Pediatric Atypical Teratoid/Rhabdoid Tumors of the Brain: Identification of Metabolic Subgroups Using In Vivo 1H-MR Spectroscopy.

BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors. MATERIALS AND METHODS: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples. RESULTS: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression (P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine (P < .05) and myo-inositol (P < .05) concentrations. CONCLUSIONS: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies.

NMDA and glutamate evoke excitotoxicity at distinct cellular locations in rat cortical neurons in vitro.

The development of cortical neurons in vivo and in vitro is accompanied by alterations in NMDA receptor subunit expression and concomitant modifications in the pharmacological profile of NMDA-activated ionic currents. For example, we observed that with decreasing NR2B/NR2A subunit expression ratio, the block of NMDA receptor-mediated whole-cell responses by the NR2B-selective antagonist haloperidol was also decreased. In mature cultures (>22 d in vitro), however, NMDA responses obtained from excised nucleated macropatches, which comprised a large portion of the soma, remained strongly antagonized by haloperidol. These results suggest that in more mature neurons NR1/NR2B receptors appear to be preferentially expressed in the cell body. As predicted from the whole-cell recording pharmacological profile, NMDA-induced toxicity was largely unaffected by haloperidol in mature cultures. However, haloperidol effectively blocked glutamate toxicity in the same cultures, suggesting that the neurotoxic actions of this amino acid were mostly due to the activation of somatic NMDA receptors. In experiments in which the potency of glutamate toxicity was increased by the transport inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid, the neuroprotective effects of haloperidol were significantly diminished. This was likely because of the fact that glutamate, now toxic at much lower concentrations, was able to reach and activate dendritic receptors under these conditions. These results strongly argue that exogenous glutamate and NMDA normally induce excitotoxicity at distinct cellular locations in mature mixed neuronal cultures and that NR1/NR2B receptors remain an important component in the expression of glutamate, but not NMDA-induced excitotoxicity.

MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma.

Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. As miR-124 expression is repressed in various cancer types (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared with regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38α and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 reintroduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression.