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.

Department of Biochemistry and Molecular Biology Drexel University College of Medicine Philadelphia PA

Department of Biology of Cytoskeleton Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

Department of Neurobiology and Anatomy Drexel University College of Medicine Philadelphia PA

Department of Oncology University of Alberta Cross Cancer Institute Edmonton Alberta Canada; Department of Physics University of Alberta Edmonton Alberta Canada

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 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

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