Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma.

Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma.
Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort ( n = 82).
Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEV ^SDC1 originating from GBM tumors, as plEV ^SDC1 correlated with SDC1 protein expression in matched patient tumors, and plEV ^SDC1 was decreased postoperatively depending on the extent of surgery.
Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.
(©2019 American Association for Cancer Research.)