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Tang J, Amin MA, Campian JL. Glioblastoma Stem Cells at the Nexus of Tumor Heterogeneity, Immune Evasion, and Therapeutic Resistance. Cells 2025; 14:562. [PMID: 40277888 PMCID: PMC12025403 DOI: 10.3390/cells14080562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/26/2025] Open
Abstract
Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches-such as perivascular or hypoxic microenvironments-that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients.
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Affiliation(s)
- Justin Tang
- Department of Biomedical Science, University of Guelph, Guelph, ON N1G 2W1, Canada
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
| | - Md Al Amin
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
| | - Jian L. Campian
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
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Dimou J, D'Abaco G, Paradiso L, Kountouri N, Ng W, Stylli S, Drummond K, Burgess A, Kaye A, Morokoff A. Akt inhibition is effective against PTEN-deleted, chemoirradiation-resistant glioblastoma stem cells. Growth Factors 2025; 43:20-36. [PMID: 40078116 DOI: 10.1080/08977194.2025.2470185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 02/17/2025] [Indexed: 03/14/2025]
Abstract
Activated Akt and loss of phosphatase and tensin homolog (PTEN) tumour suppression aid chemo- and radio-resistance in glioblastoma stem cells (GSC), contributing to treatment failure in glioblastoma. In this study, sixteen GSC lines were generated from 66 individual glioma samples, in gliomasphere culture conditions. Thirteen of 16 GSC lines expressed hyperphosphorylated Akt (Ser473); Akt phosphorylation did not correlated with EGFR expression. An LDH colorimetric assay was used to measure the in vitro cytotoxicity of eight of these lines. Akt X (20 µM) proved more effective at inducing in vitro GSC cytotoxicity (range: 22-73%) over 48 hours than triciribine (20 µM) (0-27%), although both agents inhibited Akt phosphorylation as detected by western blot analysis. A statistically significant correlation between PTEN loss (western blot) and the extent of Akt X-induced cytotoxicity was found (p = 0.03). Akt inhibition reduces in vitro proliferation of treatment-resistant GSC lines, especially in PTEN-deficient lines, warranting further translational investigation in glioblastoma.
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Affiliation(s)
- James Dimou
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Giovanna D'Abaco
- Department of Surgery, The University of Melbourne, Parkville, Australia
| | - Lucy Paradiso
- Department of Surgery, The University of Melbourne, Parkville, Australia
| | - Nicole Kountouri
- Department of Surgery, The University of Melbourne, Parkville, Australia
| | - Wayne Ng
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Stanley Stylli
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Katharine Drummond
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Antony Burgess
- Department of Structural Biology, Walter and Eliza Hall Institute, Parkville, Australia
| | - Andrew Kaye
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Andrew Morokoff
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
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Zou Y, Xu L, Wang W, Zhu X, Lin J, Li H, Chen J, Xu W, Gao H, Wu X, Yin Z, Wang Q. Muscone restores anoikis sensitivity in TMZ-resistant glioblastoma cells by suppressing TOP2A via the EGFR/Integrin β1/FAK signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155714. [PMID: 38723526 DOI: 10.1016/j.phymed.2024.155714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 04/15/2024] [Accepted: 05/04/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND Temozolomide (TMZ) resistance is the main obstacle faced by glioblastoma multiforme (GBM) treatment. Muscone, one of the primary active pharmacological ingredients of Shexiang (Moschus), can cross the blood-brain barrier (BBB) and is being investigated as an antineoplastic medication. However, muscone treatment for GBM has received little research, and its possible mechanisms are still unclear. PURPOSE This study aims to evaluate the effect and the potential molecular mechanism of muscone on TMZ-resistant GBM cells. METHODS The differentially expressed genes (DEGs) between TMZ-resistant GBM cells and TMZ-sensitive GBM cells were screened using GEO2R. By progressively raising the TMZ concentration, a relatively stable TMZ-resistant human GBM cell line was established. The drug-resistance traits of U251-TR cells were assessed via the CCK-8 assay and Western Blot analysis of MGMT and TOP2A expression. Cell viability, cell proliferation, cell migration ability, and drug synergism were detected by the CCK-8 assay, colony formation assay, wound healing assay, and drug interaction relationship test, respectively. Anoikis was quantified by Calcein-AM/EthD-1 staining, MTT assay, and flow cytometry. Measurements of cell cycle arrest, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were performed using cell cycle staining, Annexin V-FITC/PI labeling, JC-1 assay, and ROS assay, respectively. DNA damage was measured by TUNEL assay, alkaline comet assay, and γ-H2AX foci assay. GEPIA was used to investigate the link between the anoikis marker (FAK)/drug resistance gene and critical proteins in the EGFR/Integrin β1 signaling pathway. Molecular docking was used to anticipate the probable targets of muscone. The intracellular co-localization and expression of EGFR and FAK were shown using immunofluorescence. The U251-TR cell line stably overexpressing EGFR was constructed using lentiviral transduction to assess the involvement of EGFR-related signaling in anoikis resistance. Western Blot was employed to detect the expression of migration-related proteins, cyclins, anoikis-related proteins, DNA damage/repair-related proteins, and associated pathway proteins. RESULTS DEGs analysis identified 97 deregulated chemotherapy-resistant genes and 3779 upregulated genes in TMZ-resistant GBM cells. Subsequent experiments verified TMZ resistance and the hyper-expression of DNA repair-related genes (TOP2A and MGMT) in continuously low-dose TMZ-induced U251-TR cells. Muscone exhibited dose-dependent inhibition of U251-TR cell migration and proliferation, and its co-administration with TMZ showed the potential for enhanced therapeutic efficacy. By downregulating FAK, muscone reduced anoikis resistance in anchorage-independent U251-TR cells. It also caused cell cycle arrest in the G2/M phase by upregulating p21 and downregulating CDK1, CDK2, and Cyclin E1. Muscone-induced anoikis was accompanied by mitochondrial membrane potential collapse, ROS production, an increase in the BAX/Bcl-2 ratio, as well as elevated levels of Cytochrome c (Cyt c), cleaved caspase-9, and cleaved caspase-3. These findings indicated that muscone might trigger mitochondrial-dependent anoikis via ROS generation. Moreover, significant DNA damage, DNA double-strand breaks (DSBs), the formation of γ-H2AX foci, and a reduction in TOP2A expression are also associated with muscone-induced anoikis. Overexpression of EGFR in U251-TR cells boosted the expression of Integrin β1, FAK, β-Catenin, and TOP2A, whereas muscone suppressed the expression levels of EGFR, Integrin β1, β-Catenin, FAK, and TOP2A. Muscone may influence the expression of the key DNA repair enzyme, TOP2A, by suppressing the EGFR/Integrin β1/FAK pathway. CONCLUSION We first demonstrated that muscone suppressed TOP2A expression through the EGFR/Integrin β1/FAK pathway, hence restoring anoikis sensitivity in TMZ-resistant GBM cells. These data suggest that muscone may be a promising co-therapeutic agent for enhancing GBM treatment, particularly in cases of TMZ-resistant GBM with elevated TOP2A expression.
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Affiliation(s)
- Yuheng Zou
- Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China; Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Lanyang Xu
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Wanyu Wang
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Xiao Zhu
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jiaqi Lin
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Huazhao Li
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jiali Chen
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Wei Xu
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Haiqiong Gao
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Xianghui Wu
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Zhixin Yin
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Qirui Wang
- Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China; Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
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Obrador E, Moreno-Murciano P, Oriol-Caballo M, López-Blanch R, Pineda B, Gutiérrez-Arroyo JL, Loras A, Gonzalez-Bonet LG, Martinez-Cadenas C, Estrela JM, Marqués-Torrejón MÁ. Glioblastoma Therapy: Past, Present and Future. Int J Mol Sci 2024; 25:2529. [PMID: 38473776 PMCID: PMC10931797 DOI: 10.3390/ijms25052529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.
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Affiliation(s)
- Elena Obrador
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Paz Moreno-Murciano
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
| | - María Oriol-Caballo
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Rafael López-Blanch
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Begoña Pineda
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Julia Lara Gutiérrez-Arroyo
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Alba Loras
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Luis G. Gonzalez-Bonet
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon, Spain;
| | - Conrado Martinez-Cadenas
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - José M. Estrela
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain
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Kumaria A, Ashkan K. Novel therapeutic strategies in glioma targeting glutamatergic neurotransmission. Brain Res 2023; 1818:148515. [PMID: 37543066 DOI: 10.1016/j.brainres.2023.148515] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 07/11/2023] [Accepted: 07/30/2023] [Indexed: 08/07/2023]
Abstract
High grade gliomas carry a poor prognosis despite aggressive surgical and adjuvant approaches including chemoradiotherapy. Recent studies have demonstrated a mitogenic association between neuronal electrical activity and glioma growth involving the PI3K-mTOR pathway. As the predominant excitatory neurotransmitter of the brain, glutamate signalling in particular has been shown to promote glioma invasion and growth. The concept of the neurogliomal synapse has been established whereby glutamatergic receptors on glioma cells have been shown to promote tumour propagation. Targeting glutamatergic signalling is therefore a potential treatment option in glioma. Antiepileptic medications decrease excess neuronal electrical activity and some may possess anti-glutamate effects. Although antiepileptic medications continue to be investigated for an anti-glioma effect, good quality randomised trial evidence is lacking. Other pharmacological strategies that downregulate glutamatergic signalling include riluzole, memantine and anaesthetic agents. Neuromodulatory interventions possessing potential anti-glutamate activity include deep brain stimulation and vagus nerve stimulation - this contributes to the anti-seizure efficacy of the latter and the possible neuroprotective effect of the former. A possible role of neuromodulation as a novel anti-glioma modality has previously been proposed and that hypothesis is extended to include these modalities. Similarly, the significant survival benefit in glioblastoma attributable to alternating electrical fields (Tumour Treating Fields) may be a result of disruption to neurogliomal signalling. Further studies exploring excitatory neurotransmission and glutamatergic signalling and their role in glioma origin, growth and propagation are therefore warranted.
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Affiliation(s)
- Ashwin Kumaria
- Department of Neurosurgery, Queen's Medical Centre, Nottingham University Hospitals, Nottingham, UK.
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El Baba R, Pasquereau S, Haidar Ahmad S, Monnien F, Abad M, Bibeau F, Herbein G. EZH2-Myc driven glioblastoma elicited by cytomegalovirus infection of human astrocytes. Oncogene 2023:10.1038/s41388-023-02709-3. [PMID: 37147437 DOI: 10.1038/s41388-023-02709-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/07/2023]
Abstract
Mounting evidence is identifying human cytomegalovirus (HCMV) as a potential oncogenic virus. HCMV has been detected in malignant gliomas. EZH2 and Myc play a potential oncogenic role, correlating with the glioma grade. Herewith, we present the first experimental evidence for HCMV as a reprogramming vector, straight through the dedifferentiation of mature human astrocytes, and generation of CMV-Elicited Glioblastoma Cells (CEGBCs) possessing glioblastoma-like traits. HCMV counterparts the progression of the perceived cellular and molecular mechanisms succeeding the transformation and invasion processes with CEGBCs involved in spheroid formation and invasiveness. Glioblastoma multiforme (GBM) biopsies were characterized by an elevated EZH2 and Myc expression, possessing a strong positive correlation between the aforementioned markers in the presence of HCMV. From GBM tissues, we isolated HCMV clinical strains that transformed HAs toward CEGBCs exhibiting upregulated EZH2 and Myc. Spheroids generated from CEGBCs possessed invasion potential and were sensitive to EZH2 inhibitor, ganciclovir, and temozolomide triple therapy. HCMV clinical strains transform HAs and fit with an HCMV-induced glioblastoma model of oncogenesis, and supports the tumorigenic properties of Myc and EZH2 which might be highly pertinent in the pathophysiology of astrocytic brain tumors and thereby paving the way for new therapeutic strategies.
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Affiliation(s)
- Ranim El Baba
- Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France
| | - Sébastien Pasquereau
- Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France
| | - Sandy Haidar Ahmad
- Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France
| | | | - Marine Abad
- Department of Pathology, CHU Besançon, Besançon, France
| | | | - Georges Herbein
- Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France.
- Department of Virology, CHU Besançon, Besançon, France.
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Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy. Int J Mol Sci 2023; 24:ijms24065665. [PMID: 36982740 PMCID: PMC10055343 DOI: 10.3390/ijms24065665] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/12/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Primarily, “Reprogramming Therapy”, which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy.
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Ermiş E, Althaus A, Blatti M, Uysal E, Leiser D, Norouzi S, Riggenbach E, Hemmatazad H, Ahmadli U, Wagner F. Therapy Resistance of Glioblastoma in Relation to the Subventricular Zone: What Is the Role of Radiotherapy? Cancers (Basel) 2023; 15:cancers15061677. [PMID: 36980563 PMCID: PMC10046464 DOI: 10.3390/cancers15061677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/02/2023] [Accepted: 03/05/2023] [Indexed: 03/12/2023] Open
Abstract
Glioblastoma is a highly heterogeneous primary malignant brain tumor with marked inter-/intratumoral diversity and a poor prognosis. It may contain a population of neural stem cells (NSC) and glioblastoma stem cells that have the capacity for migration, self-renewal and differentiation. While both may contribute to resistance to therapy, NSCs may also play a role in brain tissue repair. The subventricular zone (SVZ) is the main reservoir of NSCs. This study investigated the impact of bilateral SVZ radiation doses on patient outcomes. We included 147 patients. SVZs were delineated and the dose administered was extracted from dose–volume histograms. Tumors were classified based on their spatial relationship to the SVZ. The dose and outcome correlations were analyzed using the Kaplan–Meier and Cox proportional hazards regression methods. Median progression-free survival (PFS) was 7 months (range: 4–11 months) and median overall survival (OS) was 14 months (range: 9–23 months). Patients with an ipsilateral SVZ who received ≥50 Gy showed significantly better PFS (8 versus 6 months; p < 0.001) and OS (16 versus 11 months; p < 0.001). Furthermore, lower doses (<32 Gy) to the contralateral SVZ were associated with improved PFS (8 versus 6 months; p = 0.030) and OS (15 versus 11 months; p = 0.001). Targeting the potential tumorigenic cells in the ipsilateral SVZ while sparing contralateral NSCs correlated with an improved outcome. Further studies should address the optimization of dose distribution with modern radiotherapy techniques for the areas surrounding infiltrated and healthy SVZs.
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Affiliation(s)
- Ekin Ermiş
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Correspondence:
| | - Alexander Althaus
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Marcela Blatti
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Emre Uysal
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Dominic Leiser
- Center for Proton Therapy, Paul Scherrer Institute, 5232 Villigen, Switzerland
| | - Shokoufe Norouzi
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Elena Riggenbach
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Hossein Hemmatazad
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Uzeyir Ahmadli
- Department of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Franca Wagner
- Department of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
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Wang Y, Wang B, Zhou F, Lv K, Xu X, Cao W. CircNDC80 promotes glioblastoma multiforme tumorigenesis via the miR-139-5p/ECE1 pathway. J Transl Med 2023; 21:22. [PMID: 36635757 PMCID: PMC9837923 DOI: 10.1186/s12967-022-03852-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/24/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have been shown to be essential for the emergence and growth of different cancers. However, further research is required to validate the function of circRNA in glioblastoma (GBM). METHODS CircNDC80 expression in both normal brain tissues (NBTs) and glioma tissues was determined using real-time PCR. The impact of circNDC80 on GBM cell proliferation, migration, and invasion was then confirmed by CCK-8, colony formation, EdU incorporation, Transwell, and wound healing assays. To determine how circNDC80 affects the capacity of glioma stem cells (GSCs) to maintain their stemness and self-renewal, a CellTiter-Glo assay, clonogenic assay and extreme limiting dilution assay were utilized. To ascertain the impact of circNDC80 in vivo, intracranial xenograft models were established. RESULTS When compared to NBT, glioblastoma tissue had a higher level of circNDC80 expression. In functional assays, circNDC80 promoted glioblastoma cell proliferation, migration, and invasion, while sustaining the stemness and fostering the self-renewal of glioma stem cells. In addition, a dual luciferase reporter assay and circRIP were used to verify that circNDC80 simultaneously affects the expression of ECE1 mRNA by sponging miR-139-5p, and a rescue experiment was used to verify the above results further. CONCLUSIONS According to our research, circNDC80 is an oncogenic factor that promotes glioblastoma through the miR-139-5p/ECE1 pathway. This implies that circNDC80 may be employed as a novel therapeutic target and a possible predictive biomarker.
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Affiliation(s)
- Yuhang Wang
- grid.412676.00000 0004 1799 0784Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000 Jiangsu China
| | - Binbin Wang
- grid.412676.00000 0004 1799 0784Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000 Jiangsu China
| | - Fengqi Zhou
- grid.412676.00000 0004 1799 0784Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000 Jiangsu China
| | - Kun Lv
- grid.412676.00000 0004 1799 0784Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000 Jiangsu China
| | - Xiupeng Xu
- grid.412676.00000 0004 1799 0784Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000 Jiangsu China
| | - Wenping Cao
- grid.412676.00000 0004 1799 0784Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000 Jiangsu China
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Adnani L, Spinelli C, Tawil N, Rak J. Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature. Semin Cancer Biol 2022; 87:196-213. [PMID: 36371024 DOI: 10.1016/j.semcancer.2022.11.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/25/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the underlying circuitry, as crucial constituents of angiogenesis, angiocrine stimulation, non-angiogenic vascular growth, interactions with the coagulation system and other responses. Tumour-vascular interactions involve soluble factors, extracellular matrix molecules, cell-cell contacts, as well as extracellular vesicles (EVs) carrying assemblies of molecular effectors. Oncogenic mutations and transforming changes in the cancer cell genome, epigenome and signalling circuitry exert important and often cancer-specific influences upon pathways of tumour-vascular interactions, including the biogenesis, content, and biological activity of EVs and responses of cancer cells to them. Notably, EVs may carry and transfer bioactive, oncogenic macromolecules (oncoproteins, RNA, DNA) between tumour and vascular cells and thereby elicit unique functional changes and forms of vascular growth and remodeling. Cancer EVs influence the state of the vasculature both locally and systemically, as exemplified by cancer-associated thrombosis. EV-mediated communication pathways represent attractive targets for therapies aiming at modulation of the tumour-vascular interface (beyond angiogenesis) and could also be exploited for diagnostic purposes in cancer.
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Affiliation(s)
- Lata Adnani
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Cristiana Spinelli
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Nadim Tawil
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Janusz Rak
- McGill University and Research Institute of the McGill University Health Centre, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
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11
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Zhuang Q, Yang H, Mao Y. The Oncogenesis of Glial Cells in Diffuse Gliomas and Clinical Opportunities. Neurosci Bull 2022; 39:393-408. [PMID: 36229714 PMCID: PMC10043159 DOI: 10.1007/s12264-022-00953-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/06/2022] [Indexed: 11/25/2022] Open
Abstract
Glioma is the most common and lethal intrinsic primary tumor of the brain. Its controversial origins may contribute to its heterogeneity, creating challenges and difficulties in the development of therapies. Among the components constituting tumors, glioma stem cells are highly plastic subpopulations that are thought to be the site of tumor initiation. Neural stem cells/progenitor cells and oligodendrocyte progenitor cells are possible lineage groups populating the bulk of the tumor, in which gene mutations related to cell-cycle or metabolic enzymes dramatically affect this transformation. Novel approaches have revealed the tumor-promoting properties of distinct tumor cell states, glial, neural, and immune cell populations in the tumor microenvironment. Communication between tumor cells and other normal cells manipulate tumor progression and influence sensitivity to therapy. Here, we discuss the heterogeneity and relevant functions of tumor cell state, microglia, monocyte-derived macrophages, and neurons in glioma, highlighting their bilateral effects on tumors. Finally, we describe potential therapeutic approaches and targets beyond standard treatments.
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Affiliation(s)
- Qiyuan Zhuang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Institute for Translational Brain Research, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
- Neurosurgical Institute of Fudan University, Shanghai, 200032, China.
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12
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Alkailani MI, Aittaleb M, Tissir F. WNT signaling at the intersection between neurogenesis and brain tumorigenesis. Front Mol Neurosci 2022; 15:1017568. [PMID: 36267699 PMCID: PMC9577257 DOI: 10.3389/fnmol.2022.1017568] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
Neurogenesis and tumorigenesis share signaling molecules/pathways involved in cell proliferation, differentiation, migration, and death. Self-renewal of neural stem cells is a tightly regulated process that secures the accuracy of cell division and eliminates cells that undergo mitotic errors. Abnormalities in the molecular mechanisms controlling this process can trigger aneuploidy and genome instability, leading to neoplastic transformation. Mutations that affect cell adhesion, polarity, or migration enhance the invasive potential and favor the progression of tumors. Here, we review recent evidence of the WNT pathway’s involvement in both neurogenesis and tumorigenesis and discuss the experimental progress on therapeutic opportunities targeting components of this pathway.
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Affiliation(s)
- Maisa I. Alkailani
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Mohamed Aittaleb
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Fadel Tissir
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
- *Correspondence: Fadel Tissir,
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13
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Ding J, Li X, Khan S, Zhang C, Gao F, Sen S, Wasylishen AR, Zhao Y, Lozano G, Koul D, Alfred Yung WK. EGFR suppresses p53 function by promoting p53 binding to DNA-PKcs: a noncanonical regulatory axis between EGFR and wild-type p53 in glioblastoma. Neuro Oncol 2022; 24:1712-1725. [PMID: 35474131 PMCID: PMC9527520 DOI: 10.1093/neuonc/noac105] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) amplification and TP53 mutation are the two most common genetic alterations in glioblastoma multiforme (GBM). A comprehensive analysis of the TCGA GBM database revealed a subgroup with near mutual exclusivity of EGFR amplification and TP53 mutations indicative of a role of EGFR in regulating wild-type-p53 (wt-p53) function. The relationship between EGFR amplification and wt-p53 function remains undefined and this study describes the biological significance of this interaction in GBM. METHODS Mass spectrometry was used to identify EGFR-dependent p53-interacting proteins. The p53 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) interaction was detected by co-immunoprecipitation. We used CRISPR-Cas9 gene editing to knockout EGFR and DNA-PKcs and the Edit-R CRIPSR-Cas9 system for conditional knockout of EGFR. ROS activity was measured with a CM-H2DCFDA probe, and real-time PCR was used to quantify expression of p53 target genes. RESULTS Using glioma sphere-forming cells (GSCs), we identified, DNA-PKcs as a p53 interacting protein that functionally inhibits p53 activity. We demonstrate that EGFR knockdown increased wt-p53 transcriptional activity, which was associated with decreased binding between p53 and DNA-PKcs. We further show that inhibition of DNA-PKcs either by siRNA or an inhibitor (nedisertib) increased wt-p53 transcriptional activity, which was not enhanced further by EGFR knockdown, indicating that EGFR suppressed wt-p53 activity through DNA-PKcs binding with p53. Finally, using conditional EGFR-knockout GSCs, we show that depleting EGFR increased animal survival in mice transplanted with wt-p53 GSCs. CONCLUSION This study demonstrates that EGFR signaling inhibits wt-p53 function in GBM by promoting an interaction between p53 and DNA-PKcs.
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Affiliation(s)
- Jie Ding
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xiaolong Li
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sabbir Khan
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Chen Zhang
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Feng Gao
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shayak Sen
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Amanda R Wasylishen
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yang Zhao
- Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA
- Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Guillermina Lozano
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Dimpy Koul
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - W K Alfred Yung
- Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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14
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Zeng J, Hua S, Liu J, Mungur R, He Y, Feng J. Identification of core genes as potential biomarkers for predicting progression and prognosis in glioblastoma. Front Genet 2022; 13:928407. [PMID: 36238156 PMCID: PMC9552700 DOI: 10.3389/fgene.2022.928407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Glioblastoma is a common malignant neuroepithelial neoplasm with poor clinical outcomes and limited treatment options. It is extremely important to search and confirm diverse hub genes that are effective in the advance and prediction of glioblastoma. Methods: We analyzed GSE50161, GSE4290, and GSE68848, the three microarray datasets retrieved from the GEO database. GO function and KEGG pathway enrichment analyses for differentially expressed genes (DEGs) were performed using DAVID. The PPI network of the DEGs was analyzed using the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape software. Hub genes were identified through the PPI network and a robust rank aggregation method. The Cancer Genome Atlas (TCGA) and the Oncomine database were used to validate the hub genes. In addition, a survival curve analysis was conducted to verify the correlation between the expression of hub genes and patient prognosis. Human glioblastoma cells and normal cells were collected, and then RT-PCR, Western blot, and immunofluorescence were conducted to validate the expression of the NDC80 gene. A cell proliferation assay was used to detect the proliferation of glioma cells. The effects of NDC80 expression on migration and invasion of GBM cell lines were evaluated by conducting scratch and transwell assays. Results: A total of 716 DEGs were common to all three microarray datasets, which included 188 upregulated DEGs and 528 downregulated DEGs. Furthermore, we found that among the common DEGs, 10 hub genes showed a high degree of connectivity. The expression of the 10 hub genes in TCGA and the Oncomine database was significantly overexpressed in glioblastoma compared with normal genes. Additionally, the survival analysis showed that the patients with low expression of six genes (BIR5C, CDC20, NDC80, CDK1, TOP2A, and MELK) had a significantly favorable prognosis (p < 0.01). We discovered that NDC80, which has been shown to be important in other cancers, also has an important role in malignant gliomas. The RT-PCR, Western blot, and immunofluorescence results showed that the expression level of NDC80 was significantly higher in human glioblastoma cells than in normal cells. Moreover, we identified that NDC80 increased the proliferation and invasion abilities of human glioblastoma cells. Conclusion: The six genes identified here may be utilized to form a panel of disease progression and predictive biomarkers of glioblastoma for clinical purposes. NDC80, one of the six genes, was discovered to have a potentially important role in GBM, a finding that needs to be further studied.
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Affiliation(s)
- Jianping Zeng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Jianping Zeng,
| | - Shushan Hua
- Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Liu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Rajneesh Mungur
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Yongsheng He
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiugeng Feng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
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15
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Singh DK, Shivalingappa PKM, Sharma A, Mondal A, Muzumdar D, Shiras A, Bapat SA. NSG-70, a new glioblastoma cell line with mixed proneural-mesenchymal features, associates NOTCH1-WNT5A signaling with stem cell maintenance and angiogenesis. J Neurooncol 2022; 157:575-591. [DOI: 10.1007/s11060-022-04002-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/03/2022] [Indexed: 11/24/2022]
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16
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A Tumor Suppressor Gene, N-myc Downstream-Regulated Gene 1 (NDRG1), in Gliomas and Glioblastomas. Brain Sci 2022; 12:brainsci12040473. [PMID: 35448004 PMCID: PMC9029626 DOI: 10.3390/brainsci12040473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/24/2022] [Accepted: 04/02/2022] [Indexed: 12/04/2022] Open
Abstract
The development of potent and selective therapeutic approaches to glioblastoma (GBM) requires the identification of molecular pathways that critically regulate the survival and proliferation of GBM. Glioblastoma stem-like cells (GSCs) possess stem-cell-like properties, self-renewal, and differentiation into multiple neural cell lineages. From a clinical point of view, GSCs have been reported to resist radiation and chemotherapy. GSCs are influenced by the microenvironment, especially the hypoxic condition. N-myc downstream-regulated gene 1 (NDRG1) is a tumor suppressor with the potential to suppress the proliferation, invasion, and migration of cancer cells. Previous studies have reported that deregulated expression of NDRG1 affects tumor growth and clinical outcomes of patients with GBM. This literature review aimed to clarify the critical role of NDRG1 in tumorigenesis and acquirement of resistance for anti-GBM therapies, further to discussing the possibility and efficacy of NDRG1 as a novel target of treatment for GBM. The present review was conducted by searching the PubMed and Scopus databases. The search was conducted in February 2022. We review current knowledge on the regulation and signaling of NDRG1 in neuro-oncology. Finally, the role of NDRG1 in GBM and potential clinical applications are discussed.
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17
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Beiriger J, Habib A, Jovanovich N, Kodavali CV, Edwards L, Amankulor N, Zinn PO. The Subventricular Zone in Glioblastoma: Genesis, Maintenance, and Modeling. Front Oncol 2022; 12:790976. [PMID: 35359410 PMCID: PMC8960165 DOI: 10.3389/fonc.2022.790976] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.
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Affiliation(s)
- Jamison Beiriger
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Ahmed Habib
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Nicolina Jovanovich
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Chowdari V. Kodavali
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Lincoln Edwards
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Nduka Amankulor
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Pascal O. Zinn
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
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18
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Sun R, Kim AH. The multifaceted mechanisms of malignant glioblastoma progression and clinical implications. Cancer Metastasis Rev 2022; 41:871-898. [PMID: 35920986 PMCID: PMC9758111 DOI: 10.1007/s10555-022-10051-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/20/2022] [Indexed: 02/06/2023]
Abstract
With the application of high throughput sequencing technologies at single-cell resolution, studies of the tumor microenvironment in glioblastoma, one of the most aggressive and invasive of all cancers, have revealed immense cellular and tissue heterogeneity. A unique extracellular scaffold system adapts to and supports progressive infiltration and migration of tumor cells, which is characterized by altered composition, effector delivery, and mechanical properties. The spatiotemporal interactions between malignant and immune cells generate an immunosuppressive microenvironment, contributing to the failure of effective anti-tumor immune attack. Among the heterogeneous tumor cell subpopulations of glioblastoma, glioma stem cells (GSCs), which exhibit tumorigenic properties and strong invasive capacity, are critical for tumor growth and are believed to contribute to therapeutic resistance and tumor recurrence. Here we discuss the role of extracellular matrix and immune cell populations, major components of the tumor ecosystem in glioblastoma, as well as signaling pathways that regulate GSC maintenance and invasion. We also highlight emerging advances in therapeutic targeting of these components.
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Affiliation(s)
- Rui Sun
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Albert H. Kim
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110 USA ,The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110 USA
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19
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Uddin MS, Kabir MT, Mamun AA, Sarwar MS, Nasrin F, Emran TB, Alanazi IS, Rauf A, Albadrani GM, Sayed AA, Mousa SA, Abdel-Daim MM. Natural Small Molecules Targeting NF-κB Signaling in Glioblastoma. Front Pharmacol 2021; 12:703761. [PMID: 34512336 PMCID: PMC8429794 DOI: 10.3389/fphar.2021.703761] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/09/2021] [Indexed: 12/13/2022] Open
Abstract
Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes that mediate various cellular activities, including propagation, differentiation, motility, and survival. Abnormal activation of NF-κB is a common incidence in several cancers. Glioblastoma multiforme (GBM) is the most aggressive brain cancer described by high cellular heterogeneity and almost unavoidable relapse following surgery and resistance to traditional therapy. In GBM, NF-κB is abnormally activated by various stimuli. Its function has been associated with different processes, including regulation of cancer cells with stem-like phenotypes, invasion of cancer cells, and radiotherapy resistance identification of mesenchymal cells. Even though multimodal therapeutic approaches such as surgery, radiation therapy, and chemotherapeutic drugs are used for treating GBM, however; the estimated mortality rate for GBM patients is around 1 year. Therefore, it is necessary to find out new therapeutic approaches for treating GBM. Many studies are focusing on therapeutics having less adverse effects owing to the failure of conventional chemotherapy and targeted agents. Several studies of compounds suggested the involvement of NF-κB signaling pathways in the growth and development of a tumor and GBM cell apoptosis. In this review, we highlight the involvement of NF-κB signaling in the molecular understanding of GBM and natural compounds targeting NF-κB signaling.
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Affiliation(s)
- Md. Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | | | - Abdullah Al Mamun
- Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong
| | - Md. Shahid Sarwar
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Fatema Nasrin
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, QLD, Australia
- School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
| | - Ibtesam S. Alanazi
- Department of Biology, Faculty of Sciences, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Khyber Pakhtunkhwa, Pakistan
| | - Ghadeer M. Albadrani
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Amany A. Sayed
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States
| | - Mohamed M. Abdel-Daim
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
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20
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Khotimchenko R, Bryukhovetskiy I, Khotimchenko M, Khotimchenko Y. Bioactive Compounds with Antiglioma Activity from Marine Species. Biomedicines 2021; 9:biomedicines9080886. [PMID: 34440090 PMCID: PMC8389718 DOI: 10.3390/biomedicines9080886] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 11/21/2022] Open
Abstract
The search for new chemical compounds with antitumor pharmacological activity is a necessary process for creating more effective drugs for each specific malignancy type. This review presents the outcomes of screening studies of natural compounds with high anti-glioma activity. Despite significant advances in cancer therapy, there are still some tumors currently considered completely incurable including brain gliomas. This review covers the main problems of the glioma chemotherapy including drug resistance, side effects of common anti-glioma drugs, and genetic diversity of brain tumors. The main emphasis is made on the characterization of natural compounds isolated from marine organisms because taxonomic diversity of organisms in seawaters significantly exceeds that of terrestrial species. Thus, we should expect greater chemical diversity of marine compounds and greater likelihood of finding effective molecules with antiglioma activity. The review covers at least 15 classes of organic compounds with their chemical formulas provided as well as semi-inhibitory concentrations, mechanisms of action, and pharmacokinetic profiles. In conclusion, the analysis of the taxonomic diversity of marine species containing bioactives with antiglioma activity is performed noting cytotoxicity indicators and to the tumor cells in comparison with similar indicators of antitumor agents approved for clinical use as antiglioblastoma chemotherapeutics.
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Affiliation(s)
- Rodion Khotimchenko
- School of Biomedicine, Far Eastern Federal University, 690090 Vladivostok, Russia; (R.K.); (I.B.); (M.K.)
| | - Igor Bryukhovetskiy
- School of Biomedicine, Far Eastern Federal University, 690090 Vladivostok, Russia; (R.K.); (I.B.); (M.K.)
| | - Maksim Khotimchenko
- School of Biomedicine, Far Eastern Federal University, 690090 Vladivostok, Russia; (R.K.); (I.B.); (M.K.)
| | - Yuri Khotimchenko
- School of Biomedicine, Far Eastern Federal University, 690090 Vladivostok, Russia; (R.K.); (I.B.); (M.K.)
- Laboratory of Pharmacology, A. V. Zhirmunsky National Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, 690950 Vladivostok, Russia
- Correspondence:
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21
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Chu YH, Lin JD, Nath S, Schachtrup C. Id proteins: emerging roles in CNS disease and targets for modifying neural stemcell behavior. Cell Tissue Res 2021; 387:433-449. [PMID: 34302526 PMCID: PMC8975794 DOI: 10.1007/s00441-021-03490-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/18/2021] [Indexed: 12/14/2022]
Abstract
Neural stem/progenitor cells (NSPCs) are found in the adult brain and spinal cord, and endogenous or transplanted NSPCs contribute to repair processes and regulate immune responses in the CNS. However, the molecular mechanisms of NSPC survival and integration as well as their fate determination and functionality are still poorly understood. Inhibitor of DNA binding (Id) proteins are increasingly recognized as key determinants of NSPC fate specification. Id proteins act by antagonizing the DNA-binding activity of basic helix-loop-helix (bHLH) transcription factors, and the balance of Id and bHLH proteins determines cell fate decisions in numerous cell types and developmental stages. Id proteins are central in responses to environmental changes, as they occur in CNS injury and disease, and cellular responses in adult NSPCs implicate Id proteins as prime candidates for manipulating stemcell behavior. Here, we outline recent advances in understanding Id protein pleiotropic functions in CNS diseases and propose an integrated view of Id proteins and their promise as potential targets in modifying stemcell behavior to ameliorate CNS disease.
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Affiliation(s)
- Yu-Hsuan Chu
- Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Jia-di Lin
- Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Suvra Nath
- Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Christian Schachtrup
- Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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22
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Tang X, Zuo C, Fang P, Liu G, Qiu Y, Huang Y, Tang R. Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy. Front Oncol 2021; 11:701291. [PMID: 34307170 PMCID: PMC8297686 DOI: 10.3389/fonc.2021.701291] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GBM) remains the most lethal and common primary brain tumor, even after treatment with multiple therapies, such as surgical resection, chemotherapy, and radiation. Although great advances in medical development and improvements in therapeutic methods of GBM have led to a certain extension of the median survival time of patients, prognosis remains poor. The primary cause of its dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. During the last decade, glioblastoma stem cells (GSCs) have been successfully isolated from GBM, and it has been demonstrated that these cells are likely to play an indispensable role in the formation, maintenance, and recurrence of GBM tumors, indicating that GSCs are a crucial target for treatment. Herein, we summarize the current knowledge regarding GSCs, their related signaling pathways, resistance mechanisms, crosstalk linking mechanisms, and microenvironment or niche. Subsequently, we present a framework of targeted therapy for GSCs based on direct strategies, including blockade of the pathways necessary to overcome resistance or prevent their function, promotion of GSC differentiation, virotherapy, and indirect strategies, including targeting the perivascular, hypoxic, and immune niches of the GSCs. In summary, targeting GSCs provides a tremendous opportunity for revolutionary approaches to improve the prognosis and therapy of GBM, despite a variety of challenges.
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Affiliation(s)
- Xuejia Tang
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China.,Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Chenghai Zuo
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Pengchao Fang
- Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Guojing Liu
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yongyi Qiu
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Huang
- Department of Neurosurgery, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Rongrui Tang
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China
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23
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Spinelli C, Tawil N, Adnani L, Rak J, Choi D. Extracellular Vesicle Mediated Vascular Pathology in Glioblastoma. Subcell Biochem 2021; 97:247-273. [PMID: 33779920 DOI: 10.1007/978-3-030-67171-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
Abstract
Glioblastoma (GBM) is an incurable, infiltrative high-grade brain tumour associated with dramatic vascular responses observed both locally (angiogenesis, vascular cooption, angiocrine effects, microthrombosis) and systemically (venous thromboembolism). GBM-associated vascular pathology is diagnostically relevant and constitutes a source of morbidity, mortality and progressive changes in tumour biology. Extracellular vesicles (EVs) have emerged as unique mediators of vascular effects in brain tumours acting as vehicles for intercellular transfer of oncoproteins (e.g. EGFRvIII), RNA, DNA and molecular effectors of angiogenesis and thrombosis. Vascular effects of GBM EVs are regulated by cancer cell genome, epigenome and microenvironment and differ between subtypes of cancer cells and stem cells. Understanding and targeting EV-driven vascular processes in GBM may offer new approaches to diagnose and treat these intractable tumours.
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Affiliation(s)
- Cristiana Spinelli
- McGill University and the Research Institute of the McGill University Health Centre, QC, Canada
| | - Nadim Tawil
- McGill University and the Research Institute of the McGill University Health Centre, QC, Canada
| | - Lata Adnani
- McGill University and the Research Institute of the McGill University Health Centre, QC, Canada
| | - Janusz Rak
- McGill University and the Research Institute of the McGill University Health Centre, QC, Canada.
| | - Dongsic Choi
- McGill University and the Research Institute of the McGill University Health Centre, QC, Canada.
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24
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Curry RN, Glasgow SM. The Role of Neurodevelopmental Pathways in Brain Tumors. Front Cell Dev Biol 2021; 9:659055. [PMID: 34012965 PMCID: PMC8127784 DOI: 10.3389/fcell.2021.659055] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Disruptions to developmental cell signaling pathways and transcriptional cascades have been implicated in tumor initiation, maintenance and progression. Resurgence of aberrant neurodevelopmental programs in the context of brain tumors highlights the numerous parallels that exist between developmental and oncologic mechanisms. A deeper understanding of how dysregulated developmental factors contribute to brain tumor oncogenesis and disease progression will help to identify potential therapeutic targets for these malignancies. In this review, we summarize the current literature concerning developmental signaling cascades and neurodevelopmentally-regulated transcriptional programs. We also examine their respective contributions towards tumor initiation, maintenance, and progression in both pediatric and adult brain tumors and highlight relevant differentiation therapies and putative candidates for prospective treatments.
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Affiliation(s)
- Rachel N. Curry
- Department of Neuroscience, Baylor College of Medicine, Center for Cell and Gene Therapy, Houston, TX, United States
- Integrative Molecular and Biomedical Sciences, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX, United States
| | - Stacey M. Glasgow
- Neurobiology Section, Division of Biological Sciences, University of California, San Diego, San Diego, CA, United States
- Neurosciences Graduate Program, University of California, San Diego, San Diego, CA, United States
- Biomedical Sciences Graduate Program, University of California, San Diego, San Diego, CA, United States
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25
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Integrated Gene Expression and Methylation Analyses Identify DLL3 as a Biomarker for Prognosis of Malignant Glioma. J Mol Neurosci 2021; 71:1622-1635. [PMID: 33713320 DOI: 10.1007/s12031-021-01817-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 02/15/2021] [Indexed: 12/21/2022]
Abstract
Glioma is one of the most common neurological malignancies worldwide. Delta-like ligand 3 (DLL3), an inhibitory ligand-driven activation of the Notch pathway, has been shown to be significantly associated with overall survival in patients with glioma. Therefore, the purpose of this study was to determine whether DLL3 as a biomarker in glioma is associated with patients' clinicopathological features and prognosis. We identified differences in transcriptome and promoter methylation in the Chinese Glioma Genome Atlas (CGGA) in patients with malignant glioma with shorter (less than 1 year) and longer (greater than 3 years) survival time. Further analysis of The Cancer Genome Atlas (TCGA) revealed that four genes (DLL3, TSPAN15, RTN1, PAK7) are highly associated with patient prognosis and play an indispensable role in evolution. We chose the expression level of DLL3 in glioma patients for our study. Patients were divided into groups with low and high expression of DLL3 according to the cutoff values obtained, and Kaplan-Meier and Cox analysis were used to examine the correlation between DLL3 gene expression and patient survival. We then performed a gene set enrichment analysis (GSEA) to identify significantly enriched signaling pathways. Our results confirmed that the overall survival of patients with low DLL3 expression was significantly shorter than that of patients with high DLL3 expression. GSEA showed that the signaling pathways of the immune process and immune response, among others, were enhanced with the DLL3 low-expression phenotype. Collectively, our findings signify that DLL3 is a potent prognostic factor for glioma, which can provide a viable approach for glioma prognostic assessment and valuable insights for anti-tumor immune-targeted therapies.
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26
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Fontán-Lozano Á, Morcuende S, Davis-López de Carrizosa MA, Benítez-Temiño B, Mejías R, Matarredona ER. To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells. Front Oncol 2020; 10:602217. [PMID: 33330101 PMCID: PMC7729188 DOI: 10.3389/fonc.2020.602217] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs.
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27
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Wang B, Xu X, Liu X, Wang D, Zhuang H, He X, Han T, Hong J. Enolase-phosphatase 1 acts as an oncogenic driver in glioma. J Cell Physiol 2020; 236:1184-1194. [PMID: 32654229 DOI: 10.1002/jcp.29926] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 07/01/2020] [Indexed: 12/15/2022]
Abstract
Enolase-phosphatase 1 (ENOPH1), a newly identified enzyme involved in l-methionine biosynthesis, is associated with anxiety and depression. In this study, ENOPH1 was found to play a crucial role in promoting the proliferation and migration of glioma cells. Among high-grade glioma patients, the overall survival of the group showing high ENOPH1 expression was shorter than that of the group showing low ENOPH1 expression. ENOPH1 knockdown inhibited glioma cell proliferation and migration. In parallel, ENOPH1 knockdown suppressed tumor growth capacity and prolonged survival in an orthotopic glioma model. Mechanistically, we found that ENOPH1 activates the PI3K/AKT/mTOR signaling pathway by regulating THEM4. In conclusion, ENOPH1 is an important mediator that promotes glioma cell proliferation and migration.
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Affiliation(s)
- Bo Wang
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, Tianjin, China.,State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Xin Xu
- Department of Neurosurgery, Xuanwu Hospital, International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Xi Liu
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, China
| | - Dong Wang
- Department of Neurosurgery, Tianjin Medical University, General Hospital, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of Nervous System, Tianjin Neurological Institute, Tianjin, China
| | - Hao Zhuang
- Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Xin He
- Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia.,Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin
| | - Tong Han
- Department of Medical Imaging, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, Tianjin, China
| | - Jian Hong
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, Tianjin, China
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28
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Jung E, Alfonso J, Monyer H, Wick W, Winkler F. Neuronal signatures in cancer. Int J Cancer 2020; 147:3281-3291. [PMID: 32510582 DOI: 10.1002/ijc.33138] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/26/2020] [Accepted: 06/02/2020] [Indexed: 12/14/2022]
Abstract
Despite advances in the treatment of solid tumors, the prognosis of patients with many cancers remains poor, particularly of those with primary and metastatic brain tumors. In the last years, "Cancer Neuroscience" emerged as novel field of research at the crossroads of oncology and classical neuroscience. In primary brain tumors, including glioblastoma (GB), communicating networks that render tumor cells resistant against cytotoxic therapies were identified. To build these networks, GB cells extend neurite-like protrusions called tumor microtubes (TMs). Synapses on TMs allow tumor cells to retrieve neuronal input that fosters growth. Single cell sequencing further revealed that primary brain tumors recapitulate many steps of neurodevelopment. Interestingly, neuronal characteristics, including the ability to extend neurite-like protrusions, neuronal gene expression signatures and interactions with neurons, have now been found not only in brain and neuroendocrine tumors but also in some cancers of epithelial origin. In this review, we will provide an overview about neurite-like protrusions as well as neurodevelopmental origins, hierarchies and gene expression signatures in cancer. We will also discuss how "Cancer Neuroscience" might provide a framework for the development of novel therapies.
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Affiliation(s)
- Erik Jung
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Julieta Alfonso
- Department of Clinical Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hannah Monyer
- Department of Clinical Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Clinical Neurobiology, Medical Faculty, Heidelberg University, Heidelberg, Germany
| | - Wolfgang Wick
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Winkler
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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29
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Wang B, Cao C, Liu X, He X, Zhuang H, Wang D, Chen B. BRCA1-associated protein inhibits glioma cell proliferation and migration and glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway. Cell Oncol (Dordr) 2019; 43:223-235. [PMID: 31776938 DOI: 10.1007/s13402-019-00482-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2019] [Indexed: 01/24/2023] Open
Abstract
PURPOSE BRCA1-associated protein (BRAP) was first identified by its ability to bind to the nuclear localization signalling motif of BRCA1 and other proteins. Subsequently, human BRAP has been found to exert multiple functions, many of which are related to cancer development. Up till now, however, the role of BRAP in glioma development has remained obscure. Here, we report a role for BRAP in mediating the proliferation and migration of glioma cells both in vitro and in vivo. METHODS The expression of BRAP in 98 glioma patient samples was determined by immunohistochemistry, after which associations between BRAP expression and patient prognosis were assessed. A short hairpin RNA (shRNA) was used to knock down BRAP and an expression vector was used to exogenously overexpress BRAP in glioma cells. The effects of BRAP expression on tumour cell behaviour in vitro and in an in vivo xenograft mouse model were examined. RESULTS We found that in glioma patients BRAP expression was associated with a favourable prognosis. We also found that shRNA-mediated knockdown of BRAP facilitated the proliferation and migration of glioma cells and the self-renewal of glioma stem cells. In parallel, we found that BRAP knockdown increased tumour growth and invasion and decreased survival in an in vivo glioma xenograft mouse model. Mechanistically, we found that BRAP inhibited glioma cell proliferation and migration, as well as glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway. CONCLUSIONS Together, our findings identify BRAP as a mediator of glioma cell proliferation, migration and glioma stem cell self-renewal.
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Affiliation(s)
- Bo Wang
- Department of Neurosurgery, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China.,State Key Laboratory of Medicinal Chemical Biology, Nankai University, No.94 Weijin Road, Tianjin, 300071, China
| | - Chen Cao
- Department of Medical Imaging, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China
| | - Xi Liu
- Department of Gastroenterology, Tianjin Nankai Hospital, No.6 Changjiang Road, Tianjin, 300100, China
| | - Xin He
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Hao Zhuang
- Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, 450008, Henan Province, China.
| | - Dong Wang
- Department of Neurosurgery, General Hospital; Tianjin Key Laboratory of Injuries, Variations, and Regeneration of Nervous System; Tianjin Neurological Institute, Tianjin Medical University, No.154 Anshan Road, Tianjin, 300052, China.
| | - Budong Chen
- Department of Neurosurgery, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China.
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30
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Jung E, Alfonso J, Osswald M, Monyer H, Wick W, Winkler F. Emerging intersections between neuroscience and glioma biology. Nat Neurosci 2019; 22:1951-1960. [PMID: 31719671 DOI: 10.1038/s41593-019-0540-y] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 10/17/2019] [Indexed: 12/22/2022]
Abstract
The establishment of neuronal and glial networks in the brain depends on the activities of neural progenitors, which are influenced by cell-intrinsic mechanisms, interactions with the local microenvironment and long-range signaling. Progress in neuroscience has helped identify key factors in CNS development. In parallel, studies in recent years have increased our understanding of molecular and cellular factors in the development and growth of primary brain tumors. To thrive, glioma cells exploit pathways that are active in normal CNS progenitor cells, as well as in normal neurotransmitter signaling. Furthermore, tumor cells of incurable gliomas integrate into communicating multicellular networks, where they are interconnected through neurite-like cellular protrusions. In this Review, we discuss evidence that CNS development, organization and function share a number of common features with glioma progression and malignancy. These include mechanisms used by cells to proliferate and migrate, interact with their microenvironment and integrate into multicellular networks. The emerging intersections between the fields of neuroscience and neuro-oncology considered in this review point to new research directions and novel therapeutic opportunities.
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Affiliation(s)
- Erik Jung
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, Heidelberg, Germany.,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Julieta Alfonso
- Department of Clinical Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias Osswald
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, Heidelberg, Germany.,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hannah Monyer
- Department of Clinical Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Clinical Neurobiology, Medical Faculty, Heidelberg University, Heidelberg, Germany
| | - Wolfgang Wick
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, Heidelberg, Germany.,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Winkler
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, Heidelberg, Germany. .,Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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31
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Sharifi Z, Abdulkarim B, Meehan B, Rak J, Daniel P, Schmitt J, Lauzon N, Eppert K, Duncan HM, Petrecca K, Guiot MC, Jean-Claude B, Sabri S. Mechanisms and Antitumor Activity of a Binary EGFR/DNA-Targeting Strategy Overcomes Resistance of Glioblastoma Stem Cells to Temozolomide. Clin Cancer Res 2019; 25:7594-7608. [PMID: 31540977 DOI: 10.1158/1078-0432.ccr-19-0955] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/21/2019] [Accepted: 09/18/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contribute to resistance to the DNA-damaging chemotherapy, temozolomide. The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs. We aimed to investigate EGFR/DNA combi-targeting in GBM. EXPERIMENTAL DESIGN ZR2002 is a "combi-molecule" designed to inflict DNA damage through its chlorethyl moiety and induce irreversible EGFR tyrosine kinase inhibition. We assessed its in vitro efficacy in temozolomide-resistant patient-derived GSCs, mesenchymal temozolomide-sensitive and resistant in vivo-derived GSC sublines, and U87/EGFR isogenic cell lines stably expressing EGFR/wild-type or variant III (EGFRvIII). We evaluated its antitumor activity in mice harboring orthotopic EGFRvIII or mesenchymal TMZ-resistant GSC tumors. RESULTS ZR2002 induced submicromolar antiproliferative effects and inhibited neurosphere formation of all GSCs with marginal effects on normal human astrocytes. ZR2002 inhibited EGF-induced autophosphorylation of EGFR, downstream Erk1/2 phosphorylation, increased DNA strand breaks, and induced activation of wild-type p53; the latter was required for its cytotoxicity through p53-dependent mechanism. ZR2002 induced similar effects on U87/EGFR cell lines and its oral administration significantly increased survival in an orthotopic EGFRvIII mouse model. ZR2002 improved survival of mice harboring intracranial mesenchymal temozolomide-resistant GSC line, decreased EGFR, Erk1/2, and AKT phosphorylation and was detected in tumor brain tissue by MALDI imaging mass spectrometry. CONCLUSIONS These findings provide the molecular basis of binary EGFR/DNA targeting and uncover the oral bioavailability, blood-brain barrier permeability, and antitumor activity of ZR2002 supporting potential evaluation of this first-in-class drug in recurrent GBM.
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Affiliation(s)
- Zeinab Sharifi
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.,Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Bassam Abdulkarim
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.,Department of Oncology, McGill University, Montreal, Quebec, Canada
| | - Brian Meehan
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Janusz Rak
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Paul Daniel
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.,Department of Oncology, McGill University, Montreal, Quebec, Canada
| | - Julie Schmitt
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Nidia Lauzon
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Kolja Eppert
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Heather M Duncan
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.,Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Kevin Petrecca
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Marie-Christine Guiot
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.,Department of Pathology, McGill University, Montreal, Quebec, Canada
| | - Bertrand Jean-Claude
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Siham Sabri
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada. .,Department of Pathology, McGill University, Montreal, Quebec, Canada
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32
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11PS04 is a new chemical entity identified by microRNA-based biosensing with promising therapeutic potential against cancer stem cells. Sci Rep 2019; 9:11916. [PMID: 31417117 PMCID: PMC6695485 DOI: 10.1038/s41598-019-48359-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 07/31/2019] [Indexed: 02/07/2023] Open
Abstract
Phenotypic drug discovery must take advantage of the large amount of clinical data currently available. In this sense, the impact of microRNAs (miRs) on human disease and clinical therapeutic responses is becoming increasingly well documented. Accordingly, it might be possible to use miR-based signatures as phenotypic read-outs of pathological status, for example in cancer. Here, we propose to use the information accumulating regarding the biology of miRs from clinical research in the preclinical arena, adapting it to the use of miR biosensors in the earliest steps of drug screening. Thus, we have used an amperometric dual magnetosensor capable of monitoring a miR-21/miR-205 signature to screen for new drugs that restore these miRs to non-tumorigenic levels in cell models of breast cancer and glioblastoma. In this way we have been able to identify a new chemical entity, 11PS04 ((3aR,7aS)-2-(3-propoxyphenyl)-7,7a-dihydro-3aH-pyrano[3,4-d]oxazol-6(4H)-one), the therapeutic potential of which was suggested in mechanistic assays of disease models, including 3D cell culture (oncospheres) and xenografts. These assays highlighted the potential of this compound to attack cancer stem cells, reducing the growth of breast and glioblastoma tumors in vivo. These data demonstrate the enhanced chain of translatability of this strategy, opening up new perspectives for drug-discovery pipelines and highlighting the potential of miR-based electro-analytical sensors as efficient tools in modern drug discovery.
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33
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A reignited debate over the cell(s) of origin for glioblastoma and its clinical implications. Front Med 2019; 13:531-539. [DOI: 10.1007/s11684-019-0700-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/21/2019] [Indexed: 01/08/2023]
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34
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Shin YJ, Sa JK, Lee Y, Kim D, Chang N, Cho HJ, Son M, Oh MYT, Shin K, Lee JK, Park J, Jo YK, Kim M, Paddison PJ, Tergaonkar V, Lee J, Nam DH. PIP4K2A as a negative regulator of PI3K in PTEN -deficient glioblastoma. J Exp Med 2019; 216:1120-1134. [PMID: 30898893 PMCID: PMC6504209 DOI: 10.1084/jem.20172170] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 08/20/2018] [Accepted: 02/27/2019] [Indexed: 01/01/2023] Open
Abstract
Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.
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Affiliation(s)
- Yong Jae Shin
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jason K Sa
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Yeri Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Donggeon Kim
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | | | - Hee Jin Cho
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Miseol Son
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Division of Cancer Cell Signaling, Institute of Molecular and Cell Biology, Singapore
| | - Michael Y T Oh
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
| | - Kayoung Shin
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea
| | - Jin-Ku Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Jiwon Park
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
| | - Yoon Kyung Jo
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Misuk Kim
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Patrick J Paddison
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Vinay Tergaonkar
- Division of Cancer Cell Signaling, Institute of Molecular and Cell Biology, Singapore
- Department of Pathology, National University of Singapore, Singapore
| | - Jeongwu Lee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Do-Hyun Nam
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea
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35
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Garnier D, Meehan B, Kislinger T, Daniel P, Sinha A, Abdulkarim B, Nakano I, Rak J. Divergent evolution of temozolomide resistance in glioblastoma stem cells is reflected in extracellular vesicles and coupled with radiosensitization. Neuro Oncol 2019; 20:236-248. [PMID: 29016925 DOI: 10.1093/neuonc/nox142] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Background Glioblastoma (GBM) is almost invariably fatal due to failure of standard therapy. The relapse of GBM following surgery, radiation, and systemic temozolomide (TMZ) is attributed to the ability of glioma stem cells (GSCs) to survive, evolve, and repopulate the tumor mass, events on which therapy exerts a poorly understood influence. Methods Here we explore the molecular and cellular evolution of TMZ resistance as it emerges in vivo (xenograft models) in a series of human GSCs with either proneural (PN) or mesenchymal (MES) molecular characteristics. Results We observed that the initial response of GSC-initiated intracranial xenografts to TMZ is eventually replaced by refractory growth pattern. Individual tumors derived from the same isogenic GSC line expressed divergent and complex profiles of TMZ resistance markers, with a minor representation of O6-methylguanine DNA methyltransferase (MGMT) upregulation. In several independent TMZ-resistant tumors originating from MES GSCs we observed a consistent diminution of mesenchymal features, which persisted in cell culture and correlated with increased expression of Nestin, decline in transglutaminase 2 and sensitivity to radiation. The corresponding mRNA expression profiles reflective of TMZ resistance and stem cell phenotype were recapitulated in the transcriptome of exosome-like extracellular vesicles (EVs) released by GSCs into the culture medium. Conclusions Intrinsic changes in the tumor-initiating cell compartment may include loss of subtype characteristics and reciprocal alterations in sensitivity to chemo- and radiation therapy. These observations suggest that exploiting therapy-induced changes in the GSC phenotype and alternating cycles of therapy may be explored to improve GBM outcomes.
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Affiliation(s)
- Delphine Garnier
- McGill University, Research Institute of the McGill University Health Centre (RIMUHC), Montreal, Quebec, Canada.,CRCINA INSERM U1232, Institut de Recherche en Santé de l'Université de Nantes, Nantes Cedex, France
| | - Brian Meehan
- McGill University, Research Institute of the McGill University Health Centre (RIMUHC), Montreal, Quebec, Canada
| | - Thomas Kislinger
- Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Paul Daniel
- McGill University, Research Institute of the McGill University Health Centre (RIMUHC), Montreal, Quebec, Canada
| | - Ankit Sinha
- Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Bassam Abdulkarim
- McGill University, Research Institute of the McGill University Health Centre (RIMUHC), Montreal, Quebec, Canada
| | - Ichiro Nakano
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Janusz Rak
- McGill University, Research Institute of the McGill University Health Centre (RIMUHC), Montreal, Quebec, Canada
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Lagadec C, Toillon RA, Le Bourhis X. WhatsApp com between glioma stem cells and differentiated cells to sustain tumor growth. Stem Cell Investig 2018; 5:28. [PMID: 30363752 DOI: 10.21037/sci.2018.08.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 08/27/2018] [Indexed: 11/06/2022]
Affiliation(s)
- Chann Lagadec
- INSERM U908 "Cell Plasticity and Cancer", University of Lille, Lille, France
| | | | - Xuefen Le Bourhis
- INSERM U908 "Cell Plasticity and Cancer", University of Lille, Lille, France
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Vastrad C, Vastrad B. Bioinformatics analysis of gene expression profiles to diagnose crucial and novel genes in glioblastoma multiform. Pathol Res Pract 2018; 214:1395-1461. [PMID: 30097214 DOI: 10.1016/j.prp.2018.07.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 06/27/2018] [Accepted: 07/22/2018] [Indexed: 02/07/2023]
Abstract
Therefore, the current study aimed to diagnose the genes associated in the pathogenesis of GBM. The differentially expressed genes (DEGs) were diagnosed using the limma software package. The ToppFun was used to perform pathway and Gene Ontology (GO) enrichment analysis of the DEGs. Protein-protein interaction (PPI) networks, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network were used to obtain insight into the actions of DEGs. Survival analysis for DEGs carried out. A total of 701 DEGs, including 413 upregulated and 288 downregulated genes, were diagnosed between U1118MG cell line (PK 11195 treated with 1 h exposure) and U1118MG cell line (PK 11195 treated with 24 h exposure). The up-regulated genes were enriched in superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis, cell cycle, cell cycle process and chromosome. The down-regulated genes were enriched in folate transformations I, biosynthesis of amino acids, cellular amino acid metabolic process and vacuolar membrane. The current study screened the genes in PPI network, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network with higher degrees as hub genes, which included MYC, TERF2IP, CDK1, EEF1G, TXNIP, SLC1A5, RGS4 and IER5L Survival suggested that low expressed NR4A2, SLC7 A5, CYR61 and ID1 in patients with GBM was linked with a positive prognosis for overall survival. In conclusion, the current study could improve our understanding of the molecular mechanisms in the progression of GBM, and these crucial as well as new molecular markers might be used as therapeutic targets for GBM.
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Affiliation(s)
- Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad, 580001, Karanataka, India.
| | - Basavaraj Vastrad
- Department of Pharmaceutics, SET`S College of Pharmacy, Dharwad, Karnataka, 580002, India
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Hira VV, Aderetti DA, van Noorden CJ. Glioma Stem Cell Niches in Human Glioblastoma Are Periarteriolar. J Histochem Cytochem 2018; 66:349-358. [PMID: 29328867 PMCID: PMC5958355 DOI: 10.1369/0022155417752676] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 12/11/2017] [Indexed: 12/22/2022] Open
Abstract
Survival of primary brain tumor (glioblastoma) patients is seriously hampered by glioma stem cells (GSCs) that are distinct therapy-resistant self-replicating pluripotent cancer cells. GSCs reside in GSC niches, which are specific protective microenvironments in glioblastoma tumors. We have recently found that GSC niches are hypoxic periarteriolar, whereas in most studies, GSC niches are identified as hypoxic perivascular. The aim of this review is to critically evaluate the literature on perivascular GSC niches to establish whether these are periarteriolar, pericapillary, perivenular, and/or perilymphatic. We found six publications showing images of human glioblastoma tissue containing perivascular GSC niches without any specification of the vessel type. However, it is frequently assumed that these vessels are capillaries which are exchange vessels, whereas arterioles and venules are transport vessels. Closer inspection of the figures of these publications showed vessels that were not capillaries. Whether these vessels were arterioles or venules was difficult to determine in one case, but in the other cases, these were clearly arterioles and their perivascular niches were similar to the periarteriolar niches we have found. Therefore, we conclude that in human glioblastoma tumors, GSC niches are hypoxic periarteriolar and are structurally and functionally look-alikes of hematopoietic stem cell niches in the bone marrow.
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Affiliation(s)
- Vashendriya V.V. Hira
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Diana A. Aderetti
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis J.F. van Noorden
- Cancer Center Amsterdam, Department of Medical Biology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Aderetti DA, Hira VVV, Molenaar RJ, van Noorden CJF. The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastoma. Biochim Biophys Acta Rev Cancer 2018; 1869:346-354. [PMID: 29684521 DOI: 10.1016/j.bbcan.2018.04.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 04/17/2018] [Accepted: 04/18/2018] [Indexed: 12/22/2022]
Abstract
Glioblastoma is the most lethal primary brain tumor and poor survival of glioblastoma patients is attributed to the presence of glioma stem cells (GSCs). These therapy-resistant, quiescent and pluripotent cells reside in GSC niches, which are specific microenvironments that protect GSCs against radiotherapy and chemotherapy. We previously showed the existence of hypoxic peri-arteriolar GSC niches in glioblastoma tumor samples. However, other studies have described peri-vascular niches, peri-hypoxic niches, peri-immune niches and extracellular matrix niches of GSCs. The aim of this review was to critically evaluate the literature on these five different types of GSC niches. In the present review, we describe that the five niche types are not distinct from one another, but should be considered to be parts of one integral GSC niche model, the hypoxic peri-arteriolar GSC niche. Moreover, hypoxic peri-arteriolar GSC niches are structural and functional look-alikes of hematopoietic stem cell (HSC) niches in the bone marrow. GSCs are maintained in peri-arteriolar niches by the same receptor-ligand interactions as HSCs in bone marrow. Our concept should be rigidly tested in the near future and applied to develop therapies to expel and keep GSCs out of their protective niches to render them more vulnerable to standard therapies.
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Affiliation(s)
- Diana A Aderetti
- Department of Medical Biology, Cancer Center Amsterdam at the Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Vashendriya V V Hira
- Department of Medical Biology, Cancer Center Amsterdam at the Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Remco J Molenaar
- Department of Medical Biology, Cancer Center Amsterdam at the Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands; Department of Medical Oncology, Cancer Center Amsterdam at the Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Cornelis J F van Noorden
- Department of Medical Biology, Cancer Center Amsterdam at the Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands; Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia.
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Lowenstein PR, Castro MG. Evolutionary basis of a new gene- and immune-therapeutic approach for the treatment of malignant brain tumors: from mice to clinical trials for glioma patients. Clin Immunol 2018; 189:43-51. [PMID: 28720549 PMCID: PMC5768465 DOI: 10.1016/j.clim.2017.07.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/14/2017] [Accepted: 07/14/2017] [Indexed: 02/06/2023]
Abstract
Glioma cells are one of the most aggressive and malignant tumors. Following initial surgery, and radio-chemotherapy they progress rapidly, so that patients' median survival remains under two years. They invade throughout the brain, which makes them difficult to treat, and are universally lethal. Though total resection is always attempted it is not curative. Standard of care in 2016 comprises surgical resection, radiotherapy and chemotherapy (temozolomide). Median survival is currently ~14-20months post-diagnosis though it can be higher in high complexity medical university centers, or during clinical trials. Why the immune system fails to recognize the growing brain tumor is not completely understood. We believe that one reason for this failure is that the brain lacks cells that perform the role that dendritic cells serve in other organs. The lack of functional dendritic cells from the brain causes the brain to be deficient in priming systemic immune responses to glioma antigens. To overcome this drawback we reconstituted the brain immune system for it to initiate and prime anti-glioma immune responses from within the brain. To achieve brain immune reconstitution adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1 derived thymidine kinase which converts ganciclovir into phospho-ganciclovir which becomes cytotoxic to dividing cells. The second adenovirus expresses the cytokine fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L differentiates precursors into dendritic cells and acts as a chemokine for dendritic cells. This results in HSV-1/ganciclovir killing of tumor cells, and the release of tumor antigens, which are then taken up by dendritic cells recruited to the brain tumor microenvironment by Flt3L. Concomitant release of HMGB1, a TLR2 agonist that activates dendritic cells, stimulates dendritic cells loaded with glioma antigens to migrate to the cervical lymph nodes to prime a systemic CD8+ T cytotoxic killing of brain tumor cells. This induced immune response causes glioma-specific cytotoxicity, induces immunological memory, and does not cause brain toxicity or autoimmunity. A Phase I Clinical Trial, to test our hypothesis in human patients, was opened in December 2013 (see: NCT01811992, Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma, at ClinicalTrials.gov). This trial is a first in human trial to test whether the re-engineering of the brain immune system can serve to treat malignant brain tumors. The long and winding road from the laboratory to the clinical trial follows below.
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Affiliation(s)
- Pedro R Lowenstein
- Department of Neurosurgery, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States; Department of Cell and Developmental Biology, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States.
| | - Maria G Castro
- Department of Neurosurgery, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States; Department of Cell and Developmental Biology, The University of Michigan, The Medical School, Ann Arbor, Michigan, United States
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Shao F, Liu C. Revisit the Candidacy of Brain Cell Types as the Cell(s) of Origin for Human High-Grade Glioma. Front Mol Neurosci 2018. [PMID: 29515370 PMCID: PMC5826356 DOI: 10.3389/fnmol.2018.00048] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
High-grade glioma, particularly, glioblastoma, is the most aggressive cancer of the central nervous system (CNS) in adults. Due to its heterogeneous nature, glioblastoma almost inevitably relapses after surgical resection and radio-/chemotherapy, and is thus highly lethal and associated with a dismal prognosis. Identifying the cell of origin has been considered an important aspect in understanding tumor heterogeneity, thereby holding great promise in designing novel therapeutic strategies for glioblastoma. Taking advantage of genetic lineage-tracing techniques, performed mainly on genetically engineered mouse models (GEMMs), multiple cell types in the CNS have been suggested as potential cells of origin for glioblastoma, among which adult neural stem cells (NSCs) and oligodendrocyte precursor cells (OPCs) are the major candidates. However, it remains highly debated whether these cell types are equally capable of transforming in patients, given that in the human brain, some cell types divide so slowly, therefore may never have a chance to transform. With the recent advances in studying adult NSCs and OPCs, particularly from the perspective of comparative biology, we now realize that notable differences exist among mammalian species. These differences have critical impacts on shaping our understanding of the cell of origin of glioma in humans. In this perspective, we update the current progress in this field and clarify some misconceptions with inputs from important findings about the biology of adult NSCs and OPCs. We propose to re-evaluate the cellular origin candidacy of these cells, with an emphasis on comparative studies between animal models and humans.
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Affiliation(s)
- Fangjie Shao
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Chong Liu
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
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42
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Patyka M, Sharifi Z, Petrecca K, Mansure J, Jean-Claude B, Sabri S. Sensitivity to PRIMA-1MET is associated with decreased MGMT in human glioblastoma cells and glioblastoma stem cells irrespective of p53 status. Oncotarget 2018; 7:60245-60269. [PMID: 27533246 PMCID: PMC5312382 DOI: 10.18632/oncotarget.11197] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 07/18/2016] [Indexed: 12/20/2022] Open
Abstract
Alterations of the TP53 tumor suppressor gene occur in ~30% of primary glioblastoma (GBM) with a high frequency of missense mutations associated with the acquisition of oncogenic “gain-of-function” (GOF) mutant (mut)p53 activities. PRIMA-1MET/APR-246, emerged as a promising compound to rescue wild-type (wt)p53 function in different cancer types. Previous studies suggested the role of wtp53 in the negative regulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), a major determinant in resistance to therapy in GBM treatment. The potential role of MGMT in expression of p53 and the efficacy of PRIMA-1MET with respect to TP53 status and expression of MGMT in GBM remain unknown. We investigated response to PRIMA-1MET of wtp53/MGMT-negative (U87MG, A172), mutp53/MGMT-positive U138, LN-18, T98/Empty vector (T98/EV) and its isogenic MGMT/shRNA gene knockdown counterpart (T98/shRNA). We show that MGMT silencing decreased expression of mutp53/GOF in T98/shRNA. PRIMA-1MET further cleared T98/shRNA cells of mutp53, decreased proliferation and clonogenic potential, abrogated the G2 checkpoint control, increased susceptibility to apoptotic cell death, expression of GADD45A and sustained expression of phosphorylated Erk1/2. PRIMA-1MET increased expression of p21 protein in U87MG and A172 and promoted senescence in U87MG cell line. Importantly, PRIMA-1MET decreased relative cell numbers, disrupted the structure of neurospheres of patient-derived GBM stem cells (GSCs) and enabled activation of wtp53 with decreased expression of MGMT in MGMT-positive GSCs or decreased expression of mutp53. Our findings highlight the cell-context dependent effects of PRIMA-1MET irrespective of p53 status and suggest the role of MGMT as a potential molecular target of PRIMA-1MET in MGMT-positive GSCs.
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Affiliation(s)
- Mariia Patyka
- Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Zeinab Sharifi
- Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Kevin Petrecca
- Department of Neurology and Neurosurgery, McGill University, The Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
| | - Jose Mansure
- Department of Urologic Oncology Research, McGill University Health Centre, Montreal, Quebec, Canada
| | - Bertrand Jean-Claude
- Department of Medicine, Division of Experimental Medicine, McGill University, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Siham Sabri
- Department of Oncology, Division of Radiation Oncology, McGill University, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
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Zhu W, Krishna S, Garcia C, Lin CCJ, Mitchell BD, Scott KL, Mohila CA, Creighton CJ, Yoo SH, Lee HK, Deneen B. Daam2 driven degradation of VHL promotes gliomagenesis. eLife 2017; 6. [PMID: 29053101 PMCID: PMC5650470 DOI: 10.7554/elife.31926] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 09/26/2017] [Indexed: 01/01/2023] Open
Abstract
Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis. Glioblastoma is the deadliest form of brain cancer, and the rate of patient survival has not significantly improved over the past 70 years. This cancer arises when glial cells, which provide support and insulation to nerve cells, develop mutations that alter the activity of certain genes or alter the role they play in cells. However, there are also several key genes linked to glioblastomas that don’t exhibit mutations, such as the gene that encodes the Von Hippel Landau protein (or VHL for short). This protein normally helps to protect us from developing cancer, but it is not clear how this protein is prevented from performing this role in glioblastomas. One possibility is that proteins that regulate how cells grow and develop may control VHL. For example, a protein called Daam2 plays a critical role in a signaling pathway that is required for glial cell development. Zhu et al. used biochemical techniques to study Daam2 and VHL in both human cells and mouse models of glioblastoma. The experiments show that glioblastoma cells have lower levels of VHL compared to normal cells. This decrease is caused by Daam 2, which interacts with VHL and promotes its degradation. Further experiments found that in several different types of cancer, higher levels of Daam2 are linked with the presence of lower levels of VHL. These findings indicate that the interaction between Daam2 and VHL could be a new target for drugs to treat glioblastoma and possibly other forms of cancer. Daam2 and VHL have also been linked to multiple sclerosis, cerebral palsy and other diseases that affect the nervous system. Therefore, understanding how these proteins interact may also help to develop new treatments for these conditions.
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Affiliation(s)
- Wenyi Zhu
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States.,The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United States
| | - Saritha Krishna
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States
| | - Cristina Garcia
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States
| | - Chia-Ching John Lin
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States
| | - Bartley D Mitchell
- Department of Neurosurgery, Baylor College of Medicine, Houston, United States
| | - Kenneth L Scott
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, United States
| | - Carrie A Mohila
- Department of Pathology, Texas Children's Hospital, Houston, United States
| | - Chad J Creighton
- Dan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, United States.,Department of Medicine, Baylor College of Medicine, Houston, United States
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, The University of Texas Heath Science Center at Houston, Houston, United States
| | - Hyun Kyoung Lee
- Department of Pediatrics, Division of Neurology, Baylor College of Medicine, Houston, United States.,Neurological Research Institute, Texas Children's Hospital, Houston, United States.,Department of Neuroscience, Baylor College of Medicine, Houston, United States
| | - Benjamin Deneen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States.,The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United States.,Neurological Research Institute, Texas Children's Hospital, Houston, United States.,Department of Neuroscience, Baylor College of Medicine, Houston, United States
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Jahan N, Lee JM, Shah K, Wakimoto H. Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus. Int J Cancer 2017; 141:1671-1681. [PMID: 28567859 PMCID: PMC5796532 DOI: 10.1002/ijc.30811] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 02/21/2017] [Accepted: 05/15/2017] [Indexed: 01/14/2023]
Abstract
Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial.
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Affiliation(s)
- Nusrat Jahan
- Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Jae M. Lee
- Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Khalid Shah
- Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138
| | - Hiroaki Wakimoto
- Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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Sharma V, Malgulwar PB, Purkait S, Patil V, Pathak P, Agrawal R, Kulshreshtha R, Mallick S, Julka PK, Suri A, Sharma BS, Suri V, Sharma MC, Sarkar C. Genome-wide ChIP-seq analysis of EZH2-mediated H3K27me3 target gene profile highlights differences between low- and high-grade astrocytic tumors. Carcinogenesis 2017; 38:152-161. [PMID: 27993893 DOI: 10.1093/carcin/bgw126] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 11/30/2016] [Indexed: 01/19/2023] Open
Abstract
Enhancer of zeste homolog-2(EZH2) is a key epigenetic regulator that functions as oncogene and also known for inducing altered trimethylation of histone at lysine-27 (H3K27me3) mark in various tumors. However, H3K27me3 targets and their precise relationship with gene expression are largely unknown in astrocytic tumors. In this study, we checked EZH2 messenger RNA and protein expression in 90 astrocytic tumors of different grades using quantitative PCR and immunohistochemistry, respectively. Further, genome-wide ChIP-seq analysis for H3K27me3 modification was also performed on 11 glioblastomas (GBMs) and 2 diffuse astrocytoma (DA) samples. Our results showed EZH2 to be highly overexpressed in astrocytic tumors with a significant positive correlation with grade. Interestingly, ChIP-seq mapping revealed distinct differences in genes and pathways targeted by these H3K27me3 modifications between GBM versus DA. Neuroactive ligand receptor pathway was found most enriched in GBM (P = 9.4 × 10-25), whereas DA were found to be enriched in metabolic pathways. Also, GBM showed a higher enrichment of H3K27me3 targets reported in embryonic stem cells and glioma stem cells as compared with DAs. Our results show majority of these H3K27me3 target genes were downregulated, not only due to H3K27me3 modification but also due to concomitant DNA methylation. Further, H3K27me3 modification-associated gene silencing was not restricted to promoter but also present in gene body and transcription start site regions. To the best of our knowledge, this is the first high-resolution genome-wide mapping of H3K27me3 modification in adult astrocytic primary tissue samples of human, highlighting the differences between grades. Interestingly, we identified SLC25A23 as important target of H3K27me3 modification, which was downregulated in GBM and its low expression was associated with poor prognosis in GBMs.
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Affiliation(s)
- Vikas Sharma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Prit Benny Malgulwar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Suvendu Purkait
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Vikas Patil
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, Karnataka, India
| | - Pankaj Pathak
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Rahul Agrawal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi 110016, India
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi 110016, India
| | | | | | - Ashish Suri
- Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Bhawani Shankar Sharma
- Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Vaishali Suri
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Mehar Chand Sharma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Chitra Sarkar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
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46
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NSPc1 promotes cancer stem cell self-renewal by repressing the synthesis of all-trans retinoic acid via targeting RDH16 in malignant glioma. Oncogene 2017; 36:4706-4718. [DOI: 10.1038/onc.2017.34] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 12/17/2016] [Accepted: 01/05/2017] [Indexed: 12/26/2022]
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O'Duibhir E, Carragher NO, Pollard SM. Accelerating glioblastoma drug discovery: Convergence of patient-derived models, genome editing and phenotypic screening. Mol Cell Neurosci 2017; 80:198-207. [PMID: 27825983 PMCID: PMC6128397 DOI: 10.1016/j.mcn.2016.11.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 10/05/2016] [Accepted: 11/02/2016] [Indexed: 12/27/2022] Open
Abstract
Patients diagnosed with glioblastoma (GBM) continue to face a bleak prognosis. It is critical that new effective therapeutic strategies are developed. GBM stem cells have molecular hallmarks of neural stem and progenitor cells and it is possible to propagate both non-transformed normal neural stem cells and GBM stem cells, in defined, feeder-free, adherent culture. These primary stem cell lines provide an experimental model that is ideally suited to cell-based drug discovery or genetic screens in order to identify tumour-specific vulnerabilities. For many solid tumours, including GBM, the genetic disruptions that drive tumour initiation and growth have now been catalogued. CRISPR/Cas-based genome editing technologies have recently emerged, transforming our ability to functionally annotate the human genome. Genome editing opens prospects for engineering precise genetic changes in normal and GBM-derived neural stem cells, which will provide more defined and reliable genetic models, with critical matched pairs of isogenic cell lines. Generation of more complex alleles such as knock in tags or fluorescent reporters is also now possible. These new cellular models can be deployed in cell-based phenotypic drug discovery (PDD). Here we discuss the convergence of these advanced technologies (iPS cells, neural stem cell culture, genome editing and high content phenotypic screening) and how they herald a new era in human cellular genetics that should have a major impact in accelerating glioblastoma drug discovery.
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Affiliation(s)
- Eoghan O'Duibhir
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Institute of Genetics and Molecular Medicine, CRUK Edinburgh Centre, University of Edinburgh, UK
| | - Neil O Carragher
- Institute of Genetics and Molecular Medicine, CRUK Edinburgh Centre, University of Edinburgh, UK.
| | - Steven M Pollard
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Institute of Genetics and Molecular Medicine, CRUK Edinburgh Centre, University of Edinburgh, UK.
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48
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Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells. Sci Rep 2017; 7:44075. [PMID: 28287096 PMCID: PMC5347040 DOI: 10.1038/srep44075] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 02/02/2017] [Indexed: 01/12/2023] Open
Abstract
Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.
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John Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Zhang Y, Zhu W, Mohila CA, Ahmed N, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, Deneen B. Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 2017; 20:396-405. [PMID: 28166219 PMCID: PMC5824716 DOI: 10.1038/nn.4493] [Citation(s) in RCA: 385] [Impact Index Per Article: 48.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 12/28/2016] [Indexed: 12/14/2022]
Abstract
Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting-based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to synaptogenesis and tumor pathophysiology, providing a blueprint for understanding diverse astrocyte contributions to neurological disease.
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Affiliation(s)
- Chia-Ching John Lin
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Kwanha Yu
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Asante Hatcher
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
| | - Teng-Wei Huang
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Hyun Kyoung Lee
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
- Neurological Research Institute at Texas' Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
- Department of Pediatrics, Division of Neurology, Texas Children's Hospital, Houston, Texas, USA
| | - Jeffrey Carlson
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Matthew C Weston
- Department of Neurological Sciences, University of Vermont, Vermont, Vermont, USA
| | - Fengju Chen
- Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas, USA
| | - Yiqun Zhang
- Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas, USA
| | - Wenyi Zhu
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Carrie A Mohila
- Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Nabil Ahmed
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
| | - Akash J Patel
- Neurological Research Institute at Texas' Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA
| | - Benjamin R Arenkiel
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
- Neurological Research Institute at Texas' Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Jeffrey L Noebels
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
| | - Chad J Creighton
- Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Benjamin Deneen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
- Neurological Research Institute at Texas' Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA
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50
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Bressan RB, Dewari PS, Kalantzaki M, Gangoso E, Matjusaitis M, Garcia-Diaz C, Blin C, Grant V, Bulstrode H, Gogolok S, Skarnes WC, Pollard SM. Efficient CRISPR/Cas9-assisted gene targeting enables rapid and precise genetic manipulation of mammalian neural stem cells. Development 2017; 144:635-648. [PMID: 28096221 PMCID: PMC5312033 DOI: 10.1242/dev.140855] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 12/15/2016] [Indexed: 01/09/2023]
Abstract
Mammalian neural stem cell (NSC) lines provide a tractable model for discovery across stem cell and developmental biology, regenerative medicine and neuroscience. They can be derived from foetal or adult germinal tissues and continuously propagated in vitro as adherent monolayers. NSCs are clonally expandable, genetically stable, and easily transfectable - experimental attributes compatible with targeted genetic manipulations. However, gene targeting, which is crucial for functional studies of embryonic stem cells, has not been exploited to date in NSC lines. Here, we deploy CRISPR/Cas9 technology to demonstrate a variety of sophisticated genetic modifications via gene targeting in both mouse and human NSC lines, including: (1) efficient targeted transgene insertion at safe harbour loci (Rosa26 and AAVS1); (2) biallelic knockout of neurodevelopmental transcription factor genes; (3) simple knock-in of epitope tags and fluorescent reporters (e.g. Sox2-V5 and Sox2-mCherry); and (4) engineering of glioma mutations (TP53 deletion; H3F3A point mutations). These resources and optimised methods enable facile and scalable genome editing in mammalian NSCs, providing significant new opportunities for functional genetic analysis.
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Affiliation(s)
| | - Pooran Singh Dewari
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Maria Kalantzaki
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Ester Gangoso
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Mantas Matjusaitis
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Claudia Garcia-Diaz
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Carla Blin
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Vivien Grant
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Harry Bulstrode
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Sabine Gogolok
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - William C Skarnes
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
| | - Steven M Pollard
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
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