Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood

Abstract

To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age. Method: 37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics. Results: Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n = 4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found. Conclusions: Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.

Regulation of FGF2-induced proliferation by inhibitory GPCR in normal pituitary cells

“…The antiproliferative effect of SST can be mediated by the five SSTR, according to receptor subtypes and target cells ( 39 , 40 ). In the pituitary gland, SSTR2 and SSTR5 are the most abundantly expressed SSTRs ( 41 ) Here, we demonstrated that SSTa inhibited the proliferative effect induced by FGF2 in lactotroph and somatotroph cells which expressed both receptors. This effect could be mediated by a major contribution of SSTR2, since octreotide has a high affinity for SSTR2 and a low affinity for SSTR5.…”

Low-grade epilepsy-associated neuroepithelial tumors: Tumor spectrum and diagnosis based on genetic alterations

“…RAS-RAF-MAPK signaling cascade have been described in GG and DNET with BRAF V600E mutations, which were always accompanied by the activation of mTOR signaling cascade with increased phosphorylated ribosomal S6 protein (pS6) (LaSarge and Danzer, 2014;Prabowo et al, 2014;Ehrstedt et al, 2020); in addition, c-MYB/MYBL1, as one of the regulated transcription factors of both signaling cascades, have also been demonstrated in IDG and AG with MYB-QKI fusion (Blümcke et al, 2016;Qaddoumi et al, 2016;Slegers and Blumcke, 2020). Particularly, the MAP kinase activation can be regulated by substrates of the PI3K-AKT-mTOR signaling cascade and vice versa, which have been identified as more related to focal malformations of cortical development (MCD), such as tuberous sclerosis complex (TSC), hemimegalencephaly, and FCD (Crino, 2015;Pernice et al, 2016).…”

“…In summary, genetic alterations detected in LEAT entities involve and connect two major signaling pathways, namely, the mitogen-activated protein kinase (MAPK) pathway and the mammalian target of rapamycin (mTOR) pathway ( Figure 1 ; Blümcke et al, 2016 ; Pernice et al, 2016 ; Delev et al, 2020 ). For example, FGFR1 as receptor signaling at upstream of both pathways has been identified in DNETs with FGFR1 alterations; BRAF as a substrate further downstream of the RAS-RAF-MAPK signaling cascade have been described in GG and DNET with BRAF V600E mutations, which were always accompanied by the activation of mTOR signaling cascade with increased phosphorylated ribosomal S6 protein (pS6) ( LaSarge and Danzer, 2014 ; Prabowo et al, 2014 ; Ehrstedt et al, 2020 ); in addition, c-MYB/MYBL1, as one of the regulated transcription factors of both signaling cascades, have also been demonstrated in IDG and AG with MYB-QKI fusion ( Blümcke et al, 2016 ; Qaddoumi et al, 2016 ; Slegers and Blumcke, 2020 ). Particularly, the MAP kinase activation can be regulated by substrates of the PI3K-AKT-mTOR signaling cascade and vice versa, which have been identified as more related to focal malformations of cortical development (MCD), such as tuberous sclerosis complex (TSC), hemimegalencephaly, and FCD ( Crino, 2015 ; Pernice et al, 2016 ).…”