Background Gliomas 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. Methods Tumor 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. Results A 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. Conclusions The 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.

中文翻译：

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不同级别胶质瘤的患者来源异种移植物保留了人类胶质瘤的异质组织学和遗传特征。

背景 胶质瘤占原发性脑肿瘤的主要部分。根据其组织学和分子变化，成人神经胶质瘤已分为四个等级，每个等级都有不同的生物学和结果。以前的研究集中在基于细胞系的模型和来自患者来源的胶质瘤培养物的患者来源的异种移植物 (PDX) 用于 IV 级胶质母细胞瘤。然而，由于在体外和体内难以生长胶质瘤细胞，低级别弥漫性胶质瘤的 PDX，特别是那些携带内源性 IDH 突变的胶质瘤很少。本研究的目的是开发一组来自患者的不同级别神经胶质瘤的皮下异种移植物，代表人类神经胶质瘤的异质组织病理学和遗传特征。方法 将手术标本的肿瘤片皮下植入 NOD-Prkdcscid ll2rgnull 小鼠的侧腹。然后，我们使用卡方检验分析了植入成功率与临床参数之间的关联，以及使用免疫组织化学、免疫荧光、短串联重复分析、定量实时聚合酶链反应和全外显子组测序与患者原始肿瘤的相似性之间的关联。 . 结果 16个手术标本共成功建立11个皮下异种移植物。与具有突变 IDH 和低 Ki67 表达的胶质瘤相比，观察到具有野生型异柠檬酸脱氢酶 (IDH) 和高 Ki67 表达的胶质瘤的植入成功率增加。复发性和远处侵袭性异种移植物存在于 WHO II 至 IV 级原发性植入肿瘤碎片附近。异种移植物在组织学上代表了相应的患者肿瘤，并重建了不同级别胶质瘤的异质性。然而，在繁殖的异种移植物中发现增加的 Ki67 表达。来自患者来源异种移植物的小鼠的内皮细胞经过几代人的移植取代了相应的人类肿瘤血管。短串联重复和全外显子组测序分析表明，胶质瘤 PDX 肿瘤在几代人的移植过程中保持其基因组特征。结论 本研究中患者来源的胶质瘤异种移植物组再现了不同级别胶质瘤的不同异质性，