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Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment

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Glioblastoma is the most malignant form of glioma, which is the most commonly occurring tumor of the central nervous system. Notch signaling in glioblastoma is considered to be a marker of an undifferentiated tumor cell state, associated with tumor stem cells. Notch is also known for facilitating tumor dormancy escape, recurrence and progression after treatment. Studies in vitro suggest that reducing, removing or blocking the expression of this gene triggers tumor cell differentiation, which shifts the phenotype away from stemness status and consequently facilitates treatment. In contrast, in the vasculature, Notch appears to also function as an important receptor that defines mature non-leaking vessels, and increasing its expression promotes tumor normalization in models of cancer in vivo. Failures in clinical trials with Notch inhibitors are potentially related to their opposing effects on the tumor versus the tumor vasculature, which points to the need for a greater understanding of this signaling pathway.

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Acknowledgements

We would like to dedicate this review to the memory of CJ Buckley.

Funding

The authors are supported by the Credit Unions Kids at Heart Team (to DP) and the C.J. Buckley Pediatric Brain Tumor Fund (DP).

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Authors and Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Franciele C. Kipper & Dipak Panigrahy

  2. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Franciele C. Kipper & Dipak Panigrahy

  3. Day One Biopharmaceutical, VP Clinical Development, South San Francisco, CA, USA

    Mark W. Kieran

  4. Cooper Medical School of Rowan University and Cooper University Hospital, Camden, NJ, USA

    Ajith Thomas

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The paper was conceptualized by F.C.K. Writing, reviewing, and editing of the paper were conducted by F.C.K., M.W.K., A.T., and D.P. All authors have read and agreed to the published version of the manuscript.

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Simple summary

The role of Notch in the regulation of stemness is well defined, both in embryonic and adult organs. In many normal and tumoral tissues, Notch1 maintains cells in an undifferentiated highly proliferative state and its downregulation is required for the acquisition of the differentiated state. In the endothelium, Notch1 expression is critical to maintain cells in the stalk phenotype, as its downregulation leads to a transition to tip cells, consequently causing the sprouting of new vessels. Weighing the role of Notch on cancer stem cells and in the endothelium of vessels is an important component of managing treatment in the context of tumor normalization.

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Kipper, F.C., Kieran, M.W., Thomas, A. et al. Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment. Cancer Metastasis Rev 41, 737–747 (2022). https://doi.org/10.1007/s10555-022-10041-7

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  • DOI: https://doi.org/10.1007/s10555-022-10041-7

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