Page 13 - Molecular features of low-grade developmental brain tumours

GENERAL INTRODUCTION & OUTLINE OF THE THESIS
have been classified as LEATs such as papillary glioneuronal tumours (PGNT), rosette‐ forming glioneuronal tumours (RGNT), polymorphous low-grade neuroepithelial tumours of the young (PLNTY), mutinodular and vacuolating neuronal tumour (MVNT) of the cerebrum, diffuse leptomeningeal glioneuronal tumour (DLGNT), PA, PXA, diffuse astrocytomas, oligodendrogliomas and angiocentric glioma.
Histologically DNTs can display a typical multinodular architecture with glial nodules and/or specific glioneuronal elements (characterized by columnar bundles of axons surrounded by oligodendrocyte-like cells oriented perpendicularly to the cortical surface and separated by a myxoid matrix that contains floating neurones) (Figure 1a-b) 3,34. GGs consist of a mixture of neurons and glial tumour cells mainly represented by a large spectrum of astroglial cells (Figure 1c-e). Furthermore, CD34 expression in tumour satellites has been suggested to reflect offspring from dysplastic or developmentally compromised neural precursors (Figure 1f) 35. The neuronal component, which varies in amount, is represented by dysplastic neurons with abnormal shape and size, lacking uniform orientation and often expression of the phosphorylated form of the downstream target ribosomal S6 protein (S6) of mTORC1. Interestingly, the BRAFV600E mutation, which is generally found in glioneuronal tumours (GNTs), has been shown to be significantly associated with the expression of pS6 in these tumours 17. BRAF-induced phosphorylation of LKB1 may represent a possible mechanism contributing to mTOR activation in BRAFV600E mutated GNTs, possibly through uncoupling of the LKB1-AMPK-mTOR signalling. However, seizure activity itself and the inflammatory environment (i.e. via interleukin-1β) could also contribute to the activation of the PI3K-AKT3-mTOR signalling pathway 36,37. Furthermore, the recently reported genetic alterations detected in LEATs provide evidence of a functional connection between two major signalling pathways: RAS–RAF–MAPK and PI3K–AKT–mTOR 6.
The ERK/MAPK pathway
The majority of LEATs and pLGGs are driven by a single genetic event that results in activation of the affected ERK/MAPK pathway (Figure 2) 21,22,38. In total there are four conventional MAPK cascades defined based on the components ERK1/2, c-Jun N-terminal kinase (JNK), p38 MAPK and ERK5, which can all regulate basic cell processes such as proliferation, differentiation and motility 39-41. The mammalian ERK/MAPK pathway includes the MAPKKKs A-Raf, B-Raf, and Raf- 1, the MAPKKs MEK1 and MEK2, and the MAPKs ERK1 and ERK2, together forming the Ras- Raf-MEK-ERK pathway 42. Most often extracellular agents such as growth factors, cytokines and hormones activate the ERK/MAPK pathway by binding and activating the transmembrane glycoproteins of the receptor tyrosine kinase (RTK) family. The phosphorylated residues of RTK can function as binding sites for proteins containing Src homology 2 (SH2) or phosphotyrosine-binding (PTB) domains, such as growth factor receptor-binding protein 2 (GRB2) 43. Together with GRB2, guanine nucleotide exchange factors (GEFs) such as Son of Sevenless (SOS) convert GDP to GTP resulting in RAS activity 44,45. This process may be reversed by GTPase-activating proteins (GAPs), such as neurofibromin 46. RAS activation can recruit RAF kinases to the plasma membrane for RAF activation 47. The C-terminal catalytic
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