Review

突破胶质母细胞瘤中的低氧：临床前与临床的最新进展

Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme

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Cell Death & Disease

影响因子:9.6

分区:生物学1区 Top / 细胞生物学2区

发表日期:2024 Jul 13

作者: Jolie Bou-Gharios, Georges Noël, Hélène Burckel

DOI: 10.1038/s41419-024-06904-2

摘要

胶质母细胞瘤（GBM）是成人最常见的原发性脑肿瘤。GBM的标准临床治疗包括最大范围的手术切除，随后进行同步放疗（RT）和替莫唑胺（TMZ）化疗，以及辅助的TMZ周期。尽管治疗方案严苛，但GBM具有高度抗药性，且几乎所有病例都会复发，自2005年以来，该治疗方案未发生改变。有限扩散或慢性低氧被认为是驱动这种侵袭性表型的关键因素之一。肿瘤内的低氧存在促进低氧诱导因子（HIFs）介导的低氧信号通路激活，从而激活多种生物机制，确保GBM在有限氧气和营养供应条件下的适应与存活。激活的下游通路涉及维持干细胞样表型、诱导间质转变、侵袭和迁移，改变细胞及氧代谢，增加血管生成、自噬和免疫抑制。因此，本文将讨论近年来旨在靶向肿瘤低氧状态以增强GBM对常规治疗反应的最新临床前及临床策略，以及其在临床转化中的结果与限制。

Abstract

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard clinical treatment of GBM includes a maximal surgical resection followed by concomitant radiotherapy (RT) and chemotherapy sessions with Temozolomide (TMZ) in addition to adjuvant TMZ cycles. Despite the severity of this protocol, GBM is highly resistant and recurs in almost all cases while the protocol remains unchanged since 2005. Limited-diffusion or chronic hypoxia has been identified as one of the major key players driving this aggressive phenotype. The presence of hypoxia within the tumor bulk contributes to the activation of hypoxia signaling pathway mediated by the hypoxia-inducing factors (HIFs), which in turn activate biological mechanisms to ensure the adaptation and survival of GBM under limited oxygen and nutrient supply. Activated downstream pathways are involved in maintaining stem cell-like phenotype, inducing mesenchymal shift, invasion, and migration, altering the cellular and oxygen metabolism, and increasing angiogenesis, autophagy, and immunosuppression. Therefore, in this review will discuss the recent preclinical and clinical approaches that aim at targeting tumor hypoxia to enhance the response of GBM to conventional therapies along with their results and limitations upon clinical translation.