Page 181 - Molecular features of low-grade developmental brain tumours

proliferation after 2-3 days suggesting that combined therapy is only beneficial over a longer period of time 51,57. Furthermore, it is suggested that rapamycin alone is cytostatic, whereas combined therapy of rapamycin and MAPK/ERK inhibitors decreases cell viability and can induce cell death 51,58. However, the effect of combined therapy seemed to be dependent on the type of MAPK/ERK inhibitors and duration of treatment, which could explain why we did not find similar results on the cell viability of cells. Considering side effects, it may also be difficult to treat patients with multiple inhibitors at the same time 60,61. Nevertheless, therapeutic interventions resulting in decreased ERK/MAPK signaling in SEGAs could be used as an alternative to the current treatments available, especially in TSC patients who do not adequately respond to mTORC1 inhibitors.
To the best of our knowledge the mechanism that activates the ERK/MAPK pathway in SEGA and other TSC lesions has not been determined. We found LAMTOR1-5 over- expressed on both gene and protein level in SEGA, which together can form “the Regulator complex” that activates both mTORC1 and MAPK/ERK pathway. Furthermore, we show that LAMTOR1–5 co-expresses with pERK and pS6 suggesting that the Ragulator complex might be involved with the activation of the MAPK/ERK and mTOR pathway in SEGA and could be an interesting target for therapy. However, further research is needed to show the direct link between the Ragulator complex and SEGA development. Moreover, the Regulator complex might be an interesting target for other low grade gliomas were both the ERK/MAPK and mTOR pathway are affected.
Extracellular matrix organisation in SEGA
Besides the MAPK/ERK pathway we identified differential expression of genes related to the ECM)organization in SEGAs. MMPs play an important role in the ECM organization and are known to be involved in cancer pathology, where they play a role in the degradation of ECM, tissue morphogenesis, cell migration, angiogenesis, blood-brain barrier dysfunction, wound healing, inflammation, proliferation and the metastasis of tumour cells 62-70. Dysregulation of ECM organization has been seen in TSC cortical tubers with a specific role for MMPs and TIMPs, suggesting that the ECM might play an important role in TSC 53,71. In chapter 5 we investigated the expression of MMPs and TIMPs in SEGA and identified higher expression of MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP19, MMP25, TIMP1, TIMP2 and TIMP3 in SEGA as compared to controls. This suggests that the dysregulation of the MMP/TIMP proteolytic system is conserved across TSC pathology and might also affect migration during early brain development in TSC. In cortical tubers the expression of MMPs and TIMPs has been associated with neuroinflammation and BBB dysfunction 71. Multiple studies have shown the presence of neuroinflammation in TSC cortical tubers and SEGA 27,52,53,72-74. In chapters 3 & 4 we confirm the presence of inflammation markers and differential expression of genes related to the immune system in SEGAs. MMPs can contribute to the inflammatory response, whereas neuroinflammation can increase the expression and activity of MMPs and infiltrating immune cells such as leukocytes 75,76. Therefore, the link between the neuroinflammation and MMPs in SEGA deserves further investigation.
GENERAL DISCUSSION
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