临床前和临床进展，以克服多形胶质母细胞瘤的缺氧
Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme
影响因子:9.60000
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
摘要
胶质母细胞瘤多形（GBM）是最常见的成年原发性脑肿瘤。 GBM的标准临床治疗包括最大外科手术切除，然后进行放射治疗（RT）和替莫唑胺（TMZ）的化学疗法课程，除了辅助TMZ周期外。尽管该方案严重程度，但GBM具有高度抵抗力，并且在几乎所有情况下都具有抗性，而该协议自2005年以来保持不变。有限的扩散或慢性缺氧已被确定为推动这种侵略性表型的主要关键参与者之一。肿瘤大量内缺氧的存在有助于通过诱导缺氧因素（HIF）介导的低氧信号传导途径的激活，这又激活了生物学机制，以确保在有限的氧气和养分供应下GBM的适应性和存活。活化的下游途径参与维持干细胞样表型，诱导间充质转移，侵袭和迁移，改变细胞和氧代谢，增加血管生成，自噬和免疫抑制。因此，在这篇综述中将讨论旨在靶向肿瘤缺氧的最新临床前和临床方法，以增强GBM对常规疗法的反应以及它们的结果和对临床翻译的局限性。
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.