Overcoming therapeutic resistance in glioblastoma: the way forward
Satoru Osuka, Erwin G. Van Meir
Satoru Osuka, Erwin G. Van Meir
Published February 1, 2017
Citation Information: J Clin Invest. 2017;127(2):415-426. https://doi.org/10.1172/JCI89587.
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Overcoming therapeutic resistance in glioblastoma: the way forward

Abstract

Glioblastoma is the most common and lethal primary malignant brain tumor in adults. Patients die from recurrent tumors that have become resistant to therapy. New strategies are needed to design future therapies that target resistant cells. Recent genomic studies have unveiled the complexity of tumor heterogeneity in glioblastoma and provide new insights into the genomic landscape of tumor cells that survive and initiate tumor recurrence. Resistant cells also co-opt developmental pathways and display stem-like properties; hence we propose to name them recurrence-initiating stem-like cancer (RISC) cells. Genetic alterations and genomic reprogramming underlie the innate and adaptive resistance of RISC cells, and both need to be targeted to prevent glioblastoma recurrence.

Authors

Satoru Osuka, Erwin G. Van Meir

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Figure 1

The complexity of inter- and intratumoral heterogeneity in glioblastoma.

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The complexity of inter- and intratumoral heterogeneity in glioblastoma....
(A) Heterogeneity between individual patient tumors stems from both the cell of origin and the subsequent major epigenetic and genetic alterations. These variations produce different types of tumor-initiating cells (TICs). (B) TICs expand and establish genetically divergent clonal cell populations. During this clonal evolution process, cellular offspring acquire diverse genetic alterations and engender a variety of clones. Cells with similar types of genetic alterations exist in close spatial proximity, but their invasive properties will lead to clonal mixing and normal brain invasion. (C) Further heterogeneity at the cellular level is added by environmental factors. Proximity to blood vessels (vascular and hypoxic niches), paracrine signals between tumor cells, and immune responses (inflammatory niche), will influence individual tumor cell biology, including regulating stemness versus differentiation state of glioma stem cells (GSCs).