Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Cells. 2024 May 30;13(11):942. doi: 10.3390/cells13110942.
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.
胶质母细胞瘤（GBM）是最常见但普遍致命的成人脑癌。肿瘤内的分子和细胞异质性是导致 GBM 治疗抵抗和无效的主要因素。分子异质性表现为分子亚型簇，其中神经前体（PN）亚型与显著延长的长期生存相关，与高度耐药的间充质（MES）亚型相比。此外，人们普遍认识到，一小部分胶质母细胞瘤细胞称为胶质母细胞瘤干细胞（GSCs），作为肿瘤复发和进展的储库。GSC 分子亚型对治疗的克隆进化驱动肿瘤内异质性，仍然是 GBM 结局的关键决定因素。特别是，目前 GBM 治疗中 GSCs 的肿瘤内 MES 重编程已成为治疗抵抗的主要假说。通过新的治疗方法防止 GBM 向 MES 亚型的肿瘤内发散进化，将极大地提高 GBM 患者的长期生存率，并对 GBM 结局产生重大影响。在这篇综述中，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面临的挑战，并为解决 GBM 治疗抵抗的未满足需求提供了未来的展望。
