Mouse Models of Experimental Glioblastoma

Jin, Fang; Jin-Lee, Helen J.; Johnson, Aaron J.

doi:10.36255/exonpublications.gliomas.2021.chapter2

Cited by 15 publications

(16 citation statements)

References 166 publications

(249 reference statements)

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Section: Cell Lines and Mouse Models Of Gliomamentioning

confidence: 99%

“…The Cre-LoxP system allows for the targeting of tumor genes in mouse brain tissue of interest which provides for insight into the genetic drivers of GBM and the differences in genetic drivers between primary and secondary GBMs ( 36 ). To create this model, a mouse strain known as the “Cre driver strain” which has Cre recombinase with a promoter, and a mouse strain known as the “LoxP floxed strain” that has LoxP floxed exons of the target gene, were bred together ( 36 ). By breeding these strains together this would result in a deletion of the floxed region and a subsequent inactivation of the gene in the desired brain tissue of interest, leaving the target gene active in tissues outside this region ( 36 ).…”

Section: Cell Lines and Mouse Models Of Gliomamentioning

confidence: 99%

“…To create this model, a mouse strain known as the “Cre driver strain” which has Cre recombinase with a promoter, and a mouse strain known as the “LoxP floxed strain” that has LoxP floxed exons of the target gene, were bred together ( 36 ). By breeding these strains together this would result in a deletion of the floxed region and a subsequent inactivation of the gene in the desired brain tissue of interest, leaving the target gene active in tissues outside this region ( 36 ). Specifically, this model has been used to test the role of p53 and PTEN function in GFAP positive GBM.…”

Section: Cell Lines and Mouse Models Of Gliomamentioning

confidence: 99%

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Pre-clinical models for evaluating glioma targeted immunotherapies

Frederico

Zhang²,

Hu³

et al. 2023

Front. Immunol.

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Gliomas have an extremely poor prognosis in both adult and pediatric patient populations as these tumors are known to grow aggressively and respond poorly to standard of care treatment. Currently, treatment for gliomas involves surgical resection followed by chemoradiation therapy. However, some gliomas, such as diffuse midline glioma, have more limited treatment options such as radiotherapy alone. Even with these interventions, the prognosis for those diagnosed with a glioma remains poor. Immunotherapy is highly effective for some cancers and there is great interest in the development of effective immunotherapies for the treatment of gliomas. Clinical trials evaluating the efficacy of immunotherapies targeted to gliomas have largely failed to date, and we believe this is partially due to the poor choice in pre-clinical mouse models that are used to evaluate these immunotherapies. A key consideration in evaluating new immunotherapies is the selection of pre-clinical models that mimic the glioma-immune response in humans. Multiple pre-clinical options are currently available, each one with their own benefits and limitations. Informed selection of pre-clinical models for testing can facilitate translation of more promising immunotherapies in the clinical setting. In this review we plan to present glioma cell lines and mouse models, as well as alternatives to mouse models, that are available for pre-clinical glioma immunotherapy studies. We plan to discuss considerations of model selection that should be made for future studies as we hope this review can serve as a guide for investigators as they choose which model is best suited for their study.

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Section: Cell Lines and Mouse Models Of Gliomamentioning

confidence: 99%

Section: Cell Lines and Mouse Models Of Gliomamentioning

confidence: 99%

Section: Cell Lines and Mouse Models Of Gliomamentioning

confidence: 99%

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Pre-clinical models for evaluating glioma targeted immunotherapies

Frederico

Zhang²,

Hu³

et al. 2023

Front. Immunol.

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“…Wherein a tumor cell suspension is intracranially injected into brain areas associated with seizure vulnerability and/or propagation ( Table 2 ). Genetic manipulation of epilepsy-associated known oncogenes via IUE CRISPR/Cas9-mediated deletion or utilization of inducible-Cre-LoxP transgenic models has recently been employed to aid the investigation into genetic mechanisms of GBM-associated epileptogenesis ( Table 2 ; Hatcher et al, 2020 ; Jin et al, 2021 ). The majority of existing studies utilize transplantation methods (Köhling et al, 2006 ; Bouckaert et al, 2020 ), with many seminal articles employing xenografting ( Table 2 ; Buckingham et al, 2011 ; Campbell et al, 2012 , 2015 ).…”

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Hills

Kostarelos

Wykes

2022

Front. Mol. Neurosci.

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Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.

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“…Although the CRISPR-Cas9 approaches take less time to develop animal models, off-target effects result in a wide range of GBM phenotypes. While transposon-based insertional mutagenesis systems can prevent and enhance transcription, the amount of insertional transgenes is strictly limited [32]. Also, injecting allograft cell lines into immunocompetent mice reduces immunological rejection, it fails to replicate certain aspects of human GBM [32].…”

Section: In Vivo Gbm Modelsmentioning

confidence: 99%

Glioblastoma organoid technology: an emerging preclinical models for drug discovery

et al. 2022

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Glioblastoma multiforme (GBM) is the most prevalent type of primary brain tumor among adults, and it has a median overall survival of 12 to 15 months upon diagnosis. Despite significant improvements in GBM research, therapeutic options are still limited and survival rates have not significantly improved. Accordingly, clinical and translational studies are hampered due to the lack of suitable preclinical models that accurately reflect the brain tumor architecture and its microenvironment. Scientists have recently developed cerebral organoids, which are artificial 3-dimensional brain-like tissue. Organoid technology provides new cancer modeling options, which could help us better understand GBM pathogenesis and design personalized treatments. In this review, we summarize recent developments in organoid GBM models, highlighting their advantages in cancer modeling, as well as their challenges and limitations and potential future directions in GBM therapy.

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Mouse Models of Experimental Glioblastoma

Cited by 15 publications

References 166 publications

Pre-clinical models for evaluating glioma targeted immunotherapies

Pre-clinical models for evaluating glioma targeted immunotherapies

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Glioblastoma organoid technology: an emerging preclinical models for drug discovery

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