Laboratory of Nervous System Diseases and Therapy, GIGA Neuroscience, GIGA Institute, University of Liège, Liège, Belgium.
Department of Neurosurgery, CHU Liège, Liège, Belgium.
Acta Neuropathol Commun. 2023 Jun 16;11(1):96. doi: 10.1186/s40478-023-01586-x.
Pediatric high-grade gliomas (pHGG) are brain tumors occurring in children and adolescents associated with a dismal prognosis despite existing treatments. Therapeutic failure in both adult and pHGG has been partially imputed to glioma stem cells (GSC), a subset of cancer cells endowed with stem-like cell potential and malignant, invasive, adaptative, and treatment-resistant capabilities. Whereas GSC have largely been portrayed in adult tumors, less information has been provided in pHGG. The aim of our study was to comprehensively document the stem-like capacities of seven in-use pediatric glioma cell cultures (Res259, UW479, SF188, KNS42, SF8628, HJSD-DIPG-007 and HJSD-DIPG-012) using parallel in vitro assays assessing stem cell-related protein expression, multipotency, self-renewal and proliferation/quiescence, and in vivo investigation of their tumorigenicity and invasiveness. Data obtained from in vitro experiments revealed glioma subtype-dependent expression of stem cell-related markers and varying abilities for differentiation, self-renewal, and proliferation/quiescence. Among tested cultures, DMG H3-K27 altered cultures displayed a particular pattern of stem-like markers expression and a higher fraction of cells with self-renewal potential. Four cultures displaying distinctive stem-like profiles were further tested for their ability to initiate tumors and invade the brain tissue in mouse orthotopic xenografts. The selected cell cultures all showed a great tumor formation capacity, but only DMG H3-K27 altered cells demonstrated a highly infiltrative phenotype. Interestingly, we detected DMG H3-K27 altered cells relocated in the subventricular zone (SVZ), which has been previously described as a neurogenic area, but also a potential niche for brain tumor cells. Finally, we observed an SVZ-induced phenotypic modulation of the glioma cells, as evidenced by their increased proliferation rate. In conclusion, this study recapitulated a systematic stem-like profiling of various pediatric glioma cell cultures and call to a deeper characterization of DMG H3-K27 altered cells nested in the SVZ.
儿童高级别神经胶质瘤（pHGG）是发生在儿童和青少年中的脑肿瘤，尽管有现有的治疗方法，但预后仍然不佳。成人和 pHGG 的治疗失败部分归因于神经胶质瘤干细胞（GSC），GSC 是一类具有干细胞样潜能和恶性、侵袭性、适应性和治疗抵抗能力的癌细胞亚群。尽管 GSC 在成人肿瘤中得到了广泛的描述，但在 pHGG 中提供的信息较少。我们的研究旨在通过平行的体外检测评估干细胞相关蛋白表达、多能性、自我更新和增殖/静止能力，以及体内研究其致瘤性和侵袭性，全面记录七种使用中的儿童神经胶质瘤细胞培养物（Res259、UW479、SF188、KNS42、SF8628、HJSD-DIPG-007 和 HJSD-DIPG-012）的干细胞样能力。从体外实验中获得的数据显示，神经胶质瘤亚型依赖于干细胞相关标志物的表达，并具有不同的分化、自我更新和增殖/静止能力。在测试的培养物中，DMG H3-K27 改变的培养物显示出特定的干细胞样标志物表达模式和具有自我更新潜力的细胞比例较高。具有独特干细胞样特征的四种培养物进一步测试其在小鼠原位异种移植中启动肿瘤和侵袭脑组织的能力。所选细胞培养物均显示出很强的肿瘤形成能力，但只有 DMG H3-K27 改变的细胞显示出高度浸润性表型。有趣的是，我们检测到 DMG H3-K27 改变的细胞重新定位到侧脑室下区（SVZ），SVZ 先前被描述为一个神经发生区，但也是脑肿瘤细胞的潜在龛位。最后，我们观察到 SVZ 诱导的胶质瘤细胞表型调节，这表现为它们的增殖率增加。总之，这项研究系统地对各种儿童神经胶质瘤细胞培养物进行了干细胞样特征分析，并呼吁对嵌套在 SVZ 中的 DMG H3-K27 改变细胞进行更深入的特征描述。
