Abstract
Glioblastoma multiforme (GBM) is the most common brain cancer in adults. GBM starts from a small fraction of poorly differentiated and aggressive cancer stem cells (CSCs) responsible for aberrant proliferation and invasion. Due to extreme tumor heterogeneity, actual therapies provide poor positive outcomes, and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary against GBM. Among emerging therapies, high intensity ultra-short pulsed electric fields (PEFs) are considered extremely promising and our previous results demonstrated the ability of a specific electric pulse protocol to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells and U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independent of CSC content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the ability to form new neurospheres and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stem-ness/differentiation genes. Our results confirm this physical stimulus as a promising treatment to destabilize GBM, opening up the possibility of developing effective PEF-mediated therapies.
Highlights
Glioblastoma Multiforme (GBM) is the most lethal brain tumor in adults, with a survival time of 12–15 months after initial diagnosis [1]
We demonstrated that a specific signal of this class, named pulsed electric fields (PEFs)-5 (i.e., 5 electric pulses lasting 40 μs, pulse amplitude 0.3 MV/m, repeated at 1 Hz), irreversibly affected medulloblastoma (MB) cancer stem cells (CSCs), inducing PEF-surviving cells to better respond to a subsequent exposure to ionizing radiation (IR) [34]
According to the dynamic nature of CSCs, we evaluated the effects of PEF-5 exposure on U87-MG cells maintained in standard culture conditions (U87 ML) or as neurospheres (U87 NS)
Summary
Glioblastoma Multiforme (GBM) is the most lethal brain tumor in adults, with a survival time of 12–15 months after initial diagnosis [1]. As demonstrated in several cancers, GBM is thought to arise from cancer stem cells (CSCs), representing a small percentage of all cancer cells responsible for tumor development and progression [9–11]. These cells, characterized by a complex mixture of genetic alterations [12,13], express high levels of stem markers involved in self-renewal and are intrinsically resistant to standard therapies (such as radiotherapy and chemotherapy), causing tumor spread. CSC phenotypic heterogeneity arises from reversible cell state transitions in response to varying intracellular/extracellular signals [19]. The dynamic and bidirectional transition states among epithelial, mesenchymal and one or more hybrid epithelial/mesenchymal phenotypes [23], called “epithelial mesenchymal plasticity,” show a dynamic reversible nature in cancer cells and have a strong impact on cancer progression [19]
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