Abstract
Glioblastoma (GBM) is the most common and devastating primary cancer of the central nervous system in adults. High grade gliomas are able to modify and respond to the brain microenvironment. When GBM tumors infiltrate the Subventricular zone (SVZ) they have a more aggressive clinical presentation than SVZ-distal tumors. We suggest that cerebrospinal fluid (CSF) contact contributes to enhance GBM malignant characteristics in these tumors. We evaluated the impact of human CSF on GBM, performing a transcriptome analysis on human primary GBM cells exposed to CSF to measure changes in gene expression profile and their clinical relevance on disease outcome. In addition we evaluated the proliferation and migration changes of CSF-exposed GBM cells in vitro and in vivo. CSF induced transcriptomic changes in pathways promoting cell malignancy, such as apoptosis, survival, cell motility, angiogenesis, inflammation, and glucose metabolism. A genetic signature extracted from the identified transcriptional changes in response to CSF proved to be predictive of GBM patient survival using the TCGA database. Furthermore, CSF induced an increase in viability, proliferation rate, and self-renewing capacity, as well as the migratory capabilities of GBM cells in vitro. In vivo, GBM cells co-injected with human CSF generated larger and more proliferative tumors compared to controls. Taken together, these results provide direct evidence that CSF is a key player in determining tumor growth and invasion through the activation of complex gene expression patterns characteristic of a malignant phenotype. These findings have diagnostic and therapeutic implications for GBM patients. The changes induced by CSF contact might play a role in the increased malignancy of SVZ-proximal GBM.
Highlights
Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer in adults, accounting for 54% of new gliomas and 45% of primary malignant tumors [1]
We analyzed the expression fold change of the GBM-cerebrospinal fluid (CSF) treated samples compared to controls, and we found 1,252 differentially expressed genes (DEGs) in the GBM612 sample and 561 DEGS in the GBM276 sample (Figure 1D), among these, 97 differential gene expression (DEG) were shared between the 2 different GBM primary cultures (71 upregulated, 26 downregulated) (Figure 1E)
Most importantly, when we performed a gene ontology (GO) analysis on the common DEGs for pathway enrichment we observed processes involved in regulation of cell invasion, apoptosis, survival, and transcription of DNA (Figure 2A), all processes that support the clinical observations of Subventricular zone (SVZ)-proximal GBM being more malignant than the distal counterpart
Summary
Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer in adults, accounting for 54% of new gliomas and 45% of primary malignant tumors [1]. CSF Promotes GBM Malignancy eventually reoccur in almost 100% of cases, due to the highly invasive nature of the tumor that makes complete resection impossible and the presence of a subpopulation of cells called brain tumor initiating cells (BTICs) [6]. These cells exhibit neural stem cell (NSC) properties, such as self-renewal and the ability to differentiate into defined progenies [7, 8]. BTICs are more resistant to chemo- and radio- therapy, and if not completely removed during surgical resection, have the capacity to generate new tumors [9]
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