Gene Expression Profile of Glioblastoma Peritumoral Tissue: An Ex Vivo Study

Abstract

The gene expression pattern of glioblastoma (GBM) is well documented but the expression profile of brain adjacent to tumor is not yet analysed. This may help to understand the oncogenic pathway of GBM development. We have established the genome-wide expression profiles of samples isolated from GBM tumor mass, white matter adjacent to tumor (apparently free of tumor cells), and white matter controls by using the Affymetrix HG-U133 arrays. Array-CGH (aCGH) was also performed to detect genomic alterations. Among genes dysregulated in peritumoral white matter, 15 were over-expressed, while 42 were down-regulated when compared to white matter controls. A similar expression profile was detected in GBM cells. Growth, proliferation and cell motility/adhesion-associated genes were up-regulated while genes involved in neurogenesis were down-regulated. Furthermore, several tumor suppressor genes along with the KLRC1 (a member of natural killer receptor) were also down-regulated in the peritumoral brain tissue. Several mosaic genomic lesions were detected by aCGH, mostly in tumor samples and several GBM-associated mosaic genomic lesions were also present in the peritumoral brain tissue, with a similar mosaicism pattern. Our data could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumour tissue. Alternatively, these findings could be substained by a relevant amount of “apparently normal” cells presenting a gene profile compatible with a precancerous state or even “quiescent” cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and from an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.

Characterizing the peritumoral brain zone in glioblastoma: a multidisciplinary analysis

“…In particular, genomic analyses indicated that the deletion of chromosome 10 and the EGFR amplification present in the TZ were also present in PBZ, whereas the CDKN2A/B deletion was in most cases absent from the PBZ. The amplification of EGFR in the PBZ was also previously described [39]. These results suggest that copy number alterations targeting chromosome 7 and 10 are among the earliest events in GB tumor evolution and that some tumor clones, but not all, migrate away from the tumor.…”

PDGF receptor alpha inhibition induces apoptosis in glioblastoma cancer stem cells refractory to anti-Notch and anti-EGFR treatment

“…Cancer stem cells from GBM were isolated using defined criteria set up by neurosurgeons as described previously [ 24 , 25 ]. We can summarize these briefly: lesion removal was achieved with resection margins that included the tumor and the neighboring, apparently normal tissue (between 1-2 cm from the tumor border; larger resections were performed in tumors that grew far from eloquent areas), which were removed entirely en bloc.…”

“…We have used the same clinical materials reported in our previous papers [ 24 , 25 ]. In brief, the CSC cells were retrieved from adult patients affected by GBM and undergoing craniotomy at the Institute of Neurosurgery, Catholic University-School of Medicine of Rome, Italy.…”

Double-Targeted Knockdown of miR-21 and CXCR4 Inhibits Malignant Glioma Progression by Suppression of the PI3K/AKT and Raf/MEK/ERK Pathways

“…It is reported that patients undergoing surgery and tumor resection between 1 cm and 2 cm from the tumor and have absence of tumor cells in this area had better survival than patients who had the presence of tumor cells [ 36 ]. In addition, studies show that there are some shared gene expression and molecular pathways in glioblastoma tissues and peritumoral regions, and there are differences between short-term and long-term survivors [ 37 , 38 ]. In our study, we confirmed that the miR-21 and CXCR4 expressions were significantly upregulated in glioma tissues compared to normal tissues and cells, which suggested that miR-21 and CXCR4 might play important roles in mediating malignant glioma aggressiveness, as well as the tumorigenicity.…”