PDGF Family Expression in Glioblastoma Multiforme: Data Compilation from Ivy Glioblastoma Atlas Project Database

Abstract

Glioblastoma Multiforme (GBM) is the most frequent and lethal primary brain cancer. Due to its therapeutic resistance and aggressiveness, its clinical management is challenging. Platelet-derived Growth Factor (PDGF) genes have been enrolled as drivers of this tumour progression as well as potential therapeutic targets. As detailed understanding of the expression pattern of PDGF system in the context of GBM intra- and intertumoral heterogeneity is lacking in the literature, this study aims at characterising PDGF expression in different histologically-defined GBM regions as well as investigating correlation of these genes expression with parameters related to poor prognosis. Z-score normalised expression values of PDGF subunits from multiple slices of 36 GBMs, alongside with clinical and genomic data on those GBMs patients, were compiled from Ivy Glioblastoma Atlas Project - Allen Institute for Brain Science data sets. PDGF subunits show differential expression over distinct regions of GBM and PDGF family is heterogeneously expressed among different brain lobes affected by GBM. Further, PDGF family expression correlates with bad prognosis factors: age at GBM diagnosis, Phosphatase and Tensin Homolog deletion and Isocitrate Dehydrogenase 1 mutation. These findings may aid on clinical management of GBM and development of targeted curative therapies against this devastating tumour.

Figure 1

Workflow of Ivy Glioblastoma Atlas Project data production. Each surgically resected tumour is divided into blocks (a), which are sectioned into histological slices (b). Each section is submitted to histopathological evaluation (c), with annotation (d) of the distinct GBM histological regions (e), which are then processed by laser-microdissection and analysed separately by RNA-sequencing technique. As defined in the Technical White Paper: Overview – 2015 [accessible in glioblastoma.alleninstitute.org], Leading Edge Region: border of the tumour, tumour/normal cells ratio is approximately 1–3/100; Infiltrating Tumour: region in between Leading Edge and Cellular Tumour bulk, tumour/normal cells ratio is approximately 10–20/100; Cellular Tumour: tumour core, tumour/normal cells ratio is approximately 100–500/1; Perinecrotic Zone: boundary of tumour cells closely around necrotic areas in tumour core; Pseudopalisading Cells around Necrosis: characteristic rows of lined-up, aggregated cells surrounding necrotic areas in tumour core; Hyperplastic Blood Vessels in Cellular Tumour: aggregated blood vessels with thickened walls, in tumour core; Microvascular Proliferation: glomerulus-like conformation of a couple of blood vessels that share vessel wall, inside the tumour core. All images are credited to Allen Institute. (a), (b) and (e) are available on the Technical White Paper: Overview – 2015, accessible in glioblastoma.alleninstitute.org; (c) and (d) are available at http://glioblastoma.alleninstitute.org/ish/specimen/show/706783?gene=5127. Image credit: Allen Institute.

Figure 2

PDGF family expression patterns on each GBM histological region reveal intratumoral heterogeneity. PDGF system expression was evaluated in GBM regions of hyperplastic blood vessels in cellular tumour (a); microvascular proliferation (b); pseudopalisading cells around necrosis (c); perinecrotic zone (d); cellular tumour (e); leading edge (f), and infiltrating tumour (g).*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

Figure 3

PDGF genes are differentially expressed over different histological regions of a GBM. Expression pattern along distinct areas of a GBM was assessed for each PDGF system component: PDGFA (a); PDGFB (b); PDGFC (c); PDGFD (d); PDGFRA (e); PDGFRB (f). CT-HBV: Hyperplastic Blood Vessels in Cellular Tumour; CT-MVP: Microvascular Proliferation; CT-PAN: Pseudopalisading Cells around Necrosis; IT: Infiltrating Tumour; LE: Leading Edge; CT: Cellular Tumour. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

Figure 4

Analysis of PDGF genes expression regarding GBM location in the brain: Comparison was made on PDGF family expression between tumours located at left and at right hemispheres (a); PDGF subunits expression was studied on GBMs at temporal lobe (b), frontal lobe (c) and parietal lobe (d). *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

Figure 5

PDGF expression correlates with prognostic factors of GBM. PDGF system expression was analysed according to prognostic factors of Phosphatase and Tensin Homolog (PTEN) deletion (a,b); Isocitrate Dehydrogenase 1 (IDH1) mutation (c,d), and age at diagnosis of GBM (e,f,g). *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.