Radiotherapy and Glioma Stem Cells: Searching for Chinks in Cellular Armor

Caragher, Seamus P.; Sachdev, Sean; Ahmed, Atique U.

doi:10.1007/s40778-017-0102-8

Cited by 17 publications

(15 citation statements)

References 75 publications

(76 reference statements)

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“…From genetic anomalies and epigenetic dysregulation [1,2] to cellular plasticity [3], immunosuppression [4], and metabolic adaptability [5,6,7], GBM exhibit a wide diversity of phenotypes and possess a remarkable toolbox for colonizing the brain and resisting current treatment regimens. The failure of current radiotherapy paradigms to provide long-term tumor control in GBM has been linked to all these factors [8]. In addition to these tumor factors, GBM remains intractable because of its ability to interact with its environment, including healthy astrocytes and blood vessels.…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

Caragher

Chalmers

Gomez-Roman

2019

Cancers

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Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

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Section: Introductionmentioning

confidence: 99%

Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

Caragher

Chalmers

Gomez-Roman

2019

Cancers

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“…Glioma is the most aggressive neurological disease with high rate of mortality, which accounts for about 30% cases of central nervous cancers (Caragher, Sachdev, & Ahmed, ; Glenn et al, ). Thousands of new patients are diagnosed with glioma each year around the world (Rao et al, ).…”

Section: Introductionmentioning

confidence: 99%

LncRNA LINC01857 promotes growth, migration, and invasion of glioma by modulating miR‐1281/TRIM65 axis

Liu

Wang³

et al. 2019

Journal Cellular Physiology

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The great importance of long noncoding RNAs (lncRNAs) has been acknowledged in tumorigenesis gradually. LncRNA LINC01857 is a novel lncRNA and has been reported to promote breast cancer progression. However, the biological roles of LINC01857 in glioma are not explored. In the present research, LINC01857 levels were found to be upregulated in glioma. In addition, LINC01857 expression is negatively correlated with survival rate in glioma patients. Functional investigation revealed that LINC01857 downregulation impaired glioma proliferation and invasiveness. Furthermore, LINC01857 knockdown led to repressed growth of glioma in vivo. We found that LINC01857 could be a sponge for miR-1281 and inhibits its level to upregulate TRIM65 expression. Whatʼs more, we showed that miR-1281 mimics also attenuated tumor cell proliferation, migration, and invasion.And rescue assays demonstrated that LINC01857 promotes glioma progression through modulating miR-1281/TRIM65 pathway. Collectively, this study first demonstrated that a novel LINC01857/miR-1281/TRIM65 signaling regulates glioma progression.

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“…Despite aggressive treatment with surgical resection and subsequent chemo/radiation therapy, resistance to adjuvant therapy enhances cancer cell survival, which is a critical cause for tumor relapse 3, 4, 27. While effective for eradicating GBM cancer cells, radiotherapy is less effective for GICs 7, 28. Radiation therapy kills cancer cells by inducing irreparable DNA double-strand breaks, thus highly proliferating cancer cells are more radiosensitive than quiescent GICs.…”

Section: Discussionmentioning

confidence: 99%

Theranostic nanoparticles enhance the response of glioblastomas to radiation

Klockow

Mohanty

et al. 2019

Nanotheranostics

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Despite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre-and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG mice underwent survival analyses with Kaplan-Meier curves and a log rank (Mantel-Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.

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Radiotherapy and Glioma Stem Cells: Searching for Chinks in Cellular Armor

Cited by 17 publications

References 75 publications

Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

LncRNA LINC01857 promotes growth, migration, and invasion of glioma by modulating miR‐1281/TRIM65 axis

Theranostic nanoparticles enhance the response of glioblastomas to radiation

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