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Necrotic reshaping of the glioma microenvironment drives disease progression

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Abstract

Glioblastoma is the most common primary brain tumor and has a dismal prognosis. The development of central necrosis represents a tipping point in the evolution of these tumors that foreshadows aggressive expansion, swiftly leading to mortality. The onset of necrosis, severe hypoxia and associated radial glioma expansion correlates with dramatic tumor microenvironment (TME) alterations that accelerate tumor growth. In the past, most have concluded that hypoxia and necrosis must arise due to “cancer outgrowing its blood supply” when rapid tumor growth outpaces metabolic supply, leading to diffusion-limited hypoxia. However, growing evidence suggests that microscopic intravascular thrombosis driven by the neoplastic overexpression of pro-coagulants attenuates glioma blood supply (perfusion-limited hypoxia), leading to TME restructuring that includes breakdown of the blood–brain barrier, immunosuppressive immune cell accumulation, microvascular hyperproliferation, glioma stem cell enrichment and tumor cell migration outward. Cumulatively, these adaptations result in rapid tumor expansion, resistance to therapeutic interventions and clinical progression. To inform future translational investigations, the complex interplay among environmental cues and myriad cell types that contribute to this aggressive phenotype requires better understanding. This review focuses on contributions from intratumoral thrombosis, the effects of hypoxia and necrosis, the adaptive and innate immune responses, and the current state of targeted therapeutic interventions.

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Acknowledgements

This work was supported by the National Institutes of Health (DJB; R01 CA214928, R01 CA247905, P50 CA221747, U01 CA217613 and U01 CA199288) and the Cancer Research Institute Irvington Fellowship (JLR). Illustrations were created by Andrea Charest, MS using Adobe Illustrator in collaboration with the authors.

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  1. Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA

    Steven M. Markwell, Cheryl L. Olson & Daniel J. Brat

  2. Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA

    James L. Ross

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  2. James L. Ross
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Conceptualization: DJB; literature search: SMM; writing—original draft preparation: SMM; writing—revision, review and editing: SMM, JLR, CLO, and DJB.

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Correspondence to Daniel J. Brat.

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Markwell, S.M., Ross, J.L., Olson, C.L. et al. Necrotic reshaping of the glioma microenvironment drives disease progression. Acta Neuropathol 143, 291–310 (2022). https://doi.org/10.1007/s00401-021-02401-4

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