Tian Yu, Li Juan, Cai Xue, Huang Youcai, Wang Xiaoling, Liu Qinxian, Ashrafizadeh Milad, Guo Yu, Zhen Haining, Tu Yanyang
Research Center, the Huizhou Central People's Hospital, Guangdong Medical University, Huizhou, Guangdong, China.
Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Xian, China.
Pathol Res Pract. 2025 Aug;272:156111. doi: 10.1016/j.prp.2025.156111. Epub 2025 Jul 7.
Glioblastoma (GBM) is among the most common and aggressive forms of brain tumor and presents a formidable clinical challenge due to its infiltrative nature, recurrence, and resistance to the conventional therapies. The recent evidence has highlighted the function of epithelial-mesenchymal transition (EMT) in driving a number of malignant and aggressive features of GBM. The present review comprehensively investigates the molecular mechanisms underlying EMT in GBM, emphasizing its implications to the tumor metastasis, therapeutic resistance, and potential for localized metastasis within the central nervous system. The key pathways, including TGF-β, Wnt/β-catenin, PI3K/AKT, and Notch, are able to regulate EMT by promoting mesenchymal traits, cellular plasticity, and stemness, facilitating tumor progression and immune evasion. A number of transcription factors such as Snail, Slug, Twist, and ZEB1/2, alongside regulatory non-coding RNAs are involved reinforcing the complexity of EMT modulation in GBM. Furthermore, this review highlights the novel therapeutic interventions targeting EMT, including natural compounds, immunotherapy combinations, and nanoparticle-based delivery systems designed to overcome the blood-brain barrier and minimize systemic toxicity. There will be also a special focus on the function of EMT in the regulation of chemoresistance, particularly to temozolomide, and how pharmacological agents such as 20(S)-Rg3, quercetin, and honokiol suppress EMT. Integrative therapeutic strategies combining EMT inhibition with immune modulation and targeted drug delivery are proposed as promising candidates for enhancing GBM patient outcomes. By elucidating the intricate regulatory networks of EMT, this review would highlight the development of precision therapies capable of mitigating GBM's aggressive behavior and improving long-term survival.
胶质母细胞瘤（GBM）是最常见且侵袭性最强的脑肿瘤形式之一，由于其浸润性、复发性以及对传统疗法的耐药性，带来了严峻的临床挑战。最近的证据凸显了上皮-间质转化（EMT）在驱动GBM多种恶性和侵袭性特征方面的作用。本综述全面研究了GBM中EMT的分子机制，强调了其对肿瘤转移、治疗耐药性以及中枢神经系统内局部转移可能性的影响。关键信号通路，包括转化生长因子-β（TGF-β）、Wnt/β-连环蛋白、磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/AKT）和Notch，能够通过促进间质特性、细胞可塑性和干性来调节EMT，从而促进肿瘤进展和免疫逃逸。一些转录因子，如Snail、Slug、Twist和锌指E盒结合蛋白1/2（ZEB1/2），以及调控性非编码RNA参与其中，增强了GBM中EMT调节的复杂性。此外，本综述强调了针对EMT的新型治疗干预措施，包括天然化合物、免疫治疗联合方案以及旨在克服血脑屏障并将全身毒性降至最低的基于纳米颗粒的递送系统。还将特别关注EMT在化疗耐药性调节中的作用，尤其是对替莫唑胺的耐药性，以及诸如20（S）-人参皂苷Rg3、槲皮素和厚朴酚等药物如何抑制EMT。将EMT抑制与免疫调节和靶向药物递送相结合的综合治疗策略被认为有希望改善GBM患者的预后。通过阐明EMT复杂的调控网络，本综述将突出能够减轻GBM侵袭性行为并改善长期生存的精准治疗的发展。
