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Zhang R, Ren Y, Ju Y, Zhang Y, Zhang Y, Wang Y. FAM20C: A key protein kinase in multiple diseases. Genes Dis 2025; 12:101179. [PMID: 39790934 PMCID: PMC11714710 DOI: 10.1016/j.gendis.2023.101179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 09/23/2023] [Accepted: 10/31/2023] [Indexed: 01/12/2025] Open
Abstract
Family with sequence similarity 20 C (FAM20C) is a Golgi protein kinase that phosphorylates the serine residue in the S-x-E/pS motif of target proteins. FAM20C phosphorylates most secreted proteins, which play important roles in multiple biological processes, including cancer progression, biomineralization, and lipid homeostasis. Numerous studies have documented the potential contribution of FAM20C to the growth, invasion, and metastasis of glioma, breast cancer, and other cancers, as well as to the mineralization process of teeth and bone. In addition, FAM20C has been found to be associated with the occurrence and development of certain cardiovascular diseases and endocrine metabolism disorders. It raises hopes that understanding the disease-specific mechanisms of FAM20C may hold the key to developing new strategies for these diseases. This review comprehensively covers the existing literature to provide a summary of the structure and biological functions of FAM20C, with a particular focus on its roles in the disease context.
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Affiliation(s)
- Rui Zhang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanming Ren
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yan Ju
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuekang Zhang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yan Zhang
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuan Wang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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2
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Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt‐Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (Beijing) 2024; 5:e710. [PMID: 39309691 PMCID: PMC11416093 DOI: 10.1002/mco2.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology LabDepartment of BiotechnologyMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Ravi Bhushan
- Department of ZoologyM.S. CollegeMotihariBiharIndia
| | - Caiming Xu
- Department of General SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research InstituteCity of HopeMonroviaCaliforniaUSA
| | - Bhana Ram Gadi
- Stress Physiology and Molecular Biology LaboratoryDepartment of BotanyJai Narain Vyas UniversityJodhpurRajasthanIndia
| | | | - Vikas Yadav
- School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
| | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of BioinformaticsInternational Technology ParkBangaloreIndia
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
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3
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McBenedict B, Hauwanga WN, Pogodina A, Singh G, Thomas A, Ibrahim AMA, Johnny C, Lima Pessôa B. Approaches in Adult Glioblastoma Treatment: A Systematic Review of Emerging Therapies. Cureus 2024; 16:e67856. [PMID: 39328617 PMCID: PMC11426946 DOI: 10.7759/cureus.67856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults, characterized by complex genetic changes and a poor prognosis. Current standard therapies, including surgery, chemotherapy, and radiotherapy, have limited effectiveness. Emerging therapeutic strategies aim to address the high recurrence rate and improve outcomes by targeting glioblastoma stem cells (GSCs), the blood-brain barrier, and utilizing advanced drug delivery systems. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. An electronic search was conducted across several databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane, covering studies published from January 2019 to May 2024. The inclusion criteria encompassed primary research studies in English focusing on emerging therapies for treating GB in adults. Eligible studies included experimental and observational studies. Only peer-reviewed journal articles were considered. Exclusion criteria included non-human studies, pediatric studies, non-peer-reviewed articles, systematic reviews, case reports, conference abstracts, and editorials. The search identified 755 articles and, finally, 24 of them met the inclusion criteria. The key findings highlight various promising therapies. Despite advances in treatment approaches, the complexity and heterogeneity of GB necessitate ongoing research to optimize these innovative strategies. The study has limitations that should be considered. The inclusion of only English-language articles may introduce language bias, and the focus on peer-reviewed articles could exclude valuable data from non-peer-reviewed sources. Heterogeneity among studies, particularly in sample sizes and designs, complicates comparison and synthesis, while the reliance on preclinical models limits generalizability to clinical practice. Nonetheless, this review provides a comprehensive overview of the emerging therapies that hold promise for improving patient outcomes in GB treatment.
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Affiliation(s)
| | - Wilhelmina N Hauwanga
- Family Medicine, Faculty of Medicine, Federal University of the State of Rio de Janeiro, Rio de Janeiro, BRA
| | - Anna Pogodina
- Faculty of Medicine, University of Buckingham, Buckingham, GBR
| | - Gurinder Singh
- Medical Sciences, Specialized University of the Americas, Panama, PAN
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Sojka C, Sloan SA. Gliomas: a reflection of temporal gliogenic principles. Commun Biol 2024; 7:156. [PMID: 38321118 PMCID: PMC10847444 DOI: 10.1038/s42003-024-05833-2] [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: 09/11/2023] [Accepted: 01/18/2024] [Indexed: 02/08/2024] Open
Abstract
The hijacking of early developmental programs is a canonical feature of gliomas where neoplastic cells resemble neurodevelopmental lineages and possess mechanisms of stem cell resilience. Given these parallels, uncovering how and when in developmental time gliomagenesis intersects with normal trajectories can greatly inform our understanding of tumor biology. Here, we review how elapsing time impacts the developmental principles of astrocyte (AS) and oligodendrocyte (OL) lineages, and how these same temporal programs are replicated, distorted, or circumvented in pathological settings such as gliomas. Additionally, we discuss how normal gliogenic processes can inform our understanding of the temporal progression of gliomagenesis, including when in developmental time gliomas originate, thrive, and can be pushed towards upon therapeutic coercion.
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Affiliation(s)
- Caitlin Sojka
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Steven A Sloan
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
- Emory Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
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Kałuzińska-Kołat Ż, Kołat D, Kośla K, Płuciennik E, Bednarek AK. Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations. World J Stem Cells 2023; 15:302-322. [PMID: 37342224 PMCID: PMC10277965 DOI: 10.4252/wjsc.v15.i5.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Literature data on glioblastoma ongoingly underline the link between metabolism and cancer stemness, the latter is one responsible for potentiating the resistance to treatment, inter alia due to increased invasiveness. In recent years, glioblastoma stemness research has bashfully introduced a key aspect of cytoskeletal rearrangements, whereas the impact of the cytoskeleton on invasiveness is well known. Although non-stem glioblastoma cells are less invasive than glioblastoma stem cells (GSCs), these cells also acquire stemness with greater ease if characterized as invasive cells and not tumor core cells. This suggests that glioblastoma stemness should be further investigated for any phenomena related to the cytoskeleton and metabolism, as they may provide new invasion-related insights. Previously, we proved that interplay between metabolism and cytoskeleton existed in glioblastoma. Despite searching for cytoskeleton-related processes in which the investigated genes might have been involved, not only did we stumble across the relation to metabolism but also reported genes that were found to be implicated in stemness. Thus, dedicated research on these genes in GSCs seems justifiable and might reveal novel directions and/or biomarkers that could be utilized in the future. Herein, we review the previously identified cytoskeleton/metabolism-related genes through the prism of glioblastoma stemness.
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Affiliation(s)
- Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland.
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
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CHRDL1 Regulates Stemness in Glioma Stem-like Cells. Cells 2022; 11:cells11233917. [PMID: 36497175 PMCID: PMC9741078 DOI: 10.3390/cells11233917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/09/2022] Open
Abstract
Glioblastoma (GBM) still presents as one of the most aggressive tumours in the brain, which despite enormous research efforts, remains incurable today. As many theories evolve around the persistent recurrence of this malignancy, the assumption of a small population of cells with a stem-like phenotype remains a key driver of its infiltrative nature. In this article, we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of bone morphogenic protein 4 (BMP4), which induces GSC differentiation and, hence, reduces tumorigenicity. We, therefore, employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using the stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell-based assays (MTT, limiting dilution, and sphere formation assays), Western blots, irradiation procedures, and quantitative real-time PCR that the depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1 expression might also serve as a marker protein to determine BMP4 susceptibility.
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7
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Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma. Cells 2022; 11:cells11162530. [PMID: 36010607 PMCID: PMC9406959 DOI: 10.3390/cells11162530] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies.
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Regulation of the Cancer Stem Phenotype by Long Non-Coding RNAs. Cells 2022; 11:cells11152352. [PMID: 35954194 PMCID: PMC9367355 DOI: 10.3390/cells11152352] [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: 07/04/2022] [Revised: 07/21/2022] [Accepted: 07/24/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer stem cells are a cell population within malignant tumors that are characterized by the ability to self-renew, the presence of specific molecules that define their identity, the ability to form malignant tumors in vivo, resistance to drugs, and the ability to invade and migrate to other regions of the body. These characteristics are regulated by various molecules, such as lncRNAs, which are transcripts that generally do not code for proteins but regulate multiple biological processes through various mechanisms of action. LncRNAs, such as HOTAIR, H19, LncTCF7, LUCAT1, MALAT1, LINC00511, and FMR1-AS1, have been described as key regulators of stemness in cancer, allowing cancer cells to acquire this phenotype. It has been proposed that cancer stem cells are clinically responsible for the high recurrence rates after treatment and the high frequency of metastasis in malignant tumors, so understanding the mechanisms that regulate the stem phenotype could have an impact on the improvement of cancer treatments.
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9
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Wu Q, Berglund AE, MacAulay RJ, Etame AB. A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma. Int J Mol Sci 2021; 23:297. [PMID: 35008722 PMCID: PMC8745052 DOI: 10.3390/ijms23010297] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/30/2022] Open
Abstract
Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM. In this study, we present novel evidence that BIRC3 has an essential noncanonical role in GBM self-renewal and stemness reprogramming. We demonstrate that BIRC3 drives stemness reprogramming of human GBM cell lines, mouse GBM cell lines and patient-derived GBM stem cells (GSCs) through regulation of BMP4 signaling axis. Specifically, BIRC3 induces stemness reprogramming in GBM through downstream inactivation of BMP4 signaling. RNA-Seq interrogation of the stemness reprogramming hypoxic (pseudopalisading necrosis and perinecrosis) niche in GBM patient tissues further validated the high BIRC3/low BMP4 expression correlation. BIRC3 knockout upregulated BMP4 expression and prevented stemness reprogramming of GBM models. Furthermore, siRNA silencing of BMP4 restored stemness reprogramming of BIRC3 knockout in GBM models. In vivo silencing of BIRC3 suppressed tumor initiation and progression in GBM orthotopic intracranial xenografts. The stemness reprograming of both GSCs and non-GSCs populations highlights the impact of BIRC3 on intra-tumoral cellular heterogeneity GBM. Our study has identified a novel function of BIRC3 that can be targeted to reverse stemness programming of GBM.
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Affiliation(s)
- Qiong Wu
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;
| | - Anders E. Berglund
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;
| | - Robert J. MacAulay
- Departments of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;
| | - Arnold B. Etame
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;
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Terrié E, Déliot N, Benzidane Y, Harnois T, Cousin L, Bois P, Oliver L, Arnault P, Vallette F, Constantin B, Coronas V. Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma. Cancers (Basel) 2021; 13:cancers13143428. [PMID: 34298643 PMCID: PMC8307764 DOI: 10.3390/cancers13143428] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/05/2021] [Accepted: 07/05/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Glioblastoma is a high-grade primary brain tumor that contains a subpopulation of cells called glioblastoma stem cells, which are responsible for tumor initiation, growth and recurrence after treatment. Recent transcriptomic studies have highlighted that calcium pathways predominate in glioblastoma stem cells. Calcium channels have the ability to transduce signals from the microenvironment and are therefore ideally placed to control cellular behavior. Using multiple approaches, we demonstrate in five different primary cultures, previously derived from surgical specimens, that glioblastoma stem cells express store-operated channels (SOC) that support calcium entry into these cells. Pharmacological inhibition of SOC dramatically reduces cell proliferation and stem cell self-renewal in these cultures. By identifying SOC as a critical mechanism involved in the maintenance of the stem cell population in glioblastoma, our study will contribute to the framework for the identification of new therapies against this deadly tumor. Abstract Glioblastoma is the most frequent and deadly form of primary brain tumors. Despite multimodal treatment, more than 90% of patients experience tumor recurrence. Glioblastoma contains a small population of cells, called glioblastoma stem cells (GSC) that are highly resistant to treatment and endowed with the ability to regenerate the tumor, which accounts for tumor recurrence. Transcriptomic studies disclosed an enrichment of calcium (Ca2+) signaling transcripts in GSC. In non-excitable cells, store-operated channels (SOC) represent a major route of Ca2+ influx. As SOC regulate the self-renewal of adult neural stem cells that are possible cells of origin of GSC, we analyzed the roles of SOC in cultures of GSC previously derived from five different glioblastoma surgical specimens. Immunoblotting and immunocytochemistry experiments showed that GSC express Orai1 and TRPC1, two core SOC proteins, along with their activator STIM1. Ca2+ imaging demonstrated that SOC support Ca2+ entries in GSC. Pharmacological inhibition of SOC-dependent Ca2+ entries decreased proliferation, impaired self-renewal, and reduced expression of the stem cell marker SOX2 in GSC. Our data showing the ability of SOC inhibitors to impede GSC self-renewal paves the way for a strategy to target the cells considered responsible for conveying resistance to treatment and tumor relapse.
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Affiliation(s)
- Elodie Terrié
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
| | - Nadine Déliot
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
| | - Yassine Benzidane
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
| | - Thomas Harnois
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
| | - Laëtitia Cousin
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
| | - Patrick Bois
- EA 4379, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France;
| | - Lisa Oliver
- CRCINA-UMR 1232 INSERM, Université de Nantes, CEDEX 01, 44007 Nantes, France; (L.O.); (F.V.)
| | - Patricia Arnault
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
| | - François Vallette
- CRCINA-UMR 1232 INSERM, Université de Nantes, CEDEX 01, 44007 Nantes, France; (L.O.); (F.V.)
- CNRS GDR3697, Micronit “Microenvironment of Tumor Niches”, 37000 Tours, France
| | - Bruno Constantin
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
- CNRS GDR3697, Micronit “Microenvironment of Tumor Niches”, 37000 Tours, France
| | - Valérie Coronas
- CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France; (E.T.); (N.D.); (Y.B.); (T.H.); (L.C.); (P.A.); (B.C.)
- CNRS GDR3697, Micronit “Microenvironment of Tumor Niches”, 37000 Tours, France
- Correspondence: ; Tel.: +33-(0)5-49-45-36-55
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Mitchell K, Troike K, Silver DJ, Lathia JD. The evolution of the cancer stem cell state in glioblastoma: emerging insights into the next generation of functional interactions. Neuro Oncol 2021; 23:199-213. [PMID: 33173943 DOI: 10.1093/neuonc/noaa259] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cellular heterogeneity is a hallmark of advanced cancers and has been ascribed in part to a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). Glioblastoma (GBM), the most common primary malignant brain tumor, has served as a platform for the study of CSCs. In addition to illustrating the complexities of CSC biology, these investigations have led to a deeper understanding of GBM pathogenesis, revealed novel therapeutic targets, and driven innovation towards the development of next-generation therapies. While there continues to be an expansion in our knowledge of how CSCs contribute to GBM progression, opportunities have emerged to revisit this conceptual framework. In this review, we will summarize the current state of CSCs in GBM using key concepts of evolution as a paradigm (variation, inheritance, selection, and time) to describe how the CSC state is subject to alterations of cell intrinsic and extrinsic interactions that shape their evolutionarily trajectory. We identify emerging areas for future consideration, including appreciating CSCs as a cell state that is subject to plasticity, as opposed to a discrete population. These future considerations will not only have an impact on our understanding of this ever-expanding field but will also provide an opportunity to inform future therapies to effectively treat this complex and devastating disease.
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Affiliation(s)
- Kelly Mitchell
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Katie Troike
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case, Western Reserve University, Cleveland, Ohio
| | - Daniel J Silver
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio
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