro-corticographic activity to monitor epileptogenesis. RESULTS Ex vivo recordings from infiltrated human peritumoral cortex revealed electrophysiological and morphological alterations in neocortical neurons of patients experiencing seizures. Using an inducible immunocompetent high-grade glioma mouse model, we tracked the progression of cortical epileptogenesis during tumor infiltration. We observed several spatial and temporal changes in the peritumoral cortex of glioma mice, including progressive glial reaction and gradual neuronal reduction. We also identified intrinsic and network alterations in the cortical neurons of glioma mouse model, consistent with the electrophysiological characteristics of human peritumoral cortex prior to seizure onset. CONCLUSION Overall, our study demonstrated dynamic electrophysiological and histological changes in human and mouse peritumoral cortex during the course of tumor progression and epileptogenesis. These findings provide important insights into brain tumor associated seizures and cast light on new therapeutical targets for treatments.
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Eyüpoglu, Ilker Y., Eric Hahnen, Alexandra Heckel, et al. "Malignant glioma—induced neuronal cell death in an organotypic glioma invasion model." Journal of Neurosurgery 102, no. 4 (2005): 738–44. http://dx.doi.org/10.3171/jns.2005.102.4.0738.
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✓ Rapid growth and diffuse brain infiltration are hallmarks of malignant gliomas. The underlying molecular pathomechanisms of these tumors, however, remain to be determined. The authors present a novel glioma invasion model that allows researchers to monitor consecutively tumor cell proliferation and migration in an organotypic brain environment. Enhanced green fluorescent protein—labeled F98 rat glioma cells were implanted into slice cultures obtained from a rat hippocampus, and tumor growth was microscopically documented up to 20 days in vitro. Invasion along radially oriented migratory streams could be observed 5 days after implantation of rat F98, human U87MG, and mouse GL261 glioma cells, whereas human Be(2)c neuroblastoma cells and mouse HT22 hippocampal neurons failed to invade the brain parenchyma. Following implantation of F98 glioma cells into the entorhinal cortex, cell death was observed within the infiltrated brain parenchyma as well as in the neuroanatomically connected dentate gyrus. Application of the N-methyl-D-aspartate receptor antagonist MK801 to the culture medium significantly reduced neuronal degeneration in the dentate gyrus, whereas the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist GYKI 52466 inhibited peritumoral cytotoxicity. This new model allows researchers to address in a systematic manner the molecular pathways of brain invasion as well as specific tumor—host interactions such as necrosis.
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An, Shejuan, Kathleen McCortney, Jordain Walshon, Kaethe Leonard, Michael DeCuypere, and Craig Horbinski. "BIOM-19. METHYLATION PROFILING OF PLASMA CELL-FREE DNA IN PEDIATRIC BRAIN TUMOR PATIENTS." Neuro-Oncology 26, Supplement_8 (2024): viii23. http://dx.doi.org/10.1093/neuonc/noae165.0092.
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Abstract BACKGROUND Circulating tumor DNA (ctDNA) assays are being evaluated to inform clinical decisions in cancer care in adult patients, but the study in pediatric brain tumor patients is rare partly due to very low levels of ctDNA in blood. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. The aim of this study is to utilize methylomes from plasma ctDNA for non-invasive diagnosis in pediatric brain tumor patients. METHODS Using cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq), which with low input DNA requirement, we measured methylation profiles of plasma samples from 77 pediatric brain tumor patients and 16 patients with non-neoplastic diseases like epilepsy. Binomial GLMnet classifiers of tumor or tumor subtype were built, in 2000 iterations of 60% training sets. Performance was evaluated in 40% test sets. RESULTS. These 77 pediatric brain tumor patients were a mixture of the most common pediatric brain tumors, include circumscribed astrocytic gliomas (N=23), glioneuronal tumors (N=16), embryonal tumor (N=9), ependymal tumor (N=7), pediatric type diffuse high grade glioma (N= 5), glioma NOS (N=4), mesenchymal tumor (N=4) and other pediatric brain tumors (N=9). The methylation profile differentiated brain tumors from non-neoplastic diseases with 82.9% accuracy (precision = 92.6%, sensitivity = 86.2%, specificity = 66.7 %). For subtype analysis, the methylation profile detected circumscribed astrocytic glioma from non-neoplastic diseases with 85.7% accuracy (precision = 87.5%, sensitivity = 87.5 %, specificity = 83.3 %), and glioneuronal tumors from non- neoplastic diseases with 83.3% accuracy (all precision, sensitivity, and specificity = 83.3 %). CONCLUSIONS The results suggest that methylation profiling of plasma cell-free DNA has the potential to discriminate between pediatric brain tumor patients and patients with non- neoplastic diseases. Larger population cohorts to train even more accurate classifiers will be needed.
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Ghezelbash, Mohsen, Nahid Masoudian, and Mehdi Pooladi. "Beta Actin Expression Profile in Malignant Human Glioma Tumors." International Clinical Neuroscience Journal 5, no. 2 (2018): 72–77. http://dx.doi.org/10.15171/icnj.2018.14.
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Background: Proteomics is considered a new era in neurophysiological/ neuropathological research including brain tumors. Gliomas which are derived from glial cells are the most common type of brain tumor in humans. Methods: In the present study the total protein content of healthy cells of the brain and brain tumor cells was extracted, purified and quantified by Bradford assay. Two-dimensional electrophoresis were used for protein separation followed by statistical analysis. Primary protein detection was performed based on the differences in isoelectric pH, molecular weight of proteins and protein data banks, which was further confirmed by MALDI-TOF/TOF mass spectrometry (MS). Results: Our results showed elevated levels of beta-actin protein expression in glioma brain tumor cells. It is important to know when a cell is transformed and when it becomes malignant. Here we evaluated the beta-actin expression in malignant cells. Conclusion: Since structural changes are highly involved in tumor cell malignancy, beta-actin elevations can contribute in glioma tumor cell invasiveness.
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Gupta, Pravesh, Minghao Dang, Shivangi Oberai, et al. "Abstract 669: Immunophenotyping of human brain tumors reveals myeloid cell mediated anti-glioma axis." Cancer Research 83, no. 7_Supplement (2023): 669. http://dx.doi.org/10.1158/1538-7445.am2023-669.
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Abstract Gliomas are recalcitrant brain tumors. Differential tumor immune reactivity contributes to survival advantage of isocitrate dehydrogenase-mutant (IDHmut) over wild-type (IDHwt) gliomas. Despite this correlative pattern of immunity and survival, only a limited view of a highly complex immune contexture across IDH mutation classified gliomas is known. Herein, we present an unprecedented view of myeloid and lymphoid cell type diversity by single cell RNA sequencing and spectral cytometry-based interrogation of tumor-associated leukocytes from fifty-five IDH stratified primary and recurrent human gliomas and six non-glioma brains. Our analyses revealed twenty-two myeloid and lymphoid cell types within and across glioma subtypes. Glioma severity in relapsed IDHwt correlated with microglial attrition concomitant with a continuum of invading monocyte-derived microglia-like and macrophages amongst other infiltrating conventional T and NK lymphocytes and unconventional mucosa associated invariant T (MAIT) cells. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells (DCs). As tissue macrophages exhibit multifaceted polarization in response to microenvironmental cues, we clarify the existence of microglia/macrophage functional states beyond M1/M2 paradigms exemplified by the presence of palmitic-, oleic- acid, and glucocorticoid responsive polarized states. Immune related gene ontology analysis identified enriched antigen presentation and phagocytosis gene modules in distinct microglia-like clusters. Importantly, the phagocytic immunomodulator; Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) was upregulated in these microglia-like cells. Contrary to tumor promoting role of TREM2 myeloid cells in non-brain cancers, we identify TREM2 mediated anti-glioma axis as a regulator of antigen presentation Accelerated glioma growth was observed in Trem2 deficient mice implanted with CT2A glioma cells affirming the anti-glioma role of TREM2+ myeloid cells. In addition to providing an advanced landscape of glioma-specific immune contexture for immunotherapy applications, our reverse translational investigations discover TREM2 as a novel immunotherapy target for brain malignancies. Citation Format: Pravesh Gupta, Minghao Dang, Shivangi Oberai, Mekenzie Peshoff, Nancy Milam, Aml Ahmed, Krishna Bojja, Tuan M. Tran, Kathryn Cox, Huma Shehwana, Carlos Kamiya Matsuoka, Jianzhuo Li, Joy Gumin, Alicia Goldman, Sameer A. Seth, Atul Maheshwari, Frederick F. Lang, Nicholas E. Navin, Amy B. Heimberger, Karen Clise Dwyer, Linghua Wang, Krishna P. Bhat. Immunophenotyping of human brain tumors reveals myeloid cell mediated anti-glioma axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 669.
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Bhatia, Aashim. "EPCT-20. TECHNICAL FEASIBILITY SODIUM (23NA) MRI OF PEDIATRIC GLIOMAS." Neuro-Oncology 23, Supplement_1 (2021): i51. http://dx.doi.org/10.1093/neuonc/noab090.206.
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Abstract Pediatric glioma response to novel targeted therapy can be heterogeneous on conventional proton (1H) MRI. Sodium concentration, as measured with 23Na MRI in adult brain tumors can provide complementary assessment of tumor proliferation to conventional MRI. However, 23Na MRI pediatric brain tumor studies are lacking. Determine the technical feasibility of performing sodium23Na MRI on pediatric glioma patients. Prospective study of an immunotherapy trial for newly diagnosed and recurrent gliomas (high-grade gliomas, low-grade gliomas, brainstem gliomas) in which participants were imaged with 23Na MRI at 3.0 Tesla. The participants (n=26, 14 males) with median age of 11 years (range = 4–23 years of age) were prospectively evaluated with sodium. 23Na MRI is technically feasible in the pediatric population and can distinguish different types of pediatric gliomas at baseline.
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Lanza, Marika, Giovanna Casili, Michela Campolo, et al. "Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas." Brain Sciences 11, no. 4 (2021): 466. http://dx.doi.org/10.3390/brainsci11040466.
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Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). Microglia substantially contribute to the growth and invasion of tumor mass in brain tumors including glioblastoma (GB). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors. Large numbers of glioma associated microglia and macrophages (GAMs) can accumulate within the tumor where they appear to have an important role in prognosis. GAMs constitute the largest portion of tumor infiltrating cells, contributing up to 30% of the entire glioma mass and upon interaction with neoplastic cells. GAMs acquire a unique phenotype of activation, including both M1 and M2 specific markers. It has been demonstrated that microglia possess a dual role: on one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Concluding, as microglia significantly may contribute to glioma biology, favoring tumor growth and invasiveness, these cells represent a valuable alternative/additional target for the development of more effective treatments for gliomas.
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Yu, Kai, Yuqiong Hu, Fan Wu, et al. "Surveying brain tumor heterogeneity by single-cell RNA-sequencing of multi-sector biopsies." National Science Review 7, no. 8 (2020): 1306–18. http://dx.doi.org/10.1093/nsr/nwaa099.
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Abstract Brain tumors are among the most challenging human tumors for which the mechanisms driving progression and heterogeneity remain poorly understood. We combined single-cell RNA-seq with multi-sector biopsies to sample and analyze single-cell expression profiles of gliomas from 13 Chinese patients. After classifying individual cells, we generated a spatial and temporal landscape of glioma that revealed the patterns of invasion between the different sub-regions of gliomas. We also used single-cell inferred copy number variations and pseudotime trajectories to inform on the crucial branches that dominate tumor progression. The dynamic cell components of the multi-region biopsy analysis allowed us to spatially deconvolute with unprecedented accuracy the transcriptomic features of the core and those of the periphery of glioma at single-cell level. Through this rich and geographically detailed dataset, we were also able to characterize and construct the chemokine and chemokine receptor interactions that exist among different tumor and non-tumor cells. This study provides the first spatial-level analysis of the cellular states that characterize human gliomas. It also presents an initial molecular map of the cross-talks between glioma cells and the surrounding microenvironment with single-cell resolution.
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Comba, Andrea, Patrick J Dunn, Anna E Argento, et al. "TMIC-58. THE CELLULAR AND MOLECULAR BASIS FOR MESENCHYMAL TRANSFORMATION IN GLIOMAS." Neuro-Oncology 21, Supplement_6 (2019): vi260. http://dx.doi.org/10.1093/neuonc/noz175.1092.
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Abstract Mesenchymal gliomas are the most aggressive tumors that carry the worst prognosis. The origins of mesenchymal cells within brain tumors, remains poorly understood. They could originate either from invading mesenchymal cells, from perivascular smooth muscle actin+ cells, or from a mesenchymal transformation of tumor cells. Identifying the origin and function of mesenchymal cells within gliomas is essential as these cells contribute to increased glioma aggressiveness and tumor progression. In this study we used human biopsies and implantable and genetically engineered mouse models (GEMM) of GBM to study tumor mesenchymal transformation. GBM implantable models were used to analyze the molecular landscape by laser microdissection followed by RNA-Seq and bioinformatics analysis. Time lapse confocal imagining was implemented to analyze GBM cells dynamics. Our results indicate the existence of a complex intratumoral and peritumoral dynamic organization of glioma cells (i.e., Oncostreams). Multicellular structures of elongated cells compatible with mesenchymal differentiation. These structures play important roles in intratumoral movements, peritumoral invasion of normal brain, and overall glioma progression. We also show that oncostreams are molecularly distinct and display increased expression of mesenchymal genes such as Col1a1. Knocking down of Col1a1 in a GEMM of aggressive gliomas reduced tumor progression and significantly increased animal survival. Histological examination confirmed absence of Col1a1, and absence of morphologically identifiable oncostreams. Our results show that tumor cells, especially within oncostreams, display a fibroblastic-like morphology and express proteins typical of mesenchymal cells. The knockout of Col1a1 from tumoral cells eliminated oncostreams from tumors and delayed tumor progression. These data suggest that tumor cells expressing mesenchymal genes regulate the organization of mesenchymal multicellular structures, and determine glioma progression. We propose that inhibiting mesenchymal transformation of glioma cells will assist in the treatment of glioblastoma.
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Poole, Alisha, Xueqing Lun, Antoine Dufour, Donna Senger, and Stephen Robbins. "EXPLORING THE ROLE OF GAT1 AND GABA IN TEMOZOLOMIDE TREATED GLIOMA." Neuro-Oncology Advances 5, Supplement_2 (2023): i7—i8. http://dx.doi.org/10.1093/noajnl/vdad071.031.
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Abstract Approximately 3000 Canadians a year are diagnosed with the most aggressive and fatal form of brain cancer called glioma. Even with surgical resection, chemotherapy, and radiotherapy these patients have an average survival of less than 20 months. Research in the past has primarily focused on identifying and targeting specific genetic mutations in the tumor. However, it is apparent that the environment surrounding the tumor can influence tumor growth, tumor spread into the brain, and drug resistance. The brain presents many challenges to glioma treatment, one of which is the unique environment in which gliomas grow, which contributes to poor patient outcomes. The interaction between tumor cells, surrounding normal brain tissue, and immune cells supports the aggressiveness of glioma. Using a model of chemosensitive and chemoresistant tumors, we have identified an increase in the GABA transporter GAT1 in the chemosensitive tumor treated with the standard chemotherapy temozolomide. GAT1 is primarily expressed on neurons, but has also been shown to be expressed on astrocytes and immune cells such as macrophages. Our lab has identified that macrophages tend to concentrate in the same region as GAT1 expressing cells within the tumor environment. In addition, multiple papers have shown that an increase in GABA promotes a glioma-promoting immune microenvironment. Thus, we believe that treatment with temozolomide causes an increase in environmental GAT1 expression, resulting in a reuptake of GABA, and promoting a glioma-inhibitory macrophage phenotype. We believe that understanding how the glioma-inhibitory macrophage phenotype occurs will help improve patient outcomes.
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Lyubich, L., and M. Lisyany. "Effects of the neurogenic cells supernatant on the tumor-inducing ability of glioma 101.8 in rats." Cell and Organ Transplantology 3, no. 1 (2015): 57–61. http://dx.doi.org/10.22494/cot.v3i1.17.
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The use of neurogenic stem cells (NSCs) and neurogenic progenitor cells (NPCs) is one of the areas of brain and spinal cord lesions cell therapy. Intensive research of NSCs biology has revealed their tumor-tropic properties. Great migration potential and integration of NSCs in places of pathology in the central nervous system allows to consider their application as a means of targeted therapy of tumors. Antitumor properties of NSCs substantiate the development of treatment strategies for malignant gliomas using NSCs.The aim was to study the effect of rat neurogenic cells supernatant (NCS) on the tumor-inducing ability of glioma 101.8 cells at the intracerebral implantation in rats.Brain glioma 101.8 was modeling by intracerebral injection of 101.8-glioma cells suspension. NCS was received from whole rat brain tissue on 14th (E14) day of gestation.Modification of 101.8-glioma cells suspension by means of incubation with NCS (0.02 and 0.1 mg/ml) reduced the tumor-inducing ability of tumor cells, postponing the time of tumor clinical manifestations debut and increasing the lifetime of experimental animals.Under conditions of glioma induction with tumor cells, previously modified by NCS, cytotoxic activity of immune cells of tumor-bearing animals in MTT-test with allogeneic 101.8-glioma cells was increased.
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Ayasoufi, Katayoun, Delaney Wolf, Jiaying Zheng, et al. "Evaluation of tumor derived Serpina3n in experimental glioblastoma." Journal of Immunology 208, no. 1_Supplement (2022): 119.03. http://dx.doi.org/10.4049/jimmunol.208.supp.119.03.
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Abstract Glioblastoma (GBM) is an incurable brain cancer which is associated with severe peripheral immune suppression. Using experimental GBM, we recently determined that peripheral immunosuppression involves thymic atrophy, stunted T cell proliferation, and release of circulating factors that inhibit immune responses. RNA sequencing and proteomic studies have recently determined that transcripts and protein levels of Serpina3n are upregulated in the brain and serum of GBM patients and correlates with poor prognosis. We determined Serpina3n is a highly upregulated gene in the brain and the thymus of glioma-bearing mice using RNA sequencing technologies. We therefore sought to determine the role of Serpina3n in peripheral immunosuppression in GL261 glioma harboring wild type and Serpina3n knockout mice. Glioma implantation in Serpina3n knockout mice resulted in similar survival and peripheral immunosuppression compared to controls. Western blotting experiments confirmed that Serpina3n is expressed and secreted by GL261 gliomas isolated from WT and Serpina3n knockout mouse brains. Together this data suggests that tumor-derived, but not host derived, Serpina3n needs to be evaluated as a putative factor associated with peripheral immunosuppression. Supported by Brains Together for a Cure grant
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Rana, Vishal R., Neeraj Prajapati, Vinod K. Mogha, Shashank Sah, and Namrata Singh. "Correlation of Perfusion MRI of Brain Tumors with their Histopathological Grade." SRMS JOURNAL OF MEDICAL SCIENCE 8, no. 02 (2023): 115–21. http://dx.doi.org/10.21761/jms.v8i02.13.
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Introduction: Gliomas are the most common primary neoplasms of the central nervous system, histologically varying from low grade (benign) to high grade (malignant). Their grade can be underestimated even on histopathology because even a single lesion may be histologically heterogeneous. For planning the optimal treatment strategy and assessing prognosis, accurate histologic grading is essential because treatment options are different for high-grade and low-grade gliomas as high grades are usually treated with adjuvant and neoadjuvant radiation or chemotherapy, whereas low-grade gliomas are not. The study aims to differentiate glioma grades by using perfusion MRI and to correlate findings of brain tumors on perfusion MRI with histopathological grading. Materials and Methods: We investigated 50 consecutive patients with brain tumors who had undergone both conventional and perfusion MR imaging during a period of one and half year period. Dynamic contrast-enhanced T2*-weighted and conventional T1- and T2-weighted imaging. rCBV maps were obtained by fitting a gamma-variate function to the contrast material concentration versus time curve. rCBV ratios between tumor and normal white matter (maximum rCBV of tumor/rCBV of contralateral white matter) were calculated and compared between four grades of glioma. Results: Mean rCBV ratios were 1.00 ± 0.35 for grade 1 gliomas, 2.6 ± 1.17 for grade 2 gliomas, 4.98 ± 0.76 for grade 3 gliomas and 6.54 ± 1.47 for grade 4 gliomas, and were thus significantly different. Lymphomas have less vascularity than other tumors, with a mean rCBV of 1.85 ± 0.77. Metastasis is a relatively high vascular tumor with a mean rCBV of 4.57 ± 0.67, which is near to grade 3 gliomas. High-grade gliomas can be differentiated from low-grade gliomas with cut-off value of mean rCBV of 2.86 with a sensitivity of 93%. Conclusion: Perfusion MRI is a useful and dependable means of noninvasively preoperative diagnosis and assessing the histologic grade of brain tumors, especially gliomas and determining the appropriate treatment according to the vascularity of the tumor and respective grade of glioma
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Szadkowska, Paulina, Adria-Jaume Roura, Bartosz Wojtas, et al. "Improvements in Quality Control and Library Preparation for Targeted Sequencing Allowed Detection of Potentially Pathogenic Alterations in Circulating Cell-Free DNA Derived from Plasma of Brain Tumor Patients." Cancers 14, no. 16 (2022): 3902. http://dx.doi.org/10.3390/cancers14163902.
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Malignant gliomas are the most frequent primary brain tumors in adults. They are genetically heterogenous and invariably recur due to incomplete surgery and therapy resistance. Circulating tumor DNA (ctDNA) is a component of circulating cell-free DNA (ccfDNA) and represents genetic material that originates from the primary tumor or metastasis. Brain tumors are frequently located in the eloquent brain regions, which makes biopsy difficult or impossible due to severe postoperative complications. The analysis of ccfDNA from a patient’s blood presents a plausible and noninvasive alternative. In this study, freshly frozen tumors and corresponding blood samples were collected from 84 brain tumor patients and analyzed by targeted next-generation sequencing (NGS). The cohort included 80 glioma patients, 2 metastatic cancer patients, and 2 primary CNS lymphoma (PCNSL) patients. We compared the pattern of genetic alterations in the tumor DNA (tDNA) with that of ccfDNA. The implemented technical improvements in quality control and library preparation allowed for the detection of ctDNA in 8 out of 84 patients, including 5 out of 80 glioma patients. In 32 out of 84 patients, we found potentially pathogenic genetic alterations in ccfDNA that were not detectable in tDNA. While sequencing ccfDNA from plasma has a low efficacy as a diagnostic tool for glioma patients, we concluded that further improvements in sample processing and library preparation can make liquid biopsy a valuable diagnostic tool for glioma patients.
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Tamai, Sho, Toshiya Ichinose, Taishi Tsutsui, et al. "Tumor Microenvironment in Glioma Invasion." Brain Sciences 12, no. 4 (2022): 505. http://dx.doi.org/10.3390/brainsci12040505.
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A major malignant trait of gliomas is their remarkable infiltration capacity. When glioma develops, the tumor cells have already reached the distant part. Therefore, complete removal of the glioma is impossible. Recently, research on the involvement of the tumor microenvironment in glioma invasion has advanced. Local hypoxia triggers cell migration as an environmental factor. The transcription factor hypoxia-inducible factor (HIF) -1α, produced in tumor cells under hypoxia, promotes the transcription of various invasion related molecules. The extracellular matrix surrounding tumors is degraded by proteases secreted by tumor cells and simultaneously replaced by an extracellular matrix that promotes infiltration. Astrocytes and microglia become tumor-associated astrocytes and glioma-associated macrophages/microglia, respectively, in relation to tumor cells. These cells also promote glioma invasion. Interactions between glioma cells actively promote infiltration of each other. Surgery, chemotherapy, and radiation therapy transform the microenvironment, allowing glioma cells to invade. These findings indicate that the tumor microenvironment may be a target for glioma invasion. On the other hand, because the living body actively promotes tumor infiltration in response to the tumor, it is necessary to reconsider whether the invasion itself is friend or foe to the brain.
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Leppert, Jan, Jochen Krajewski, Sven Rainer Kantelhardt, et al. "Multiphoton Excitation of Autofluorescence for Microscopy of Glioma Tissue." Neurosurgery 58, no. 4 (2006): 759–67. http://dx.doi.org/10.1227/01.neu.0000204885.45644.22.
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Abstract OBJECTIVE: Intraoperative detection of residual tumor tissue in glioma surgery remains an important challenge because the extent of tumor removal is related to the prognosis of the disease. Multiphoton excited fluorescence tomography of living tissues provides high-resolution structural and photochemical imaging at a subcellular level. In this conceptual study, we have used multiphoton microscopy and fluorescence lifetime imaging (4D microscopy) to image cultured glioma cell lines, solid tumor, and invasive tumor cells in an experimental mouse glioma model and human glioma biopsy specimens. MATERIAL AND METHODS: A laser imaging system containing a mode-locked 80 MHz titanium:sapphire laser with a tuning range of 710 to 920 nm, a scan unit, and a time correlated single photon counting board was used to generate autofluorescence intensity images and fluorescence lifetime images of cultured cell lines, experimental intracranial gliomas in mouse brain, and biopsies of human gliomas. RESULTS: Multiphoton microscopy of native tumor bearing brain provided structural images of the normal brain anatomy at a subcellular resolution. Solid tumor, the tumor-brain interface, and single invasive tumor cells could be visualized. Fluorescence lifetime imaging demonstrated significantly different decay of the fluorescent signal in tumor versus normal brain, allowing a clear definition of the tumor-brain interface based on this parameter. Distinct fluorescence lifetimes of endogenous fluorophores were found in different cellular compartments in cultured glioma cells. The analysis of the relationship between the laser excitation wavelength and the lifetime of excitable fluorophores demonstrated distinct profiles for cells of different histotypes. CONCLUSION: Multiphoton excited fluorescence of endogenous fluorophores allows structural imaging of tumor and central nervous system histo-architecture at a subcellular level. The analysis of the decay of the fluorescent signal within specific excitation volumes by fluorescent lifetime imaging discriminates glioma cells and normal brain, and the excitation/lifetime profiles may further allow differentiation of cellular histotypes. This technology provides a noninvasive optical tissue analysis that may potentially be applied to an intraoperative analysis of resection plains in tumor surgery.
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Langhnoja, Jaldeep, Xin Wei, Phonepasong Arounleut, and Timothy Phoenix. "TMIC-65. DISSECTING THE EXPRESSION AND FUNCTION OF ANGIOPOIETIN-1 IN BRAIN TUMORS." Neuro-Oncology 24, Supplement_7 (2022): vii286. http://dx.doi.org/10.1093/neuonc/noac209.1109.
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Abstract Angiopoietin-1 (Angpt1) is a secreted protein that can promote angiogenesis and vascular stability in development and certain disease states through activation of the Tie2 receptor. However, little is known about its expression or function across brain tumor types. Surveying its expression across pediatric and adult brain tumors we show Angpt1 is upregulated in glial brain tumors, including high-grade gliomas and ependymomas, and that expression patterns correlate with cell-type expression patters we recently described in the normal developing and adult brain. To examine the cell type and location of Angpt1 expression within tumors we have generated electroporation based high-grade glioma and ependymoma mouse models in Angpt1-GFP reporter knock-in mice. Angpt1-GFP expression is found mainly in tumor cells within both tumor models, with varying expression in high-grade glioma models based on driver mutations and molecular subtype. Single-cell transcriptomic studies in these mouse models are underway to further delineate expression across tumor and non-tumor cell types. Moreover, we are leveraging this flexible electroporation-based mouse brain tumor modeling platform to examine Angpt1 function within brain tumors. Preliminary data shows that including a DNA plasmid encoding Cre-recombinase induces recombination and loss of Angpt1 in our electroporation-based brain tumor models, and ongoing studies aim to delineate its function in tumor pathogenesis, including tumor angiogenesis and blood-brain barrier function.
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Toader, Corneliu, Mugurel Petrinel Radoi, Adrian Dumitru, et al. "High-Grade Thalamic Glioma: Case Report with Literature Review." Medicina 60, no. 10 (2024): 1667. http://dx.doi.org/10.3390/medicina60101667.
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This case report delves into the case of a 56-year-old female patient presenting with progressive cephalalgia syndrome, nausea, vomiting, and gait disorders, diagnosed with a high-grade thalamic glioma. Glioma is the most common form of central nervous system (CNS) neoplasm that originates from glial cells. Gliomas are diffusely infiltrative tumors that affect the surrounding brain tissue. Glioblastoma is the most malignant type, while pilocytic astrocytomas are the least malignant brain tumors. In the past, these diffuse gliomas were classified into different subtypes and grades based on histopathologies such as a diffuse astrocytoma, oligodendrogliomas, or mixed gliomas/oligoastrocytomas. Currently, gliomas are classified based on molecular and genetic markers. After the gross total resection, a postoperative brain CT scan was conducted, which confirmed the quasi-complete resection of the tumor. The successful gross total resection of the tumor in this case, coupled with significant neurological improvement postoperatively, illustrates the potential benefits of aggressive surgical management for thalamic gliomas. This report advocates for further research to assess the efficacy of such interventions in malignant cases and to establish standardized treatment protocols, considering the heterogeneity in prognostic outcomes and the advancements in molecular diagnostics that offer deeper insights into glioma oncogenesis and progression.
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Ye, Qi, Christine Madamba, Tiffany Choy, et al. "CNSC-19. ISCHEMIC STROKE DRIVES GLIOMA PROGRESSION BY REMODELING TUMOR-ASSOCIATED ASTROCYTES." Neuro-Oncology 26, Supplement_8 (2024): viii44—viii45. http://dx.doi.org/10.1093/neuonc/noae165.0175.
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Abstract Ischemic stroke and glioma are two deadly neurological disorders worldwide. Recent epidemiological studies reveal an increased risk of brain tumors, notably glioma, in patients with a history of stroke, resulting in a 10% co-occurrence. Comparative transcriptome analyses of brain samples collected from patients with common neurological disorders show that glioma is particularly enriched with stroke-associated gene signatures, especially in pathways related to their shared pathological features. These findings suggest a stroke-glioma interrelationship; however, it remains unknown how stroke alters the brain microenvironment to drive tumor progression. Here, we induced photothrombotic stroke in three mouse glioma models recapitulating multiple aspects of human glioma. Across all glioma models, we consistently observed that stroke increases tumor proliferation and infiltration towards stroke-affected regions, accompanied by reduced survival compared to sham control groups. Further analyses using single-cell RNA sequencing and spatial transcriptomic profiling in our stroke-glioma models reveal pronounced stroke-induced glioma microenvironment changes, among which tumor-associated astrocytes (TAAs) are most dramatically remodeled. Remarkably, we identified a unique stroke-induced astrocyte (SAA) at the tumor leading edge of the stroke-glioma group, characterized by diminished physiological astrocyte signatures and increased chromosomal and metabolic reprogramming. Among the top differentially expressed genes in SAA compared with TAA, the sodium-bicarbonate cotransporter Slc4a4 is interesting due to its enriched expression in TAA in both human and mouse gliomas, and it is significantly down-regulated at the infiltrating tumor edge. Consequently, we examine whether restoring astrocytic Slc4a4 expression rescues stroke-induced glioma progression. We found that astrocytic Slc4a4 overexpression reduces glioma growth and infiltration, accompanied by extended astroglial scar formation. Collectively, our study demonstrates that a subset of TAAs induced by stroke exacerbates glioma pathology, highlighting an indispensable astrocytic contribution to the stroke-glioma interaction.
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Ristić-Vitaljić, S., Lj Smilić, and Ž. Živić. "IMPORTANCE OF AFP AND CEA DETERMINATION IN EXPERIMENTALY INDUCED GLIOMA." Praxis medica 31, no. 1 (2003): 7–10. http://dx.doi.org/10.70949/pramed200201037r.
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&lt;p&gt;Beside great improvement in diagnostical ant therapeutic aproach in curement of brain tumors, gliomas still have&lt;br /&gt;bad prognosis. Better results could be obtained only in early tumor discavery. Alpha pheto protein (AFP) and carcinoembrionic antigen (CEA) are markers specific for certain carcinomas (hepatocelular, nonseminated testicular, colorectal). Thieir specifity for gliomas still has not been stated. The aim of tis study was to determine tissue or sera levels of AFP, and CEAin experimentaly induced gliomas, and teir poential use in human gliomas diagnosis. For analyses , tissue supernatant homogenate C6 of rat glioma and sera were used during different phases of development (days 0,7,14,21 and 31). Tumor markers were also determened as well as in tissue of human brain tumors (two anaplastic astrocitomas an one glioblastoma). Techique applied was immunoenzyme type Mein method. Obtained results showed no signs of AFPeither in sera, or in rat brain tissue or human glioma tissue. CEA however, showed statisticlly, important specifity, for glioma tissue. During tumorgenesis tissue concentracion of CEA showed statisticly higher levels in comparasion with controls , starting from day 7, reachin peak of tumorgenesis on day 21, (p &amp;lt; 0.001). CEAwas not detectable in control animal group sera, and also during the period of tumor development. CEA concentracion obtained from animal brain were similar to those in human&lt;br /&gt;brain tissue tumors. Further investigation need to be caried out, in order to determine the potential role of this marker in&lt;br /&gt;diagnosis and treatment establishment course.&lt;/p&gt;
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Stewart, Connor E., María E. Guerra-García, Lixia Luo, et al. "The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma." Cancers 14, no. 18 (2022): 4506. http://dx.doi.org/10.3390/cancers14184506.
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Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.
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Zhang, Junfeng, Heng Liu, Haipeng Tong, et al. "Clinical Applications of Contrast-Enhanced Perfusion MRI Techniques in Gliomas: Recent Advances and Current Challenges." Contrast Media & Molecular Imaging 2017 (2017): 1–27. http://dx.doi.org/10.1155/2017/7064120.
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Gliomas possess complex and heterogeneous vasculatures with abnormal hemodynamics. Despite considerable advances in diagnostic and therapeutic techniques for improving tumor management and patient care in recent years, the prognosis of malignant gliomas remains dismal. Perfusion-weighted magnetic resonance imaging techniques that could noninvasively provide superior information on vascular functionality have attracted much attention for evaluating brain tumors. However, nonconsensus imaging protocols and postprocessing analysis among different institutions impede their integration into standard-of-care imaging in clinic. And there have been very few studies providing a comprehensive evidence-based and systematic summary. This review first outlines the status of glioma theranostics and tumor-associated vascular pathology and then presents an overview of the principles of dynamic contrast-enhanced MRI (DCE-MRI) and dynamic susceptibility contrast-MRI (DSC-MRI), with emphasis on their recent clinical applications in gliomas including tumor grading, identification of molecular characteristics, differentiation of glioma from other brain tumors, treatment response assessment, and predicting prognosis. Current challenges and future perspectives are also highlighted.
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Ha, Yooree, Karishma Rajani, Cecile Riviere-Cazaux, et al. "An Injury-like Signature of the Extracellular Glioma Metabolome." Cancers 16, no. 15 (2024): 2705. http://dx.doi.org/10.3390/cancers16152705.
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Aberrant metabolism is a hallmark of malignancies including gliomas. Intracranial microdialysis enables the longitudinal collection of extracellular metabolites within CNS tissues including gliomas and can be leveraged to evaluate changes in the CNS microenvironment over a period of days. However, delayed metabolic impacts of CNS injury from catheter placement could represent an important covariate for interpreting the pharmacodynamic impacts of candidate therapies. Intracranial microdialysis was performed in patient-derived glioma xenografts of glioma before and 72 h after systemic treatment with either temozolomide (TMZ) or a vehicle. Microdialysate from GBM164, an IDH-mutant glioma patient-derived xenograft, revealed a distinct metabolic signature relative to the brain that recapitulated the metabolic features observed in human glioma microdialysate. Unexpectedly, catheter insertion into the brains of non-tumor-bearing animals triggered metabolic changes that were significantly enriched for the extracellular metabolome of glioma itself. TMZ administration attenuated this resemblance. The human glioma microdialysate was significantly enriched for both the PDX versus brain signature in mice and the induced metabolome of catheter placement within the murine control brain. These data illustrate the feasibility of microdialysis to identify and monitor the extracellular metabolome of diseased versus relatively normal brains while highlighting the similarity between the extracellular metabolome of human gliomas and that of CNS injury.