Abstract
Glioblastoma (GBM) is the most lethal and frequent type of brain tumor, leading patients to death in approximately 14 months after diagnosis. GBM treatment consists in surgical removal followed by radio and chemotherapy. However, tumors commonly relapse and the treatment promotes only a slight increase in patient survival. Thus, uncovering the cellular mechanisms involved in GBM resistance is of utmost interest, and the use of cell lines has been shown to be an extremely important tool. In this work, the exploration of RNAseq data from different GBM cell lines revealed different expression signatures, distinctly correlated with the behavior of GBM cell lines regarding proliferation indexes and radio-resistance. U87MG and U138MG cells, which presented expressively reduced proliferation and increased radio-resistance, showed a particular expression signature encompassing enrichment in many extracellular matrix (ECM) and receptor genes. Contrasting, U251MG and T98G cells, that presented higher proliferation and sensibility to radiation, exhibited distinct signatures revealing consistent enrichments for DNA repair processes and although several genes from the ECM-receptor pathway showed up-regulation, enrichments for this pathway were not detected. The ECM-receptor is a master regulatory pathway that is known to impact several cellular processes including: survival, proliferation, migration, invasion, and DNA damage signaling and repair, corroborating the associations we found. Furthermore, searches to The Cancer Genome Atlas (TCGA) repository revealed prognostic correlations with glioma patients for the majority of genes highlighted in the signatures and led to the identification of 31 ECM-receptor genes individually correlated with radiation responsiveness. Interestingly, we observed an association between the number of upregulated genes and survivability greater than 5 years after diagnosis, where almost all the patients that presented 21 or more upregulated genes were deceased before 5 years. Altogether our findings suggest the clinical relevance of ECM-receptor genes signature found here for radiotherapy decision and as biomarkers of glioma prognosis.
Highlights
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults
We profiled the sensitivity of different GBM cells to ionizing radiation (IR) in order to search for correlations between cell behavior and global gene expression patterns
Kaplan-meier curves illustrate the survival of patients included in each category (Figure 6B). These data revealed that the number of genes from the ECMreceptor signature is a strong predictor of the response to radiotherapy is the main choice among the available treatments for GBM, it is known that this type of therapy induces high levels of genomic instability and considerable alterations in tumor microenvironment
Summary
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. The current protocols for treating GBM involve surgical resection followed by chemotherapy and radiotherapy, but the rate of patient survival is only 14 months [1]. The extensive interaction of tumor cells with the extracellular matrix (ECM) favors invasiveness and brain infiltration, preventing the cure even after extensive surgical resection [2]. In face of this scenario, standard treatment does not restrain recurrences and about 80% of relapses are located at the resection margin, which is the site predominantly affected by higher doses of radiation [3]. CSC responds to genotoxic agents in an adaptive manner and usually survives inside the therapeutic environment, quickly regenerating the tumor after treatment cessation and supporting relapses in a few months [5]. A better understanding of tumor cells’ response to irradiation is crucial for the comprehension of GBM aggressiveness
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