MMP-9 as Prognostic Marker for Brain Tumours: A Comparative Study on Serum-Derived Small Extracellular Vesicles

Simple Summary The invasive nature of brain tumours, particularly glioblastoma, severely limits its therapy. Matrix-metalloproteinases (MMPs), enzymes involved in the degradation of the extracellular matrix, are associated with the invasiveness of brain tumours; hence, the determination of MMPs is critical for the monitoring of cancer patients. The aim of our comparative study was to evaluate the possible additional utility of the MMP-9 level of serum-derived small extracellular vesicles (sEVs) for characterising brain tumours. We established a relationship between low MMP-9 content in sEVs and improved survival, and discovered that MMP-9 levels considerably differed between tumour types and stages, showing a positive correlation with aggressiveness. We demonstrated on a large number of samples that the high MMP-9 level of serum-sEVs may serve as a negative prognostic marker for brain tumours. Matrix metalloproteinase-9 (MMP-9) degrades the extracellular matrix, contributes to tumour cell invasion and metastasis, and its elevated level in brain tumour tissues indicates poor prognosis. High-risk tissue biopsy can be replaced by liquid biopsy; however, the blood-brain barrier (BBB) prevents tumour-associated components from entering the peripheral blood, making the development of blood-based biomarkers challenging. Therefore, we examined the MMP-9 content of small extracellular vesicles (sEVs)-which can cross the BBB and are stable in body fluids-to characterise tumours with different invasion capacity. From four patient groups (glioblastoma multiforme, brain metastases of lung cancer, meningioma, and lumbar disc herniation as controls), 222 serum-derived sEV samples were evaluated. After isolating and characterising sEVs, their MMP-9 content was measured by ELISA and assessed statistically (correlation, paired t-test, Welch's test, ANOVA, ROC). We found that the MMP-9 content of sEVs is independent of gender and age, but is affected by surgical intervention, treatment, and recurrence. We found a relation between low MMP-9 level in sEVs (<28 ppm) and improved survival (8-month advantage) of glioblastoma patients, and MMP-9 levels showed a positive correlation with aggressiveness. These findings suggest that vesicular MMP-9 level might be a useful prognostic marker for brain tumours.