Advances in Radiotherapy for Glioblastoma

Mann, Jack; Ramakrishna, Rohan; Magge, Rajiv; Wernicke, A. Gabriella

doi:10.3389/fneur.2017.00748

Cited by 115 publications

(100 citation statements)

References 92 publications

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“…RT has been shown to prolong the life of glioma patients [115]. RT alters the tumor microenvironement by increasing infiltration of immunosuppressive myeloid cells and release of tumor antigens from necrotic tissue [116,117].…”

Section: Mdscs and Rt Resistancementioning

confidence: 99%

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Khan

Mittal

McGee

et al. 2020

IJMS

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Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types—including neutrophils and myeloid-derived suppressor cells—that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.

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Section: Mdscs and Rt Resistancementioning

confidence: 99%

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Khan

Mittal

McGee

et al. 2020

IJMS

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“…Glioblastoma are grade IV tumours and are characterised by a highly aggressive and invasive phenotype, resulting in a very low 5-year survival of 6% [2]. The standard treatment for glioblastoma patients (Stupp regime) consists of surgery, radiotherapy (RT) and concurrent followed by adjuvant temozolomide [3,4]. The alkylating agent temozolomide in combination with RT was shown to prolong survival and increase median survival to 14.6 months, in comparison to 12.1 months with RT alone [3,5].…”

Section: Introductionmentioning

confidence: 99%

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma

Meneceur

Linge

Meinhardt

et al. 2020

Cancers

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Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models for preclinical testing, which faithfully reflect human cancers. The aim of this study was to establish glioblastoma patient-derived xenografts (PDXs) by heterotopic transplantation of tumour pieces in the axillae of NMRI nude mice. Ten out of 22 patients' samples gave rise to tumours in mice. Their human origin was confirmed by microsatellite analyses, though minor changes were observed. The glioblastoma nature of the PDXs was corroborated by pathological evaluation. Latency times spanned from 48.5 to 370.5 days in the first generation. Growth curve analyses revealed an increase in the growth rate with increasing passages. The methylation status of the MGMT promoter in the primary material was maintained in the PDXs. However, a trend towards a more methylated pattern could be found. A correlation was observed between the take in mice and the proportion of Sox2 + cells (r = 0.49, p = 0.016) and nestin + cells (r = 0.55, p = 0.007). Our results show that many PDXs maintain key features of the patients' samples they derive from. They could thus be used as preclinical models to test new therapies and biomarkers.

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“…Exocytosis and vesicle secretion can further facilitate release of purinergic nucleotides, inflammatory molecules, enzymes, and ROS into the extracellular milieu, which collectively can alter the TME to become pro-tumorigenic (60,68,(80)(81)(82) [ Figure 5B]. The dose and time-dependence of radiation exposure can significantly alter the impact of RT on tumor microenvironment by affecting tumor or stromal cell behavior, migration, and treatment response (26,28,29,(83)(84)(85)(86)(87)(88)(89)(90). High-dose irradiation effects include hemorrhage, cognitive decline, neurodegeneration, and premature senescence, which can progress over time (91,92).…”

Section: Discussionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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AbstractGlioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p<0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

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Advances in Radiotherapy for Glioblastoma

Cited by 115 publications

References 92 publications

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

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