Abstract
Diffuse gliomas are the most common primary malignant brain tumor. Although extracranial metastases are rarely observed, recent studies have shown the presence of circulating tumor cells (CTCs) in the blood of glioma patients, confirming that a subset of tumor cells are capable of entering the circulation. The isolation and characterization of CTCs could provide a non-invasive method for repeated analysis of the mutational and phenotypic state of the tumor during the course of disease. However, the efficient detection of glioma CTCs has proven to be challenging due to the lack of consistently expressed tumor markers and high inter- and intra-tumor heterogeneity. Thus, for this field to progress, an omnipresent but specific marker of glioma CTCs is required. In this article, we demonstrate how the recombinant malaria VAR2CSA protein (rVAR2) can be used for the capture and detection of glioma cell lines that are spiked into blood through binding to a cancer-specific oncofetal chondroitin sulfate (ofCS). When using rVAR2 pull-down from glioma cells, we identified a panel of proteoglycans, known to be essential for glioma progression. Finally, the clinical feasibility of this work is supported by the rVAR2-based isolation and detection of CTCs from glioma patient blood samples, which highlights ofCS as a potential clinical target for CTC isolation.
Highlights
Diffuse gliomas are the most common primary malignant brain tumors [1]
We investigate whether the recombinant malaria VAR2CSA protein (rVAR2) protein can be applied in both the capture and detection step and thereby broaden the use of our circulating tumor cells (CTCs)-isolation platform to include circulating glioma cells
We find that rVAR2 interacts with oncofetal chondroitin sulfate (ofCS) on several chondroitin sulfate proteoglycans (CSPGs) that have shown to be up-regulated in glioblastoma multiforme (GBM), including CD44, APLP2, CSPG4, PTPRZ1, versican, and syndecan 1
Summary
Diffuse gliomas are the most common primary malignant brain tumors [1]. As the name implies, a general trait of these tumors is their diffuse invasion into the brain parenchyma, which impedes complete surgical resection and most likely explains the poor prognosis and frequent local recurrence [2]. The isolation of circulating tumor cells (CTCs) from a liquid biopsy, such as blood or cerebrospinal fluid, could provide non-invasive, repeatable access to primary glioma cells for molecular analysis. A few studies using different isolation and detection methods have detected CTCs in blood from glioma patients [12,13,14,15] Taken together, these studies provide evidence that invasive glioma cells successfully intravasate to the blood circulation and may potentially become an important and available source of information on the mutational and phenotypic state of the primary tumor. We investigate whether the rVAR2 protein can be applied in both the capture and detection step and thereby broaden the use of our CTC-isolation platform to include circulating glioma cells. CTCs from three patient samples are analyzed by whole exome sequencing (WES), which confirms the presence of glioma-associated mutations
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