High Intra-tumoral and Sera Matrix Metalloproteinase 9 Levels Reduce Glioblastoma and Brain Metastases Patients' Survival

Purpose: Matrix metalloproteinase 9 (MMP-9) has been shown to induce glioblastoma invasion and brain metastases (BM) spread. However, its clinical significance for monitoring disease progression has yet to be established. This study evaluates intra-tumoral and sera MMP-9 levels and their correlation to glioblastoma and BM patients' overall survival (OS). Methods: 69 tumor and pre-operative sera samples were obtained from the brain tumor bank of the neurosurgery department at Soroka University Medical Center from patients who underwent tumor resection between 2015 and 2021. Clinical and imaging data from 27 glioblastoma and 30 BM patients were analyzed, and their MMP-9 levels and activity were measured and compared with 12 meningioma patients and 23 healthy subjects. Survival analyses were performed to examine MMP-9 level, activity, and clinical parameters' correlation with patients' OS. Results: Glioblastoma and BM patients demonstrated increased median intra-tumoral MMP-9 levels (8ng/ml and 4ng/ml, respectively, p<0.001), activity, and pre-operative sera levels (2.8ng/ml and 1.8ng/ml, respectively, p<0.001). MMP-9 was specifically detected within and between glioblastoma cells and tumor endothelia. High intra-tumoral and sera MMP-9 levels, but not its activity, were linked to decreased OS in glioblastoma and BM patients (15.8 versus 8.4 months, p=0.022). MMP-9 was readily measured in patient sera. Conclusions: This study suggests that intra-tumoral and sera MMP-9 can assist in identifying glioblastoma and BM recurrence/progression and that high intra-tumoral and/or sera MMP-9 levels at diagnosis correlate with significantly shorter patient OS. Importantly, sera MMP-9 could be longitudinally and non-invasively monitored in those patients and, once rising, may indicate tumor progression.