Katsetos Christos D, Reginato Mauricio J, Baas Peter W, D'Agostino Luca, Legido Agustin, Tuszyn Ski Jack A, Dráberová Eduarda, Dráber Pavel
Department of Pediatrics, Drexel University College of Medicine, Section of Neurology and Pediatric Neuro-oncology Program, St Christopher's Hospital for Children, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA.
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA.
Semin Pediatr Neurol. 2015 Mar;22(1):49-72. doi: 10.1016/j.spen.2015.03.009. Epub 2015 Apr 4.
Major advances in the genomics and epigenomics of diffuse gliomas and glioblastoma to date have not been translated into effective therapy, necessitating pursuit of alternative treatment approaches for these therapeutically challenging tumors. Current knowledge of microtubules in cancer and the development of new microtubule-based treatment strategies for high-grade gliomas are the topic in this review article. Discussed are cellular, molecular, and pharmacologic aspects of the microtubule cytoskeleton underlying mitosis and interactions with other cellular partners involved in cell cycle progression, directional cell migration, and tumor invasion. Special focus is placed on (1) the aberrant overexpression of βIII-tubulin, a survival factor associated with hypoxic tumor microenvironment and dynamic instability of microtubules; (2) the ectopic overexpression of γ-tubulin, which in addition to its conventional role as a microtubule-nucleating protein has recently emerged as a transcription factor interacting with oncogenes and kinases; (3) the microtubule-severing ATPase spastin and its emerging role in cell motility of glioblastoma cells; and (4) the modulating role of posttranslational modifications of tubulin in the context of interaction of microtubules with motor proteins. Specific antineoplastic strategies discussed include downregulation of targeted molecules aimed at achieving a sensitization effect on currently used mainstay therapies. The potential role of new classes of tubulin-binding agents and ATPase inhibitors is also examined. Understanding the cellular and molecular mechanisms underpinning the distinct behaviors of microtubules in glioma tumorigenesis and drug resistance is key to the discovery of novel molecular targets that will fundamentally change the prognostic outlook of patients with diffuse high-grade gliomas.
迄今为止，弥漫性胶质瘤和胶质母细胞瘤的基因组学和表观基因组学方面的重大进展尚未转化为有效的治疗方法，因此有必要为这些具有治疗挑战性的肿瘤寻求替代治疗方法。本文综述的主题是目前关于癌症中微管的知识以及针对高级别胶质瘤的基于微管的新治疗策略的发展。文中讨论了有丝分裂过程中微管细胞骨架的细胞、分子和药理学方面，以及与参与细胞周期进程、细胞定向迁移和肿瘤侵袭的其他细胞伙伴的相互作用。特别关注以下几点：（1）βIII微管蛋白的异常过表达，这是一种与缺氧肿瘤微环境和微管动态不稳定性相关的存活因子；（2）γ微管蛋白的异位过表达，它除了作为微管成核蛋白的传统作用外，最近还作为一种与癌基因和激酶相互作用的转录因子出现；（3）微管切断ATP酶痉挛蛋白及其在胶质母细胞瘤细胞运动中的新作用；（4）在微管与马达蛋白相互作用的背景下，微管蛋白翻译后修饰的调节作用。讨论的具体抗肿瘤策略包括下调靶向分子，以实现对目前使用的主要治疗方法的致敏作用。还研究了新型微管蛋白结合剂和ATP酶抑制剂的潜在作用。了解胶质瘤肿瘤发生和耐药中微管独特行为的细胞和分子机制，是发现将从根本上改变弥漫性高级别胶质瘤患者预后前景的新分子靶点的关键。
