Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles?
Abstract
1. Epidemiology of Glioblastoma Multiforme
1.1. Modern Treatment
1.1.1. Chemotherapy
1.1.2. Radiotherapy
1.2. Radioresistance
2. Adaptation Mechanisms in Glioblastoma’s Resistance to Radiotherapy
2.1. Glioblastoma Stem Cells
2.2. Tumor Plasticity and Heterogeneity
2.3. Tumor Microenvironment and Hypoxia
2.4. Metabolic Reprogramming and Gene Regulation
GBM Radioresistance and the Chaperone System
2.5. Non-Coding RNAs
2.5.1. miRNAs
2.5.2. lncRNAs
2.6. DNA Repair and Cell Cycle
3. Role of Extracellular Vesicles in Resistance to Radiation Therapy
3.1. Extracellular Vesicles
3.2. Neuron-Derived vs. GBM-Derived EVs
3.2.1. Role of CNS-Derived EVs in Physiological Processes
3.2.2. Role of EVs in Cancer
3.3. Bidirectional Communication between GBM and the Surrounding Tumour Microenvironment
3.4. Role of EVs in Tolerance to Radiation Therapy
4. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ATPase Family AAA Domain Containing 3A | ATAD3A |
Blood-brain barrier | BBB |
Cancer stem cells | CSCs |
Central nervous system | CNS |
Chaperone system | CS |
Double-strand DNA breaks | DSBs |
Endoplasmic reticulum | ER |
Endosomal sorting complex required for transport | ESCRT |
Endothelial cells | ECs |
Epidermal growth factor receptor | EGFR |
Extracellular vesicles | EVs |
Glioblastoma multiforme | GBM |
Glioblastoma stem cells | GSCs |
Glioma-initiating cells | GICs |
Histone deacetylase | HDAC |
Homologous recombination repair | HRR |
Hypoxia-inducible factor | HIF |
Hypoxia-inducible factor-1α | AHIF |
MicroRNAs | miRNAs |
Multivesicular bodies | MVBs |
Nicotinamide adenine dinucleotide phosphate | NADPH |
Non-homologous end-joining | NHEJ |
O6-methylguanine-DNA methyltransferase gene | MGMT |
Octamer-binding transcription factor 4 | OCT-4 |
Poly (ADP-ribose) polymerase | PARP |
Proliferating cell nuclear antigen | PCNA |
Proliferating cell nuclear antigen-associated factor | PAF |
Reactive oxygen species | ROS |
Replication stress | RS |
TP53-induced glycolysis and apoptosis regulator | TIGAR |
Transforming growth factor | TGF |
Tumor microenvironment | TME |
Valproic acid | VA |
Vascular endothelial growth factor | VEGF |
World Health Organization | WHO |
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Drug | Target | Biological Effects | Advantages | Limitations/Concerns | References |
---|---|---|---|---|---|
Temozolomide | Alkylation or methylation of guanine N7 or O6 and adenine N3 | Induction of guanine binding to thymine instead of cytosine, leading to extensive DNA damage and, eventually, apoptosis | Rapid and complete absorption. Weak plasma protein binding. Blood-brain barrier permeability. Use in patients with kidney and liver malfunction | Myelosuppression and lymphopenia. Downregulation of the O6-methylguanine-DNA. methyltransferase gene (MGMT). Lymphoblastic leukemia | [9,10,11,12,13,14] |
Carmustine | DNA and RNA alkylating agent | Binds to and modifies glutathione reductase, which leads to cell death in tumor cells | Recurrent GBM | Pulmonary fibrosis, bone marrow suppression, optical toxicity | [15,16] |
Carmustine in biodegradable polymer | Placement of wafers directly into the resection area allows more effective local treatment, resulting in improved outcomes and reduced toxicity | Cerebral oedema, intracranial hypertension, infections, seizures, and thromboembolic events | [17,18,19,20] | ||
Bevacizumab | Vascular endothelial growth factor (VEGF) | Inhibition of VEGF | Inhibition of Vascular Endothelial Growth Factor A leads to a decrease in the growth of new blood vessels, reducing the vascularization of GBM. Increases recurrence-free period in recurrent GBM | Pulmonary embolism, arterial hypertension, and hematologic toxic effects | [21,22,23,24,25] |
Vorinostat | Inhibitor of histone deacetylases 1, 2, 3, and 6 | Inhibition of tumor growth | Inhibition of growth of tumor cells resistant to alkylating drugs. A combination of Vorinostat and Temozolomide inhibits glioblastoma growth in experimental mice | Stimulation of autophagy and inhibition of tumor cells apoptosis | [26,27,28] |
Olaparib | Poly (ADP-ribose) polymerase (PARP) inhibitor | Enhance drug delivery to tumor | Higher survival rates and no damage to healthy tissues in combination with Temozolomide, and radiotherapy | Poor brain penetration | [29] |
Lomustine | Alkylating agent | Formation of O6-chloroethyl-guanine, can be reverted by O6-methyl-guanine DNA methyltransferase (MGMT) | Recurrent GBM | Restricted to patients with MGMT promoter-methylated tumors. Thrombocytopenia | [30,31,32] |
Valproic acid | Short-chain fatty acid | Inhibition of histone deacetylase | Chemical and metabolic stability. Increasing tumor cell sensitivity to ionizing radiation | Thrombocytopenia, fatigue, and hypertension | [33,34,35,36,37] |
Factor or Pathway | Properties/Mechanism | Reference |
---|---|---|
EVs | Transfer the genomic and proteomic cargo (mRNA, miRNA, lncRNA, spliceosomes, and proteins). | [187,188,189,190,191,192] |
Transfer the transcripts of DNA repair enzymes. | [193] | |
Glioblastoma stem cells | Ability to initiate carcinogenesis, sustain tumor proliferation, differentiate into all cellular subpopulations of the primary tumor, and unlimited self-renewal. | [55] |
Expression of a particular marker CD133 (prominin-1). | [55] | |
Cathepsin L co-expression. | [70] | |
PAF Overexpression. | [72] | |
Intra-tumoral and inter-tumoral tumor heterogeneity | Heterogeneity at the transcriptional, methylation, and mutational levels. | [79] |
Tumor plasticity | Epigenetic reprogramming. | [87] |
Hypoxic periarteriolar niches | Reduction of ROS formation and up-regulation of ROS scavenging. | [57,106] |
Increased expression of the VEGF and HIF-1α. | [98,107] | |
Activation of Hedgehog pathway, Notch, wingless, and INT-1 (WNT). | [108,109] | |
Mediates the functional regulation of DNA-PKcs and ERKs. | [110] | |
Activation of the OCT-4. | [111,112] | |
Cyclic periods of hypoxia. | [113,114] | |
Metabolic reprogramming | Surplus production of lactate, acetate, and increase of glucose oxidation to generate macromolecular precursors and energy. | [118,119] |
Overexpression of the heat shock proteins Hsp27, Hsp40, Hsp47, Hsp70, and Hsp90. | [146,147,148,149,150] | |
Warburg effect. | [127,128] | |
Activation of a pathway that is the source of excess NADPH with extra promotion by the IDH1 gene. | [129,132] | |
Activation of TIGAR. | [135,136] | |
Activation of ATAD3A. | [140] | |
Aberrantly expressed ncRNAs (lncRNAs and miRNAs) | Control of cell cycle, apoptosis, DNA damage checkpoints, and other critical signaling paths. | [141,142,154,155,156,157] |
DNA repair and cell cycle | Cells’ enlarged DNA repair potential | [175] |
Use of HRR, NHEJ, and alternative NHEJ as main pathways for DSBs processing. | [178] |
EVs Subtype | Size (nm) | Biogenesis Mechanism | Molecular Composition | Reference |
---|---|---|---|---|
Exosomes Small/medium EVs | 40–120 | Endocytic origin | ALIX, TSG101, GTPase, annexins, flotillin, and tetraspanin proteins (CD9, CD63, CD81). | [204,205,206,207,208,209,210,211,212] |
Microvesicles Medium/large EVs | 100–1000 | Outward budding and fission of the plasma membrane | mRNA, non-coding RNAs. Selectins, integrins. CD40. ARF6. | [203,213,214,215] |
Apoptotic bodies large EVs | >1000 | Cell fragmentation during apoptotic cell death | VAMP3. Cytoplasmic and membrane proteins, amino-phospholipids, phosphatidylserine, and ethanolamine. | [216] |
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Burko, P.; D’Amico, G.; Miltykh, I.; Scalia, F.; Conway de Macario, E.; Macario, A.J.L.; Giglia, G.; Cappello, F.; Caruso Bavisotto, C. Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles? Int. J. Mol. Sci. 2023, 24, 4883. https://doi.org/10.3390/ijms24054883
Burko P, D’Amico G, Miltykh I, Scalia F, Conway de Macario E, Macario AJL, Giglia G, Cappello F, Caruso Bavisotto C. Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles? International Journal of Molecular Sciences. 2023; 24(5):4883. https://doi.org/10.3390/ijms24054883
Chicago/Turabian StyleBurko, Pavel, Giuseppa D’Amico, Ilia Miltykh, Federica Scalia, Everly Conway de Macario, Alberto J. L. Macario, Giuseppe Giglia, Francesco Cappello, and Celeste Caruso Bavisotto. 2023. "Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles?" International Journal of Molecular Sciences 24, no. 5: 4883. https://doi.org/10.3390/ijms24054883
APA StyleBurko, P., D’Amico, G., Miltykh, I., Scalia, F., Conway de Macario, E., Macario, A. J. L., Giglia, G., Cappello, F., & Caruso Bavisotto, C. (2023). Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles? International Journal of Molecular Sciences, 24(5), 4883. https://doi.org/10.3390/ijms24054883