J Korean Neurosurg Soc.  2020 Jan;63(1):26-33. 10.3340/jkns.2019.0129.

Glioblastoma Cellular Origin and the Firework Pattern of Cancer Genesis from the Subventricular Zone

• Yoon SJ
• Park J
• Jang DS
• Kim HJ
• Lee JH
• Jo E
• Choi RJ
• Shim JK
• Moon JH
• Kim EH
• Chang JH
• Lee JH
• Kang SG

• KMID: 2501690
• DOI: http://doi.org/10.3340/jkns.2019.0129

Abstract

Glioblastoma (GBM) is a disease without any definite cure. Numerous approaches have been tested in efforts to conquer this brain disease, but patients invariably experience recurrence or develop resistance to treatment. New surgical tools, carefully chosen samples, and experimental methods are enabling discoveries at single-cell resolution. The present article reviews the cell-of-origin of isocitrate dehydrogenase (IDH)-wildtype GBM, beginning with the historical background for focusing on cellular origin and introducing the cancer genesis patterned on firework. The authors also review mutations associated with the senescence process in cells of the subventricular zone (SVZ), and biological validation of somatic mutations in a mouse SVZ model. Understanding GBM would facilitate research on the origin of other cancers and may catalyze the development of new management approaches or treatments against IDH-wildtype GBM.

Keyword

Cancer genesis; Cell-of-origin; Clock-like mutation; Firework pattern; Glioblastoma; Subventricular zone

Figure

• 

  Fig. 1. Cell-of-origin of IDH-wildtype GBM and GBM genesis mechanism. A : Illustration of IDH-wildtype GBM genesis from the SVZ43). Left : gross structure of the tumor in the brain. Red arrow (yellow background in the arrowhead) indicates migrating GBM origin cell from SVZ (red line under the sky blue lateral ventricle) to the hemisphere. Red arrow with a pink background in the arrowhead indicates the explosion (or evolutionary increase in heterogeneity) of tumor cells that creates the tumor bulk. Right : schematic overview of tumorigenesis from the SVZ to the cortex (below → top). Some portion of cells in the astrocytic band in the SVZ (‡) acquire mutations (illustrated by asterisks with blue in the SVZ; additional mutations are depicted in cells of the GBM in green and red asterisks) as an incidental consequence of senescence (*), with mutations in the TERT promoter serving as the possible initial step (†), followed by mutations in TP53, PTEN and EGFR , among others. B : Illustration of the hypothetical SVZ origin of IDH-wildtype GBM recurrence via route 1 or 2. Route 1 indicates same site recurrence, while route 2 indicates different site recurrence from the GBM cell-of-origin in the SVZ. GBM : glioblastoma, IDH : isocitrate dehydrogenase, TERTp : promoter of telomerase reverse transcriptase (Gene symbol : TERT), p53 : tumor protein p53 (Gene symbol : TP53), EGFR : epidermal growth factor receptor, PTEN : phosphatase and tensin homolog, CSF : cerebrospinal fluid, SVZ : subventricular zone.

• 

  Fig. 2. Firework pattern of IDH-wildtype GBM genesis. A : Artistic illustration of IDH-wildtype GBM originating from the SVZ (colored in gold). Each firework trail corresponds to a different cancer clone. In this metaphorical depiction, the SVZ is represented as a cannon on the ground, denoting the starting point of GBM genesis. B : Conceptual illustration of the time line of the genesis of the firework pattern of IDH-wildtype GBM. Horizontal recurrence (or classical model) : GBM recurs from SVZ (red) → tumor (blue) → recurrence (green), vertical recurrence (hypothetical model) : primary GBM originates from SVZ (red) → tumor (blue), and it recurs from SVZ (red) → recurrent tumor (orange). GBM : glioblastoma, SVZ : subventricular zone, IDH : isocitrate dehydrogenase.

Reference

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