Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications

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Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.

ABBREVIATIONS CIMP− = CpG island methylator phenotype negative; CIMP+ = CIMP positive; EGFR = epidermal growth factor receptor; GBM = glioblastoma; GSC = glioma stem cell; IDH = isocitrate dehydrogenase; ITH = intratumoral heterogeneity; NSC = neural stem cell; SVZ = subventricular zone.

Article Information

Correspondence Ichiro Nakano: University of Alabama at Birmingham, AL. inakano@uabmc.edu.

INCLUDE WHEN CITING Published online August 23, 2019; DOI: 10.3171/2019.5.JNS19364.

J.D.B. and J.H.M. contributed equally to this work.

Disclosures Dr. Bernstock hold positions and equity in Avidea Technologies and CITC Ltd. He is a member of the Board of Scientific Advisors for POCKiT Diagnostics.

© AANS, except where prohibited by US copyright law.

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    Illustration highlighting the core features of GSC/spatial distribution within the tumor. GSCs are defined by core characteristics that include sustained self-renewal, persistent proliferation, frequency within a tumor and tumor initiation on secondary transplantation (A). GSCs display functional characteristics that facilitate GBM tumor pathogenesis; these include an increased ability to invade through the brain parenchyma, immune evasion, promotion of angiogenesis, and/or chemo-/radioresistance (B). GSCs also share features with somatic NSCs, such as stem cell marker expression, the ability to generate progeny of multiple lineages, and self-renewal (C). MES = mesenchymal; PN = proneural. Copyright Joshua D. Bernstock, NIH/NINDS. Published with permission.

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