Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth

Duan, Chun Gang; Yang, Ruimeng; Lu, Yuan; Engelbach, John A.; Tsien, Christina; Rich, Keith M.; Dahiya, Sonika; Johanns, Tanner M.; Ackerman, Joseph J. H.; Garbow, Joel R.

doi:10.1016/j.ijrobp.2018.08.033

Cited by 24 publications

(33 citation statements)

References 16 publications

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“…These findings augment growing literature that illustrate the impact of the irradiated tumor microenvironment on tumor behavior [18]. Duan et al [13] previously reported a radiation dose-dependent increased growth rate of mouse GBM cells within c57Bl6 mice upon delivery of (0, 20, 30, or 40 Gy by stereotactic radiation to the ipsilateral hemisphere.…”

Section: Discussionsupporting

confidence: 79%

“…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%

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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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Section: Discussionsupporting

confidence: 79%

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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“…Prior work has demonstrated that co- implantation of radiated with non-radiated cells increases tumor aggressiveness. We ( 134 ), and others ( 133 , 135 – 137 ), have observed increased tumor aggressiveness after implantation of glioma cells into previously radiated hosts. Given the potential for senescent cells to induce tissue dysfunction and inflammation, several studies have addressed the potential of metabolically active senescent cells and SASP factors to exacerbate recurrences of various cancers ( 124 , 138 , 139 ).…”

Section: Effects Of Radiation Therapy On the Gbm Microenvironmentmentioning

confidence: 81%

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

Gupta

Burns

2018

Front. Oncol.

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Glioblastoma (GBM) is uniformly fatal with a median survival of just over 1 year, despite best available treatment including radiotherapy (RT). Impacts of prior brain RT on recurrent tumors are poorly understood, though increasing evidence suggests RT-induced changes in the brain microenvironment contribute to recurrent GBM aggressiveness. The tumor microenvironment impacts malignant cells directly and indirectly through stromal cells that support tumor growth. Changes in extracellular matrix (ECM), abnormal vasculature, hypoxia, and inflammation have been reported to promote tumor aggressiveness that could be exacerbated by prior RT. Prior radiation may have long-term impacts on microglia and brain-infiltrating monocytes, leading to lasting alterations in cytokine signaling and ECM. Tumor-promoting CNS injury responses are recapitulated in the tumor microenvironment and augmented following prior radiation, impacting cell phenotype, proliferation, and infiltration in the CNS. Since RT is vital to GBM management, but substantially alters the tumor microenvironment, we here review challenges, knowledge gaps, and therapeutic opportunities relevant to targeting pro-tumorigenic features of the GBM microenvironment. We suggest that insights from RT-induced changes in the tumor microenvironment may provide opportunities to target mechanisms, such as cellular senescence, that may promote GBM aggressiveness amplified in previously radiated microenvironment.

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“…Duan et al showed that irradiation of normal brain before tumor cell implantation contributed to aggressive tumor growth, which suggested a brain tumor microenvironment-induced, tumor-extrinsic effect (66). Tumor microenvironment (TM) is mainly composed of epithelial cells, stromal cells, extracellular matrix (ECM) components or immune cells (67).…”

Section: Inhibiting Stat3 Decreased Radiation-induced Aggressive Behamentioning

confidence: 99%

STAT3 Contributes to Radioresistance in Cancer

2020

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Radiotherapy has been used in the clinic for more than one century and it is recognized as one of the main methods in the treatment of malignant tumors. Signal Transducers and Activators of Transcription 3 (STAT3) is reported to be upregulated in many tumor types, and it is believed to be involved in the tumorigenesis, development and malignant behaviors of tumors. Previous studies also found that STAT3 contributes to chemo-resistance of various tumor types. Recently, many studies reported that STAT3 is involved in the response of tumor cells to radiotherapy. But until now, the role of the STAT3 in radioresistance has not been systematically demonstrated. In this study, we will review the radioresistance induced by STAT3 and relative solutions will be discussed.

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Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth

Cited by 24 publications

References 16 publications

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

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

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

STAT3 Contributes to Radioresistance in Cancer

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