Diagnostic potential of extracellular vesicles in meningioma patients

Abstract

Background Extracellular vesicles (EVs) play an important role in cell-cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. Here, we investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic and proteomic alterations of original tumors. Methods EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis. Results Levels of circulating EVs were elevated in meningioma patients compared to healthy individuals, and the plasma EV concentration correlated with malignancy grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection. Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in almost all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins that could potentially be utilized to enrich meningioma EVs from biofluids. Conclusions Elevated EV levels in meningioma patient plasma could aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification.

Proteome of human glioblastoma and meningioma tissue small extracellular vesicles

“…When these were compared against the MNG EV proteins we identified, a total of 11 common proteins were identified (PGK1, ALDOA, ANAXA1, HSPB1, PFN1, PKM, S100A11, SPTBN1, SPTAN1, PLEC and TF). Our study not only confirms the presence of proteins previously identified in MNG EVs (4,(7)(8)(9)(10)(11)(12)25), but also identified novel proteins that have not been previously reported in association with MNG EVs.…”

“…Differential expression analysis was utilized to reveal the relative abundance of proteins that were enriched in the EVs compared to the tumour tissue. Our study not only confirms the presence of proteins previously identified in GBM EVs from various sources (including CUSA washings, cell lines, and plasma) (4,(7)(8)(9)(10)(11)(12)25), but also crucially identified novel proteins that have not been reported before in association with GBM EVs before including proteins associated with solute carrier transporters and fatty acid transport. Recently it has been shown that solute carrier family members can promote the progression of GBM by activating the PI3-AKT signalling pathway (44).…”

“…Despite progress in understanding the significance of EVs in brain function and the genesis and progression of brain tumours, there is a gap in our knowledge. The majority of prior investigations have primarily been on EVs obtained from patient fluids or cell cultures (4,(7)(8)(9)(10)(11)(12), rather than directly from the tumour tissue itself, which is important as these EVs may not adequately represent the complexity and specificity of those in tumour tissue. Relative to the routine isolation of EVs from fluids, including conditioned cell culture media, blood, urine or CSF, many technical issues must be addressed when isolating EVs directly from solid tissue.…”

Is serum‐derived exosomal hTERT transcript a marker of oncogenic activity in primary brain tumors? An exploratory study

“…Pathological grading of meningiomas cannot reliably predict the tumor behavior and clinical course as it provides no information concerning molecular alterations indicative of tumor aggressiveness. A recent study showed that methylation profiles, mutations and copy number variations are reflected in EV‐DNA of meningiomas 20 . We showed that high exosomal hTERT transcript levels at initial diagnosis correlated with tumor recurrence.…”

“…Exosomes are nanovesicles (30–150 nm in diameter), secreted from virtually all cell types including cancer cells. They are found in biological fluids such as blood, urine, saliva, and cell culture media and carry a cargo of nucleic acids of all types, proteins and other molecules, reflecting the molecular makeup of their cells of origin 18–20 . Since the molecular composition of exosomes reflects, at least partially, the physiological or pathophysiological makeup of their cells of origin, exosomes have a significant potential as a novel type of biomarkers.…”