Insights into the Peritumoural Brain Zone of Glioblastoma: CDK4 and EXT2 May Be Potential Drivers of Malignancy

Abstract

Despite the efforts made in recent decades, glioblastoma is still the deadliest primary brain cancer without cure. The potential role in tumour maintenance and progression of the peritumoural brain zone (PBZ), the apparently normal area surrounding the tumour, has emerged. Little is known about this area due to a lack of common definition and due to difficult sampling related to the functional role of peritumoural healthy brain. The aim of this work was to better characterize the PBZ and to identify genes that may have role in its malignant transformation. Starting from our previous study on the comparison of the genomic profiles of matched tumour core and PBZ biopsies, we selected CDK4 and EXT2 as putative malignant drivers of PBZ. The gene expression analysis confirmed their over-expression in PBZ, similarly to what happens in low-grade glioma and glioblastoma, and CDK4 high levels seem to negatively influence patient overall survival. The prognostic role of CDK4 and EXT2 was further confirmed by analysing the TCGA cohort and bioinformatics prediction on their gene networks and protein–protein interactions. These preliminary data constitute a good premise for future investigations on the possible role of CDK4 and EXT2 in the malignant transformation of PBZ.

Current Knowledge about the Peritumoral Microenvironment in Glioblastoma

“…However, other research groups, including ours, could detect some abnormal gene expression in PBZs not invaded by tumor cells upon pathological analysis [15,124]. Indeed, when matching genomic alterations of a tumor core with the corresponding PBZ in a single patient, a variable amount of correlation was found [124,125]. Non-infiltrated PBZs and enhancing tumors were shown to share some genomic anomalies: del(1p36), del(2p21), MDM2 and CDK4 amplification, and amplification of 15q24.1, 219, and 222 [14].…”

“…CDK4 is a known cancer promoter gene involved in several systemic cancers, including breast carcinoma, that participates in the Cyclin D1 (CCND1)-CDK4/6-CDKN2A (p16INK4A)-Rb axis, which is often altered in the GBM [126]. Overexpression of CDK4 in the GBM PBZ is related to poor outcomes [125].…”

“…Giambra and colleagues found some peculiar gains in some loci in the short arms of chromosomes 11 and 16 in PBZs, not shared by tumor cores, focusing on the possible role of the EXT2 gene, which is involved in the biosynthesis of the heparan sulfates-glycosaminoglycans distributed on the cell surfaces and in the extracellular matrices of most tissues which could be involved in angiogenesis and tumor proliferation [125].…”

Dexamethasone Inhibits Heparan Sulfate Biosynthetic System and Decreases Heparan Sulfate Content in Orthotopic Glioblastoma Tumors in Mice

“…Unfortunately, it is not possible to compare this result with the literature data due to the lack of publications on the DXM effects on the HS biosynthesis. Indirect analogies can be made with only a few data, for example, the expression of EXT2 is significantly increased in GB [ 36 ] and its decrease under the DXM administration can be interpreted as a positive effect of DXM use, as well as in the case of a decrease in the content of HS in brain tissue. In human GB tumors, the inhibition in the transcriptional activity of HS biosynthetic system was shown, although this was due to the suppression of several other enzymes—EXT1/2 and HS6ST1/2.…”

AhRR and PPP1R3C: Potential Prognostic Biomarkers for Serous Ovarian Cancer

“…Advances in high-throughput technologies allowed the development of several approaches for the discovery of novel biomarkers. Furthermore, copy number alteration (CNA) analysis has been recently linked to gene signatures that predict adverse prognoses across multiple types of cancer [12][13][14]. In fact, copy number alterations contribute to genomic heterogeneity.…”