Page 142 - Molecular features of low-grade developmental brain tumours

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specific, but it does underlie its relevance in the dysfunctional microenvironment that is present in TSC-related brain alterations. Multiple studies have shown the presence of neuroinflammation in TSC cortical tubers and SEGA 24,26,27,29,62-64. Previously, we have shown that the immune system is among the most represented enriched pathways in SEGA 26. Furthermore, upregulation of several cytokines, including interleukin 33, TNF Superfamily member 8, C-C Motif Chemokine Ligand 3 and C-C Motif Chemokine Ligand 5 was observed in SEGA compared to controls. Moreover, albumin extravasation, with uptake in astrocytes, has been reported in cortical tubers and SEGA of TSC patients, suggesting that alterations in BBB permeability are associated with the inflammation in TSC brain lesions 62,65. MMPs can contribute to the inflammatory response by cleaving propeptides of cytokines such as TNFα and IL-1β, thereby activating them 66-68. In turn, neuroinflammation can increase the expression and activity of MMPs and infiltrating immune cells such as leukocytes, which are a major source of MMP9 69,70. The link between the neuroinflammation and MMPs in SEGA deserves further investigation.
Figure 5. MMP expression after transfection with miR-320d in fetal astrocytes. a-f. Taqman PCR of miRNA-320d (a) and RT-qPCR of MMP2 (b), MMP11 (c), MMP14 (d), MMP15 (e) and MMP19 (f) in fetal astrocytes transfected with miRNA-320d mimic (miR320d) for 24 hours (n=2 biological duplicates and 3 technical triplets). Data is normalized to lipofectamine (control). **p-value<0.01, Mann-Whitney U test.
MMPs are also known to be involved in cancer pathology in multiple ways, including intravasation and extravasation of tumour cells, migration of tumour cells in the brain and adhesion of metastatic cells to the ECM 38-40. Previous research has shown that higher MMP2 expression can be a predictor for overall survival of patients with astrocytomas 71. In another study it was found that MMP14 and MMP19 had higher expression in gliomas compared to healthy control tissue, and that co-expression of MMP14 and MMP19 predicted poor survival in human glioma 72,73. Furthermore, a correlation between higher MMP11 and MMP19 expression and increased WHO-grading of malignant tumours has been suggested 74. However, SEGA are slow-growing, WHO grade I tumours that are not associated with poor survival rates, suggesting that in SEGA the higher MMP expression is most likely not linked to overall survival 51. Furthermore, in this study we did not find any correlation with the clinical traits investigated, including pre-operative seizure frequency, duration of epilepsy, size of the tumour and tumour recurrence/regrowth. A previous study found increased expression of TIMP1 and TIMP2 in grade I brain tumours compared to grade II or III tumours
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