Cell line-based xenograft mouse model of paediatric glioma stem cells mirrors the clinical course of the patient

Larsson, Susanna C.; Wenger, Anna; Dósa, Sándor; Sabel, Magnus; Kling, Teresia; Carén, Helena

doi:10.1093/carcin/bgy091

Cited by 16 publications

(7 citation statements)

References 26 publications

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“…Invasive growth and tumor recurrence are the two key characteristics of diffuse gliomas in humans. Invasive patient-derived orthotopic xenografts (PDOXs) for gliomas have been modeled from patient surgical specimens and patient-derived short-term cultures [11, 21, 22]. In addition, invasive orthotopic gliomas have been established from subcutaneous xenografts from surgical specimens of patients with gliomas and from their propagations [23].…”

Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas

et al. 2020

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BackgroundGliomas account for the major part of primary brain tumors. Based on their histology and molecular alternations, adult gliomas have been classified into four grades, each with distinct biology and outcome. Previous studies have focused on cell-line-based models and patient-derived xenografts (PDXs) from patient-derived glioma cultures for grade IV glioblastoma. However, the PDX of lower grade diffuse gliomas, particularly those harboring the endogenous IDH mutation, are scarce due to the difficulty growing glioma cells in vitro and in vivo. The purpose of this study was to develop a panel of patient-derived subcutaneous xenografts of different grade gliomas that represented the heterogeneous histopathologic and genetic features of human gliomas.MethodsTumor pieces from surgical specimens were subcutaneously implanted into flanks of NOD-Prkdcscid ll2rgnull mice. Then, we analyzed the association between the success rate of implantation with clinical parameters using the Chi square test and resemblance to the patient’s original tumor using immunohistochemistry, immunofluorescence, short tandem repeat analysis, quantitative real-time polymerase chain reaction, and whole-exome sequencing.ResultsA total of 11 subcutaneous xenografts were successfully established from 16 surgical specimens. An increased success rate of implantation in gliomas with wild type isocitrate dehydrogenase (IDH) and high Ki67 expression was observed compared to gliomas with mutant IDH and low Ki67 expression. Recurrent and distant aggressive xenografts were present near the primary implanted tumor fragments from WHO grades II to IV. The xenografts histologically represented the corresponding patient tumor and reconstituted the heterogeneity of different grade gliomas. However, increased Ki67 expression was found in propagated xenografts. Endothelial cells from mice in patient-derived xenografts over several generations replaced the corresponding human tumor blood vessels. Short tandem repeat and whole-exome sequencing analyses indicated that the glioma PDX tumors maintained their genomic features during engraftments over several generations.ConclusionsThe panel of patient-derived glioma xenografts in this study reproduced the diverse heterogeneity of different grade gliomas, thereby allowing the study of the growth characteristics of various glioma types and the identification of tumor-specific molecular markers, which has applications in drug discovery and patient-tailored therapy.

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Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas

et al. 2020

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“…These wellcharacterised cells have been shown to be stable during culturing and maintain their DNA methylation profiles and DNA copy number alterations (CNA). The expression of stem cell proteins as well as in vivo tumour-initiating capacity of these cells [16] demonstrates their resemblance to cancer stem cells or progenitor cells. These cells hence provide a relevant and robust model system for functional studies on paediatric brain tumours.…”

Section: Resultsmentioning

confidence: 99%

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

et al. 2020

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Background: Radiation is an important therapeutic tool. However, radiotherapy has the potential to promote coevolution of genetic and epigenetic changes that can drive tumour heterogeneity, formation of radioresistant cells and tumour relapse. There is a clinical need for a better understanding of DNA methylation alterations that may follow radiotherapy to be able to prevent the development of radiation-resistant cells. Methods:We examined radiation-induced changes in DNA methylation profiles of paediatric glioma stem cells (GSCs) in vitro. Five GSC cultures were irradiated in vitro with repeated doses of 2 or 4 Gy. Radiation was given in 3 or 15 fractions. DNA methylation profiling using Illumina DNA methylation arrays was performed at 14 days postradiation. The cellular characteristics were studied in parallel. Results: Few fractions of radiation did not result in significant accumulation of DNA methylation alterations. However, extended dose fractionations changed DNA methylation profiles and induced thousands of differentially methylated positions, specifically in enhancer regions, sites involved in alternative splicing and in repetitive regions. Radiation induced dose-dependent morphological and proliferative alterations of the cells as a consequence of the radiation exposure.Conclusions: DNA methylation alterations of sites with regulatory functions in proliferation and differentiation were identified, which may reflect cellular response to radiation stress through epigenetic reprogramming and differentiation cues.

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“…The investigation of the perivascular niche in terms of the spread of glioma cells along the Scherer structures also seems to be possible in xenograft models. Cell-line-based orthotopic implantation of glioma stem cells into immunodeficient mice showed that the gliomas revealed the molecular biological characteristics of the donor gliomas and the tumors formed secondary structures, as described by Scherer in the sense of perivascular, perineuronal, and meningeal accumulation (Larsson et al, 2018). Humanized PDX models seem to have an advantage here, as the representation of Scherer structures/glioma niches could be examined in a (human) immunocompetent environment.…”

Section: The Niches In the Microenvironmentmentioning

confidence: 86%

Rodent Models to Analyze the Glioma Microenvironment

et al. 2021

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Animal models are still indispensable for understanding the basic principles of glioma development and invasion. Preclinical approaches aim to analyze the treatment efficacy of new drugs before translation into clinical trials is possible. Various animal disease models are available, but not every approach is useful for addressing specific questions. In recent years, it has become increasingly evident that the tumor microenvironment plays a key role in the nature of glioma. In addition to providing an overview, this review evaluates available rodent models in terms of usability for research on the glioma microenvironment.

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Cell line-based xenograft mouse model of paediatric glioma stem cells mirrors the clinical course of the patient

Cited by 16 publications

References 26 publications

Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas

Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

Rodent Models to Analyze the Glioma Microenvironment

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