Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by hijacking neuronal mechanisms and interacting with non-neuronal cell types, such as astrocytes and endothelial cells. To enter the interstitial space of the brain parenchyma, GBM cells significantly shrink their volume and extend the invadopodia and lamellipodia by modulating their membrane conductance repertoire. However, the changes in the compartment-specific ionic dynamics involved in this process are still not fully understood. Here, using noninvasive perforated patch-clamp and live imaging approaches on various GBM cell lines during a wound-healing assay, we demonstrate that the sodium-calcium exchanger (NCX) is highly expressed in the lamellipodia compartment, is functionally active during GBM cell migration, and correlates with the overexpression of large conductance K+ channel (BK) potassium channels. Furthermore, a NCX blockade impairs lamellipodia formation and maintenance, as well as GBM cell migration. In conclusion, the functional expression of the NCX in the lamellipodia of GBM cells at the migrating front is a conditio sine qua non for the invasion strategy of these malignant cells and thus represents a potential target for brain tumor treatment.
A growing number of studies is focusing on the pharmacology and feasibility of bioactive compounds as a novel valuable approach to target a variety of human diseases related to neurological degeneration. Among the group of the so-called medicinal mushrooms (MMs), Hericium erinaceus has become one of the most promising candidates. In fact, some of the bioactive compounds extracted from H. erinaceus have been shown to recover, or at least ameliorate, a wide range of pathological brain conditions such as Alzheimer’s disease, depression, Parkinson’s disease, and spinal cord injury. In a large body of in vitro and in vivo preclinical studies on the central nervous system (CNS), the effects of erinacines have been correlated with a significant increase in the production of neurotrophic factors. Despite the promising outcome of preclinical investigations, only a limited number of clinical trials have been carried out so far in different neurological conditions. In this survey, we summarized the current state of knowledge on H. erinaceus dietary supplementation and its therapeutic potential in clinical settings. The bulk collected evidence underlies the urgent need to carry out further/wider clinical trials to prove the safety and efficacy of H. erinaceus supplementation, offering significant neuroprotective applications in brain pathologies.
Glioblastoma (GBM) is the most aggressive type of brain tumor, and existing treatments are inadequate at preventing recurrence. Tumor Treating Fields (TTFields) is a novel treatment that has been proven to extend patients' lives during the previous two decades. The antitumoral impact of TTFields involve different mechanism and is an optional add-on to standard temozolomide maintenance. Although TTFields therapy slows tumor progression initially, it does not prevent tumor relapse in most patients. We subjected patient-derived GBM primary cultures to continuous TTFields stimulation to mimic the GBM standard of care and examine the molecular pathways behind GBM sensitivity to TTFields treatment. TTFields initially limit cellular growth well. However, even under constant TTFields administration, the remaining cells regain their ability to proliferate at their own rate in long-term trials. Prolonged treatment with TTFields increases the expression of many stemness markers as well as the overexpression of different genes involved in cell cycle progression. There is also a rise in membrane ionic conductance activity. After sustained exposure to TTFields, sodium, potassium, and chloride channels are functionally increased. This influences the properties of tumor cells. Increased sodium channel functional activity, for example, promotes membrane potential depolarization. Furthermore, earlier research has shown that the membrane form of the chloride intracellular channel 1 (tmCLIC1) is important in the development of GBM. In patient-derived GBM cells exposed to TTFields, tmCLIC1 is significantly concentrated, and membrane depolarization improves its function. The evaluation of GBM tissues obtained from many patients who were treated with TTFields validates the in vitro tumor relapse model.Our findings imply that the process by which GBM cells develop a decrease in sensitivity to TTFields correlates with an increase in stemness markers and an increase in ionic channel functional expression. Citation Format: Stefania Castiglione, Gaetano Cannavale, Francesca Cianci, Ivan Verduci, Chiara Biella, Chiara Mercurio, Emanuela Pastorelli, Monica Lupi, Laura Paracchini, Laura Mannarino, Dietmar Krex, Federico Brandalise, Michele Mazzanti. TTFields reduce sensitivity in glioblastoma is associated with the functional expression of the chloride intracellular channel 1 and with voltage dependent sodium channel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1425.
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