PDF(Pubmed)
Abstract：
Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype. Furthermore, it is universally recognized that a small subset of GBM cells known as GBM stem cells (GSCs) serve as reservoirs for tumor recurrence and progression. The clonal evolution of GSC molecular subtypes in response to therapy drives intra-tumoral heterogeneity and remains a critical determinant of GBM outcomes. In particular, the intra-tumoral MES reprogramming of GSCs using current GBM therapies has emerged as a leading hypothesis for therapeutic refractoriness. Preventing the intra-tumoral divergent evolution of GBM toward the MES subtype via new treatments would dramatically improve long-term survival for GBM patients and have a significant impact on GBM outcomes. In this review, we examine the challenges of the role of MES reprogramming in the malignant clonal evolution of glioblastoma and provide future perspectives for addressing the unmet therapeutic need to overcome resistance in GBM.
摘要：
胶质母细胞瘤（GBM）是最常见但均一致命的成人脑癌。肿瘤内分子和细胞异质性是GBM治疗性难治性和无效性的主要因素。分子异质性通过分子亚型簇表示,其中与高抗性间充质(MES)亚型相比,前神经(PN)亚型与显著增加的长期存活相关。此外，众所周知,被称为GBM干细胞(GSC)的一小部分GBM细胞充当肿瘤复发和进展的储库。响应于治疗的GSC分子亚型的克隆进化驱动肿瘤内异质性,并且仍然是GBM结果的关键决定因素。特别是,使用当前GBM疗法对GSCs进行的肿瘤内MES重编程已成为治疗性难治性的主要假设.通过新疗法预防GBM向MES亚型的肿瘤内发散演变将显著改善GBM患者的长期生存率，并对GBM结局产生显著影响。在这次审查中,我们研究了MES重编程在胶质母细胞瘤恶性克隆进化中的作用所带来的挑战,并为解决GBM中未满足的治疗需求,克服耐药提供了未来的观点.
