The Importance of Tumor Stem Cells in Glioblastoma Resistance to Therapy
Abstract
:1. Glioblastoma: An Overview
2. Heterogeneity of Human Glioblastomas and Glioblastoma Stem Cells
2.1. Markers Shared between Glioblastoma Stem Cells and Glioblastoma Cells
2.1.1. Erythropoietin-Producing Hepatocellular Carcinoma Receptors
2.1.2. Src Family
2.1.3. Cannabinoid Receptors
2.1.4. Other Markers of Interest
3. Current Therapeutic Strategies in Glioblastoma
4. Novel Anticancer Strategies Targeting Glioblastoma Stem Cells
4.1. Targeting Notch and Sonic Hedgehog Pathways
4.2. Targeting Wnt Pathway
4.3. Therapeutic Targeting of the Tumor Microenvironment
4.4. New Drugs in the Treatment of Glioblastoma Stem Cells
4.5. Potential New Immunological Drugs against Glioblastoma Stem Cells
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
GBM | Glioblastoma |
GSCs | Glioblastoma Stem Cells |
CNS | Central Nervous System |
NSCs | Neural Stem Cells |
WHO | World Health Organization |
MGMT | Methylation O6-methylguanine-DNA Methyl-transferase |
IDH1 | IDH2 Isocitrate Dehydrogenase Isozymes 1 and 2 |
EGFR | Epidermal Growth Factor Receptor |
RTs | Radiation therapies |
TMZ | Temozolomide |
CSCs | Cancer Stem Cells |
VEGF | Vascular Endothelial Growth Factor |
Eph | Erythropoietin-Producing Hepatocellular Carcinoma Receptors |
SFKs | Src Family Members of Protein Tyrosine Kinases |
CBRs | Cannabinoid Receptors |
5-ALA | 5-aminolevulinic Acid |
FDA | US Food and Drug Administration |
BCNU | Carmustine |
TTFields | Tumor-Treating Fields |
PFS | Progression-Free Survival |
OS | Overall Survival |
BBB | Blood–Brain Barrier |
CCNU | Lomustine |
ACNU | Nimustine |
FOT | Fotemustine |
GSIs | γ-secretase inhibitors |
ECM | Extracellular Matrix |
PLAGL2 | Pleomorphic adenoma gene-like 2 |
RYK | Receptor-like tyrosine kinase |
ASCL1 | Achaete-scute homolog 1 |
ECs | Endothelial cells |
TME | Tumor Microenvironment |
TAMs | Tumor-Associated Macrophages |
POSTN | Periostin |
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Cancer Stem Cell Pathway | Potential Therapeutic Target | Agents | Effects | Target Model | References |
---|---|---|---|---|---|
Notch pathway | Notch signaling | Notch-1 siRNA, Delta-like-1 siRNA, Jagged-1 siRNA, Delta-like-1 Fusion protein | Downregulation of Notch and its ligands leads to a reduction of oncogenic potential of GSCs | GBM cell lines | [80,81] |
Notch signaling | γ-secretase inhibitor GSI-18 | Inhibition of Notch by GSIs increases neuronal differentiation and decreases tumorigenicity | DAOY, PFSK, D283Med, and D425Med cell lines. HSR-GBM1 and JHH520 GBM neurosphere lines | [82,83] | |
MRK003 | |||||
Notch + autophagy targeting | MRK003 + chloroquine | Protective autophagy abrogated by combination with chloroquine | HSR-GBM1 and JHH520 GBM neurosphere lines | [83] | |
Notch + leptin | GSIs + LFDI peptide (Leu-Asp-Phe-Ile) | High expression of leptin receptors in tumorspheres from GBM | human fetal glial cells SVG p12, human | [86] | |
GBM cell lines | |||||
U-87 MG, T98G | |||||
Hypoxic tumor cells | vasorin | Vasorin acts triggering Notch under hypoxic conditions | GSCs and non-GSCs from GBM | [87] | |
Shh pathway | Shh | cyclopamine | Inhibition of hedgehog pathway by cyclopamine inhibited formation of GBM-derived neurospheres | 40–60% reduction in the growth of adherent glioma lines | [91] |
Wnt pathway | GBM differentiation pathway | Dickkopf-1 (DKK1) Wnt inhibitor suppress PLAGL2 | PLAGL2 acts as an oncogene in human GBM regulating Wnt signaling | primary GBM and established glioma cell lines | [92] |
ASCL1 | - | ASCL1 and Wnt signaling are connected and collaborate with developmental transcription factors (TFs). They support GSCs’ growth | GSC lines derived from different human tumors | [93] | |
RYK pathway | - | RYK promotes stem cell-like and tumorigenic features to glioma cells and are essential to support GSCs | GBM cell line U87MG, AM38, and U251MG cells | [94] | |
Wnt/β catenin | - | Tumor chemoresistance acquisition depends on mesenchymal transformation that is triggered by Wnt/β catenin signaling | GSCs | [93] | |
Tumor microenvironment | Microvasculature and TAMs | Erlotinib and Bevacizumab | Bevacizumab treatment reduces the number of CD133+/Nestin+ tumor initiation cells and decreases microvasculature density and tumor growth | CSCs obtained from tumors | [95] |
M2-TAMs and microvasculature | BLZ945-Inhibitor of the CSF-1 receptor (CSF-1R) | TAMs support GBM tumor growth by promoting neovascularization. They play a tumor-supportive role in GBM progression | Proneural GBM | [96] | |
TAMs | shPOSTN | Silencing POSTN that recruits TAMS reduces TAM density, inhibits tumor growth, and increases survival of mice bearing GSC-derived xenografts | Human GBM specimens and glioma-derived cells | [97] |
New Drugs and Treatment against Glioblastoma Stem Cells | ||||
---|---|---|---|---|
Natural Drugs | Compound | Source | Effects | References |
Cannabinoids | Cannabis sativa | Inhibits invasiveness and stem cell-like properties of GBM tumor | [108,109] | |
Curcumin | Curcuma longa | Targets multiple signaling pathways involved in developing aggressive and drug-resistant features of GBM | [110] | |
Resveratrol | Grape skin, blueberries, raspberries, mulberries, and peanuts | Inhibited GBM and GSC growth and infiltration, acting partially via AKT deactivation and p53 induction, and suppressed GBM growth in vivo | [111] | |
Crocetin | Saffron | Cotreatment with RTs, similar effect to TMZ | [112,113] | |
PBI-05204 | Nerium oleander | Induction of tumor cells apoptosis and antitumor effects | [114] | |
Monoclonal Antibodies | Cetuximab | Erbitux | Cotreatment with RTs for locally advanced disease, or in combination with platinum-based chemotherapy in relapsed and/or metastatic disease | [115,116] |
Clinical Trials | Treatment | Phase | References |
---|---|---|---|
An evaluation of the tolerability and feasibility of combining 5-ALA with BCNU wafers (Gliadel®) in the surgical management of primary GBM | 5-ALA | II | ClinicalTrials.gov Identifier: NCT01310868 [59,61] |
Gliadel® wafers | |||
Radiotherapy | |||
Concomitant chemotherapy | |||
Adjuvant chemotherapy | |||
Phase II study of bevacizumab and ACNU in patients with recurrent high-grade glioma | Bevacizumab | II | ClinicalTrials.gov Identifier: NCT02698280 [73] |
ACNU | |||
Randomized noncomparative phase II trial with bevacizumab and FOT in the treatment of recurrent GBM | Bevacizumab | II | ClinicalTrials.gov Identifier: NCT01474239 [74] |
FOT | |||
A randomized phase II/III open-label study of ipilimumab and nivolumab versus TMZ in patients with newly diagnosed MGMT unmethylated GBM | Ipilimumab | II/III | ClinicalTrials.gov Identifier: NCT04396860 |
Nivolumab | |||
NovoTTF-100 A device | |||
Questionnaire administration | |||
Radiation therapy | |||
TMZ | |||
A prospective, multicenter trial of NovoTTF-100 A together with TMZ compared to TMZ alone in patients with newly diagnosed GBM | NovoTTF-100A device | III | ClinicalTrials.gov Identifier: NCT00916409 [68,69,70,71] |
TMZ | |||
Phase III trial exploring the combination of bvacizumab and CCNU in patients with first recurrence of a GBM | Bevacizumab | III | ClinicalTrials.gov Identifier: NCT01290939 |
CCNU | |||
DNA methylation analysis | |||
Laboratory biomarker analysis | |||
Phase III double-blind placebo-controlled trial of conventional concurrent chemoradiation and adjuvant TMZ plus bevacizumab versus conventional concurrent chemoradiation and adjuvant TMZ in patients with newly diagnosed GBM | Radiation therapy | III | ClinicalTrials.gov Identifier: NCT00884741 |
Bevacizumab | |||
Laboratory biomarker analysis | |||
Placebo | |||
TMZ | |||
A randomized phase III open-label study of nivolumab versus bevacizumab and multiple phase I safety cohorts of nivolumab or nivolumab in combination with ipilimumab across different lines of GBM | Nivolumab | III | ClinicalTrials.gov Identifier: NCT02017717 |
Bevacizumab | |||
Ipilimumab | |||
Phase III study of standard radiotherapy plus concomitant and adjuvant OSAG 101 (Theraloc®) plus TMZ versus standard radiotherapy plus concomitant and adjuvant TMZ patient with newly diagnosed, histologically confirmed GBM multiforme grade IV | Nimotuzumab | III | ClinicalTrials.gov Identifier: NCT00753246 |
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Mattei, V.; Santilli, F.; Martellucci, S.; Delle Monache, S.; Fabrizi, J.; Colapietro, A.; Angelucci, A.; Festuccia, C. The Importance of Tumor Stem Cells in Glioblastoma Resistance to Therapy. Int. J. Mol. Sci. 2021, 22, 3863. https://doi.org/10.3390/ijms22083863
Mattei V, Santilli F, Martellucci S, Delle Monache S, Fabrizi J, Colapietro A, Angelucci A, Festuccia C. The Importance of Tumor Stem Cells in Glioblastoma Resistance to Therapy. International Journal of Molecular Sciences. 2021; 22(8):3863. https://doi.org/10.3390/ijms22083863
Chicago/Turabian StyleMattei, Vincenzo, Francesca Santilli, Stefano Martellucci, Simona Delle Monache, Jessica Fabrizi, Alessandro Colapietro, Adriano Angelucci, and Claudio Festuccia. 2021. "The Importance of Tumor Stem Cells in Glioblastoma Resistance to Therapy" International Journal of Molecular Sciences 22, no. 8: 3863. https://doi.org/10.3390/ijms22083863