Human Cerebrospinal Fluid Modulates Pathways Promoting Glioblastoma Malignancy

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.

Glioblastoma Proximity to the Lateral Ventricle Alters Neurogenic Cell Populations of the Subventricular Zone

“…Additionally, the SVZ contains many soluble factors which contribute to neurogenesis of SVZ NSCs that GBM cells may take advantage of. These factors may be released from the NSCs themselves or be contained within the nearby cerebrospinal fluid (CSF), ultimately contributing to GBM malignancy (40)(41)(42)(43). Our previous work has revealed several CSF-induced transcriptomic changes in primary GBM cells, including upregulation of SERPINA3, MYC, and SPP1 (40,41).…”

“…These factors may be released from the NSCs themselves or be contained within the nearby cerebrospinal fluid (CSF), ultimately contributing to GBM malignancy (40)(41)(42)(43). Our previous work has revealed several CSF-induced transcriptomic changes in primary GBM cells, including upregulation of SERPINA3, MYC, and SPP1 (40,41). Gene ontology analysis has indicated an upregulation in cell viability, movement, and migration pathways induced by CSF (40), all of which may contribute to the malignancy-promoting pathways in LV-proximal tumors.…”

“…Our previous work has revealed several CSF-induced transcriptomic changes in primary GBM cells, including upregulation of SERPINA3, MYC, and SPP1 ( 40 , 41 ). Gene ontology analysis has indicated an upregulation in cell viability, movement, and migration pathways induced by CSF ( 40 ), all of which may contribute to the malignancy-promoting pathways in LV-proximal tumors. These in vitro findings warrant the study of transcriptomic changes in SVZ and GBM cells in vivo using a model similar to the one presented here.…”

Sex-Specific Differences in Glioblastoma

“…Another example associating CSF with tumor progression is that neural cell adhesion molecules, which are cell surface receptors broadly expressed in the CNS, are highly expressed in the CSF and correlate with meningeal spreading of medulloblastomas [ 125 ]. CSF has been previously associated with tumor migration, but studies proving a significant difference in the influence of CSF between male and female in brain tumors are limited [ 137 ]. In addition, few reports have examined differences between sexes in CSF composition in health and disease.…”

Histological Studies of the Ventricular–Subventricular Zone as Neural Stem Cell and Glioma Stem Cell Niche

“…Many of the factors which are enriched in the cerebrospinal fluid or the niche itself have been proposed to attract glioblastoma cells, support their growth, or alter immune cell activity, and in turn glioma cell invasion has been noted to affect V-SVZ cell proliferation. [104][105][106] Systematic review of the effects of tumor contact with the lateral ventricles on MRI (and, by extension, with the V-SVZ niche) has demonstrated that this contact, and not contact with the SGZ, is an independent predictor of shorter progression-free and overall survival, underscoring the importance of understanding these interactions when working to improve glioblastoma treatment. [107][108][109] Studies of V-SVZ-contacting and V-SVZ-distant tumors using MRI imaging and bulk transcriptomics have not reliably identified broad differences in the profiles of these two classes, arguing that a finer dissection of areas proximal to the V-SVZ, or an approach that enables quantification of cellular-level phenotypes and spatial relationship, may be needed to understand the biological effects of this contact.…”