Pi3K‐mTOR Signaling and AMOG Expression in Epilepsy‐associated Glioneuronal Tumors

Abstract

Gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNTs) represent the most frequent type of neoplasms in pediatric medically intractable epilepsy. Several data suggest a pathogenetic relationship between GGs and other glioneuronal malformations of cortical development (MCDs), including activation of the Pi3K-mTOR signaling pathway. To further reveal these pathogenetic similarities, we investigated immunocytochemically the expression of phosphorylated (p)-PDK1, p-AKT, p-mTOR, p-4E-BP1, p-eIF4G, p-p70S6K and p-S6, the effector proteins ERM (ezrin/radixin/moesin) and the pathway regulator AMOG (adhesion molecule on glia) in both GGs and DNTs. Components of the Pi3K-mTOR signaling pathway were observed in a higher percentage of neuronal cells in GGs compared with control cortex. In DNTs, the expression of these components was low and comparable with the expression in control samples. Strong immunoreactivity for ERM was observed in GGs, but not in DNTs. Additionally, AMOG was strongly expressed within GGs (but not in DNTs) in CD34-positive precursor cells. These findings support the previously suggested pathogenic relationship between GG and MCDs concerning activation of the Pi3K-mTOR signaling pathway and suggest a different pathogenetic origin for DNTs. The strong expression of AMOG within the precursor cells of GG may represent an additional marker for the diagnostic evaluation of these glioneuronal lesions.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Enhanced mTOR signaling pathway activation has been detected in both GG and DNT (Fig. 1c) [28,31]. These findings support the inclusion of GNT within the group of MCD (such as FCD and TSC), characterized by cortical dysgenesis with abnormal cell proliferation ( [5]; Table 2).…”

“…The possible origin of GG from a precursor lesion is also supported by the reported association with molecular alterations of signaling pathways, such as reelin and the mammalian target of rapamycin (mTOR), which play critical roles in cell size and growth control, cortical development, and neuronal migration [26][27][28]. In particular, the deregulation of the mTOR pathway reported in GNT [28,29] may represent the link between these tumors and focal MCD, such as focal cortical dysplasia (FCD) and tubers in tuberous sclerosis complex (TSC), associated with epilepsy and neurobehavioral disabilities (for a review see [30]; Fig. 2).…”

Subunit Isoform Selectivity in Assembly of Na,K-ATPase α-β Heterodimers

“…Because the ␤ subunit is essential for maturation of the Na,K-ATPase ␣-␤ heterodimers (58) and the ␣ 2 selectively forms a complex with the ␤ 2 isoform in the brain, it is possible that stress-induced impairment of the ␤ 2 subunit folding in the ER increases the ER retention of the ␣ 2 subunit, which decreases the Na,K-ATPase ion transport activity of the ␣ 2 ␤ 2 Na,K-ATPase and thus contributes to epilepsy. Consistent with this hypothesis, abnormalities in distribution of the ␤ 2 subunit are linked to epilepsy (21,22). Therefore, the selectivity of ␣-␤ assembly, which is determined both by cell-specific expression and by isoform-specific binding preferences of ␣ and ␤ subunits, is crucial for cell-and tissue-specific functions of the Na,K-ATPase.…”

“…Decreased expression of the ␤ 1 subunit is associated with cancer (reviewed in Ref. 20), whereas abnormalities in expression and distribution of the ␤ 2 subunit are linked to glioma and epilepsy (21)(22)(23)(24).…”

Dysembryoplastic neuroepithelial tumour: insight into the pathology and pathogenesis

“…On the contrary, the study of Boer et al [9] showed that activation of the mTOR pathway is similar to the control human brain. However, it should be stressed that this study was performed on nine samples of the simple DNT type, which may explain lack of active mTOR.…”