Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity

Abstract

Glioblastoma (GBM) is the most frequent and aggressive brain tumor, characterized by great resistance to treatments, as well as inter- and intra-tumoral heterogeneity. GBM exhibits infiltration, vascularization and hypoxia-associated necrosis, characteristics that shape a unique microenvironment in which diverse cell types are integrated. A subpopulation of cells denominated GBM stem-like cells (GSCs) exhibits multipotency and self-renewal capacity. GSCs are considered the conductors of tumor progression due to their high tumorigenic capacity, enhanced proliferation, invasion and therapeutic resistance compared to non-GSCs cells. GSCs have been classified into two molecular subtypes: proneural and mesenchymal, the latter showing a more aggressive phenotype. Tumor microenvironment and therapy can induce a proneural-to-mesenchymal transition, as a mechanism of adaptation and resistance to treatments. In addition, GSCs can transition between quiescent and proliferative substates, allowing them to persist in different niches and adapt to different stages of tumor progression. Three niches have been described for GSCs: hypoxic/necrotic, invasive and perivascular, enhancing metabolic changes and cellular interactions shaping GSCs phenotype through metabolic changes and cellular interactions that favor their stemness. The phenotypic flexibility of GSCs to adapt to each niche is modulated by dynamic epigenetic modifications. Methylases, demethylases and histone deacetylase are deregulated in GSCs, allowing them to unlock transcriptional programs that are necessary for cell survival and plasticity. In this review, we described the effects of GSCs plasticity on GBM progression, discussing the role of GSCs niches on modulating their phenotype. Finally, we described epigenetic alterations in GSCs that are important for stemness, cell fate and therapeutic resistance.

Bioenergetic Profiling in Glioblastoma Multiforme Patients with Different Clinical Outcomes

“…Tumor heterogeneity and inter-individual variability are well-established GBM hallmarks, and hence, optimum decision-making post-diagnosis remains a challenge [ 44 ]. Deciphering GBM metabotypes as direct indicators of those biochemical changes which define the disease phenotype of an individual may serve as a promising strategy to reveal unique features as well as the mechanistic interplay underlying the observed phenotypic and biological plasticity of GBM [ 45 ].…”

Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments

“…Secondly, upregulated cell pathways can be targeted [ 83 , 84 , 85 ], for example, using miRNAs that disrupt those pathways [ 86 , 87 ]. Similarly, the tumour microenvironment can be a site of therapeutic interest [ 88 , 89 , 90 , 91 , 92 ]: one example is exploiting the high concentration of Reactive Oxygen Species (ROS) with ROS-sensitive NMeds that would release the drug only in the presence of ROS [ 93 , 94 ]. However, major limitations to these strategies lay in the poor stability of sensitive molecules, such as RNAs and the lack of cell specificity that could still lead to off-target effects.…”

Thermomagnetic Resonance Effect of the Extremely Low Frequency Electromagnetic Field on Three-Dimensional Cancer Models

“…The novelty of this study consists of the validation of the thermodynamic approach on 3D cancer models, the demonstration that the treatment with an ELF-EMF is effective in generating a mitochondrial metabolic switch and hampering the growth of 3D cancer masses also in a hypoxic environment, characterized by great resistance to drugs [ 55 ]. The clinical treatments applied to the cancers investigated in this work are far from definitive; on the basis of the results obtained on 3D models recapitulating some critical features of real tumors, the exposure to the specific ELF-EMF could be added to improve treatment outcome.…”