Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles?

Abstract

Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and proliferation. Routine treatment includes ablative surgery, chemotherapy, and radiotherapy. However, GMB rapidly relapses and develops radioresistance. Here, we briefly review the mechanisms underpinning radioresistance and discuss research to stop it and install anti-tumor defenses. Factors that participate in radioresistance are varied and include stem cells, tumor heterogeneity, tumor microenvironment, hypoxia, metabolic reprogramming, the chaperone system, non-coding RNAs, DNA repair, and extracellular vesicles (EVs). We direct our attention toward EVs because they are emerging as promising candidates as diagnostic and prognostication tools and as the basis for developing nanodevices for delivering anti-cancer agents directly into the tumor mass. EVs are relatively easy to obtain and manipulate to endow them with the desired anti-cancer properties and to administer them using minimally invasive procedures. Thus, isolating EVs from a GBM patient, supplying them with the necessary anti-cancer agent and the capability of recognizing a specified tissue-cell target, and reinjecting them into the original donor appears, at this time, as a reachable objective of personalized medicine.

Extracellular vesicles produced by irradiated endothelial or Glioblastoma stem cells promote tumor growth and vascularization modulating tumor microenvironment

“…Despite extensive studies on GBM resistance to radiotherapy, its mechanisms are still largely not understood because of the multifactorial and heterogeneous nature of this phenomenon. Many factors have been involved in GBM resistance to radiotherapy: intra-, inter-tumor heterogeneity and tumor plasticity, aberrant expression of non-coding RNAs (ncRNAs), metabolic and epigenetic reprogramming, alterations in DNA repair and cell cycle [ 3 ]. Among these, the existence of a rare population of self-renewing stem-like cells able to sustain tumor initiation and growth, to contribute to therapy resistance and recurrence of the disease [ 4 ].…”

A comparison study of dynamic [18F]Alfatide II imaging and [11C]MET in orthotopic rat models of glioblastoma

“…Glioblastoma multiforme (GBM), the most malignant form of astrocytoma, represents a paramount challenge in neuro-oncology due to its aggressive spreading growth pattern and complex pathophysiology (Burko et al 2023 ; Wang et al 2023 ). The current standard treatment modalities for GBM include surgical resection followed by adjuvant radiation therapy and chemotherapy with temozolomide (Clavreul et al 2022 ; Raue et al 2023 ).…”

The MDM2–p53 Axis Represents a Therapeutic Vulnerability Unique to Glioma Stem Cells

“…Therefore, the elimination of glioma stem cells is presumed to be an integral step in achieving long-term survival and, ultimately, a cure for this lethal disease by preventing tumor recurrence [9][10][11]. However, difficulties are associated with identifying cytotoxic agents that eliminate glioma stem cells due to the markedly stronger resistance of glioma stem cells to conventional chemo-and radiotherapies than their differentiated, non-stem cell progeny [6,12]. Intriguingly in this regard, we and others have revealed that glioma stem cells have unique vulnerabilities that render them "more sensitive" to certain drugs than their non-stem cell progeny [13][14][15][16][17][18].…”