Differential localization of glioblastoma subtype: implications on glioblastoma pathogenesis

Abstract

IntroductionThe subventricular zone (SVZ) has been implicated in the pathogenesis of glioblastoma. Whether molecular subtypes of glioblastoma arise from unique niches of the brain relative to the SVZ remains largely unknown. Here, we tested whether these subtypes of glioblastoma occupy distinct regions of the cerebrum and examined glioblastoma localization in relation to the SVZ.MethodsPre-operative MR images from 217 glioblastoma patients from The Cancer Imaging Archive were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Probabilistic maps of tumor location were generated for each subtype and distances were calculated from the centroid of CE tumor volumes to the SVZ. Glioblastomas that arose in a Genetically Modified Murine Model (GEMM) model were also analyzed with regard to SVZ distance and molecular subtype.ResultsClassical and mesenchymal glioblastomas were more diffusely distributed and located farther from the SVZ. In contrast, proneural and neural glioblastomas were more likely to be located in closer proximity to the SVZ. Moreover, in a GFAP-CreER; PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1−/− GEMM model of glioblastoma where tumor can spontaneously arise in different regions of the cerebrum, tumors that arose near the SVZ were more likely to be of proneural subtype (p < 0.0001).ConclusionsGlioblastoma subtypes occupy different regions of the brain and vary in proximity to the SVZ. These findings harbor implications pertaining to the pathogenesis of glioblastoma subtypes.

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

“…U87MG (ATCC line), LN229, U251, and A172 cells were cultured in Dulbecco’s modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS). GBM patient-derived neurospheres and GSC were isolated and cultured as previously described as previously described 56 – 59 . For primary glia isolation, the cerebral cortex from new born mice (2 or 3 days-old) was collected, homogenized and harvested with Leibovitz’s L-15 medium.…”

“…Gfap-CreER;Pten fl/fl ;Rb1 fl/fl ;Trp53 fl/fl ;Rbl1 −/− mice were obtained and induced for gliomagenesis as in 59 . The brain was analyzed at 8–12 weeks after injection.…”

Origin of Gliomas

“…Tumor location may correlate with distinct subtypes, clinical outcomes, and growth patterns. [14][15][16] In particular, proneural or neural GBM subtypes, based on The Cancer Genome Atlas (TCGA) system, are proximal and mesenchymal or classical TCGA subtypes are distal to the SVZ, suggesting differential cells of origin. 16 The frontal lobe is a preferential location for LGGs with IDH mutations.…”

“…[14][15][16] In particular, proneural or neural GBM subtypes, based on The Cancer Genome Atlas (TCGA) system, are proximal and mesenchymal or classical TCGA subtypes are distal to the SVZ, suggesting differential cells of origin. 16 The frontal lobe is a preferential location for LGGs with IDH mutations. 6,[17][18][19][20] Furthermore, LGGs in the frontal lobe have higher TERT promoter mutation rates compared with midline tumors that are predominantly IDH wild-type and harbor fewer TERT promoter mutations.…”

The role of inflammation in subventricular zone cancer

“…Olig2+ cells were found in proneural glioblastomas (Verhaak et al, 2010) and studies on animal models of gliomagenesis suggested Olig2+ cells in the SVZ as a potential origin of gliomas (Wang et al, 2009), including the proneural subtype (Lu et al, 2016). Interestingly, proneural and neural glioblastomas were closer to the SVZ than the other subtypes (Steed et al, 2016). Subependymomas may arise from multipotent cells in the SVZ and express glial and stem cell markers such as GFAP, Olig2 and Sox2 (D'Amico et al, 2017).…”