Clinical Relevance of Tumor Cells with Stem-Like Properties in Pediatric Brain Tumors

BackgroundPrimitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. Methodology/Principal FindingsTumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting. Conclusions/SignificanceIn brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.背景 原发性脑肿瘤是导致儿童癌症相关死亡的首要原因。具有干细胞样特性的肿瘤细胞（TSCs）被认为是驱动肿瘤发生与治疗抵抗的关键群体，此前仅从成人高级别胶质瘤中分离得到此类细胞。TSCs是否为儿童脑肿瘤的常见组成部分，且是否具有临床相关性，仍有待阐明。 研究方法与主要发现 本研究采用细胞生物学技术，从55例儿童脑肿瘤样本中的多数样本中分离得到了具有自我更新能力的肿瘤细胞，该分离结果不受肿瘤组织病理学类型与恶性分级的影响：其中胚胎性肿瘤的分离成功率为57%，低级别胶质瘤及神经胶质肿瘤为57%，室管膜瘤为70%，高级别胶质瘤为91%。 多数源自高级别胶质瘤的肿瘤球（oncospheres，10/12）可维持类似神经干细胞的长期自我更新能力（自我更新次数超过7次），而其余所有肿瘤来源的样本中，则以具有有限自我更新能力、类似神经前体细胞的细胞为主。无论肿瘤类型如何，低龄患儿群体均更易分离得到类似神经干细胞的自我更新型细胞（卡方检验，P=0.05）。 对该研究队列的生存分析显示，分离得到具有长期自我更新能力细胞的患儿，其死亡率显著更高（对数秩检验，P=0.013）。对低级别与高级别胶质瘤培养样本的检测显示，形成肿瘤球的自我更新型细胞共享一套包含胚胎干细胞与神经干细胞标志物的分子表达谱。进一步针对部分高级别胶质瘤样本及1例低级别胶质瘤培养物的特征分析显示，此类自我更新型细胞的分子表达谱可与间充质标志物共存，同时具备放化疗抵抗性，且在颅内移植后可形成侵袭性肿瘤。 结论与意义 此前针对成人脑肿瘤的研究中，TSCs仅可从高级别胶质瘤中分离得到。与之形成鲜明对比的是，本研究数据表明，具有干细胞样或前体细胞样特性的肿瘤细胞，可从多种组织学亚型与恶性分级的儿童脑肿瘤中分离得到。该结果提示，驱动成人与儿童脑肿瘤发生发展的细胞机制存在差异。