Targeting glioblastoma invasion and therapy resistance: Emerging trends and molecular pathways

Abstract

Glioblastoma (GBM) is the most common and aggressive primary central nervous system malignancy. Significant resistance to therapeutic intervention is a core feature of GBM that drives tumor recurrence and underlies the remarkably poor clinical outcomes associated with this disease. This review explores the therapeutic strategies and molecular pathways involved in GBM. Therapy resistance in GBM depends on multiple interconnected macrostructural and biomolecular mechanisms, including aggressive and diffuse invasion, tumor microtube network formation, stem-like cell enrichment, selective neurovascular permeability, an immunosuppressive microenvironment, and a high degree of inter-and intra-tumoral heterogeneity. Collectively, these pathobiological features insulate specific tumor compartments and maintain GBM viability despite significant treatment-induced cellular stress. While there is enthusiasm for addressing GBM therapeutic resistance, the scale of the challenge remains immense. The identified resistance mechanisms extensively interact and can compensate for single-target assaults. Emerging overlaps between neuro-oncology and developmental neurobiology additionally suggest that GBM may exploit therapeutic resistance mechanisms yet to be identified, functioning beyond the current scientific understanding. Thus, the scope and diversity of this problem demand a comprehensive therapeutic approach capable of targeting multiple interacting mechanisms of therapeutic resistance.

Keywords

Glioblastoma / Invasion / Tumor microtube / Cytoskeleton

Acknowledgments

We wish to acknowledge an amazing scientist and mentor, Dr. Arthur Alberts, who passed away from glioblastoma at the age of 52, as an inspiration for this review.

Funding

Departmental funds from the Department of Cell and Cancer Biology and the Department of Medical Education, College of Medicine and Life Sciences, University of Toledo, supported this work.

Conflict of interest

The authors declare they have no competing interests.

Author contributions

Conceptualization: Kathryn N. Becker, Kathryn M. Eisenmann

Writing -original draft: Kathryn N. Becker

Writing -review & editing: All authors

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data

Not applicable.

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