Radiation-Induced Alterations in the Recurrent Glioblastoma Microenvironment: Therapeutic Implications

Gupta, Kshama; Burns, Terry C.

doi:10.3389/fonc.2018.00503

Cited by 78 publications

(92 citation statements)

References 177 publications

(164 reference statements)

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“…Radiation therapy itself induces changes in the tumor microenvironment and renders the tumor more aggressive. In fact, recurrence mostly appears near the irradiated area (Gupta and Burns, 2018). Radiotherapy induces a rapid inflammatory response leading to TAMs recruitment.…”

Section: Tams and Radiotherapymentioning

confidence: 99%

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

et al. 2020

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Section: Tams and Radiotherapymentioning

confidence: 99%

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

et al. 2020

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“…This study aimed to identify the impact of high-dose radiation-induced brain injury on glioblastoma growth and aggressivity, and to probe the metabolic alterations in response to irradiation-associated growth. Radiation can severely impact the tumor microenvironment by altering the extracellular milieu at molecular and structural levels (8,25,47). Radiation treatment leads to production of ROS.…”

Section: Discussionmentioning

confidence: 99%

“…Radiation-induced changes in the brain and tumor microenvironment injury resulting in molecular, cellular, and functional changes that can facilitate tumor aggressiveness upon recurrence (8). Such changes include decreased vascularity, innate immune activation, and altered pharmacokinetics, pharmacodynamics, and therapeutic efficacy of chemotherapy agents (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…Metabolic alterations may be pro-tumorigenic, promoting glioma initiation and progression (21)(22)(23)(24). RT-induced metabolic changes in GBM depend on tumor volume, location, and dose-time regime of RT-administration, all of which can vary treatment response (8,(25)(26)(27)(28)(29). While differential metabolism of glioma tumor cells can be targeted to regress tumor growth, understanding the impact of radiation-induced metabolic alterations in GBM microenvironment can provide new avenues to maximize long term benefits of RT in GBM care.…”

Section: Introductionmentioning

confidence: 99%

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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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“…A growing body of literature has elucidated the substantial impacts of radiotherapy on non-tumor cells present in the tumor microenvironment and surrounding CNS parenchyma [10,11]. Although radiation remains standard of care and despite the nearly uniform GBM recurrence rates, we and others have made the concerning observation that the radiated microenvironment actually increases the aggressiveness of GBM cells implanted into an irradiated brain [12,13,14]. To date, studies reporting this phenomena have each evaluated a single cell line, leaving open the question of how widespread this susceptibility to increased aggressiveness may be across the clinical and moleulular spectrum of human GBM.…”

Section: Introductionmentioning

confidence: 99%

Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts

Zhang

Olson

Carlstrom

et al. 2020

Preprint

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ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumor are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. We recently demonstrated that the radiated brain tumor microenvironment promotes tumor aggressiveness in an orthotopic patient-derived xenograft (PDX) model of glioblastoma (Mayo GBM 143). Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics. MethodsFemale athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected PDX GBM cell lines (GBM 6,10,12, 39, 46, 76, 123, 164, 196; per group, per line). GBM 6 cells were additionally implanted 6 months after completion of fractionated radiation (4Gy x 10 fractions or 2Gy x 30 fractions) vs sham radiation.Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups. ResultOf nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196); similar to previous observations with GBM 143. GBM 6 was also evaluated 6 months after fractionated radiation yielding similar results. However, two lines yielded prolonged survival in the 4 pre-radiated brain (GBM 10, 12); GBM12 and 10 demonstrated the fastest baseline growth in the non-radiated brain; GBM 39, 123 whose rate of growth was not impacted by the radiated brain, demonstrated a an intermediate baseline growth rate between that of those positively and negatively impacted by the radiated brain microenvironment. No other clinical or molecular phenotype was found to consistently correlate with response to the radiated microenvironment. ConclusionAmong a total of 10 total human GBM lines evaluated to date, 60% induce faster mortality in a radiated microenvironment, and 20% induce slower mortality. These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.

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Radiation-Induced Alterations in the Recurrent Glioblastoma Microenvironment: Therapeutic Implications

Cited by 78 publications

References 177 publications

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

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

Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts

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