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1
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Mahdi A, Aittaleb M, Tissir F. Targeting Glioma Stem Cells: Therapeutic Opportunities and Challenges. Cells 2025; 14:675. [PMID: 40358199 PMCID: PMC12072158 DOI: 10.3390/cells14090675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2025] [Revised: 04/25/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025] Open
Abstract
Glioblastoma (GBM), or grade 4 glioma, is the most common and aggressive primary brain tumor in adults with a median survival of 15 months. Increasing evidence suggests that GBM's aggressiveness, invasiveness, and therapy resistance are driven by glioma stem cells (GSCs), a subpopulation of tumor cells that share molecular and functional characteristics with neural stem cells (NSCs). GSCs are heterogeneous and highly plastic. They evade conventional treatments by shifting their state and entering in quiescence, where they become metabolically inactive and resistant to radiotherapy and chemotherapy. GSCs can exit quiescence and be reactivated to divide into highly proliferative tumor cells which contributes to recurrence. Understanding the molecular mechanisms regulating the biology of GSCs, their plasticity, and the switch between quiescence and mitotic activity is essential to shape new therapeutic strategies. This review examines the latest evidence on GSC biology, their role in glioblastoma progression and recurrence, emerging therapeutic approaches aimed at disrupting their proliferation and survival, and the mechanisms underlying their resistance to therapy.
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Affiliation(s)
| | | | - Fadel Tissir
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Education City, Doha P.O. Box 5825, Qatar; (A.M.); (M.A.)
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2
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Parada C, Prieto D. Survival, Movement, and Lifespan: Decoding the Roles of Patched-Related in Drosophila melanogaster. ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY 2025; 118:e70048. [PMID: 40070106 DOI: 10.1002/arch.70048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 02/25/2025] [Indexed: 05/13/2025]
Abstract
Patched-related (Ptr) is a transmembrane protein implicated in developmental processes in Drosophila melanogaster, yet its precise role remains incompletely understood. Here, we use Ptr23c null mutants to investigate the functional significance of Ptr through the entire life cycle monitoring survival during embryonic, larval, pupal and adult development, and studying larval locomotion and muscle structure. We report that Ptr23c larvae displayed impaired hatching, indicative of defective embryonic development. Moreover, mutant larvae exhibited reduced mobility and lethargy, suggesting a potential involvement of Ptr in neuromuscular function. Morphological analysis of somatic muscles in mutant larvae revealed enlarged cell nuclei. Despite high preadult mortality, a subset of Ptr23c mutant adults display an unexpected extension in lifespan compared to controls, implicating Ptr in the regulation of longevity. Our findings provide critical insights into the multifaceted role of Ptr in Drosophila development, highlighting its contributions to post-embryonic survival, neuromuscular function, and lifespan regulation. This study underscores the significance of exploring broader genetic networks to unravel the complexities of developmental processes.
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Affiliation(s)
- Cristina Parada
- Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
- Programa de Desarrollo de las Ciencias Básicas (PEDECIBA), Uruguay
| | - Daniel Prieto
- Departamento de Neurofisiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
- Departamento de Biología del Neurodesarrollo, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
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3
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Liu F, Ye S, Zhao L, Niu Q. The role of IGF/IGF-1R signaling in the regulation of cancer stem cells. Clin Transl Oncol 2024; 26:2924-2934. [PMID: 38865036 DOI: 10.1007/s12094-024-03561-x] [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: 04/08/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024]
Abstract
Cancer stem cells (CSCs) are a group of tumor cells with high tumorigenic ability and self-renewal potential similar to those of normal stem cells. CSCs are the key "seeds" for tumor development, metastasis, and recurrence. A better insight into the key mechanisms underlying CSC survival improves the efficiency of cancer therapy via specific targeting of CSCs. Insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) signaling plays an important role in the maintenance of cancer stemness. However, the effect of IGF/IGF-1R signaling on stemness and CSCs and the underlying mechanisms are still controversial. Based on the similarity between CSCs and normal stem cells, this review discusses emerging data on the functions of IGF/IGF-1R signaling in normal stem cells and CSCs and dissects the underlying mechanisms by which IGF/IGF-1R signaling is involved in CSCs. On the other hand, this review highlighted the role of IGF/IGF-1R signaling blockade in multiple CSCs as a potential strategy to improve CSC-based therapy.
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Affiliation(s)
- Fengchao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Susu Ye
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liu Zhao
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qinghui Niu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
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4
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Sui Y, Wang T, Mei Y, Zhu Y, Jiang W, Shen J, Yan S, Lu W, Zhao K, Mo J, Wang C, Tang Y. Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance. Cancer Res 2024; 84:2690-2706. [PMID: 38775809 DOI: 10.1158/0008-5472.can-23-3306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 03/28/2024] [Accepted: 05/16/2024] [Indexed: 08/16/2024]
Abstract
Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional-targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance. Inhibition of CDK9 or CDK12 potently suppressed Hh signaling and tumor growth in various SMOi responsive or resistant Hh-driven tumor models. Systemic epigenomic profiling elucidated the Hh-driven super-enhancer (SE) landscape and identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the insulin-like growth factor (IGF) pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target in Hh-driven tumor models. Collectively, this study identifies SE-driven transcriptional dependencies that represent promising therapeutic vulnerabilities for suppressing the Hh pathway and overcoming SMOi resistance. As CDK9 and IRS inhibitors have already entered human clinical trials for cancer treatment, these findings provide comprehensive preclinical support for developing trials for Hh-driven cancers. Significance: Dissecting transcriptional dependencies driven by super-enhancers uncovers therapeutic targets in Hedgehog-driven cancers and identifies strategies for overcoming resistance to smoothened inhibitors.
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Affiliation(s)
- Yi Sui
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Teng Wang
- Centre of Biomedical Systems and Informatics, ZJU-UoE Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China
| | - Yanqing Mei
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Zhu
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenyan Jiang
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayi Shen
- Shanghai Jiao Tong University, School of Life Sciences and Biotechnology, Shanghai, China
| | - Siyuan Yan
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenjie Lu
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kewen Zhao
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialin Mo
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaochen Wang
- Centre of Biomedical Systems and Informatics, ZJU-UoE Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Yujie Tang
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Chakraborty S, Wei D, Tran M, Lang FF, Newman RA, Yang P. PBI-05204, a supercritical CO 2 extract of Nerium oleander, suppresses glioblastoma stem cells by inhibiting GRP78 and inducing programmed necroptotic cell death. Neoplasia 2024; 54:101008. [PMID: 38823209 PMCID: PMC11177059 DOI: 10.1016/j.neo.2024.101008] [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: 12/19/2023] [Revised: 05/10/2024] [Accepted: 05/15/2024] [Indexed: 06/03/2024]
Abstract
Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression in both GSC types. Knocking down GRP78 expression through GRP78 siRNA transfection in GBM9 and GSC28 GSCs also resulted in reduced spheroid size and CD44 expression. Combining PBI-05204 with GRP78 siRNA further decreased spheroid numbers compared to GRP78 siRNA treatment alone. PBI-05204 treatment led to increased expression of pRIP1K and pRIP3K, along with enhanced binding of RIPK1/RIPK3 in GBM9 and GSC28 cells, resembling the effects observed in GRP78-silenced GSCs, suggesting that PBI-05204 induced necroptosis in these cells. Furthermore, oleandrin, a principle active cardiac glycoside component of PBI-05204, showed the ability to inhibit the self-renewal capacity in GSCs. These findings highlight the potential of PBI-05204 as a promising candidate for the development of novel therapies that target GBM stem cells.
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Affiliation(s)
- Sharmistha Chakraborty
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Daoyan Wei
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Megan Tran
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Frederick F Lang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Robert A Newman
- Phoenix Biotechnology, San Antonio, Texas 78217, United States
| | - Peiying Yang
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
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Fiorentino F, Fabbrizi E, Raucci A, Noce B, Fioravanti R, Valente S, Paolini C, De Maria R, Steinkühler C, Gallinari P, Rotili D, Mai A. Uracil- and Pyridine-Containing HDAC Inhibitors Displayed Cytotoxicity in Colorectal and Glioblastoma Cancer Stem Cells. ChemMedChem 2024; 19:e202300655. [PMID: 38529661 DOI: 10.1002/cmdc.202300655] [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: 11/23/2023] [Revised: 03/01/2024] [Accepted: 03/25/2024] [Indexed: 03/27/2024]
Abstract
Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1-7), showing either hydroxamate or 2'-aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in-cell HDAC activity. Two uracil-based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine-hydroxamate 2, with 2- to 6-fold higher potency than the positive control SAHA. Finally, increased H3 acetylation as well as HDAC inhibition directly in cells by selected 2'-aminoanilide 4 and hydroxamate 5 confirmed target engagement. Further investigation will be conducted into the broad-spectrum anticancer properties of the most potent derivatives and their effects in combination with approved, conventional anticancer drugs.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Alessia Raucci
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Beatrice Noce
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Chantal Paolini
- IRBM S.p.A., Via Pontina km 30.600, 00071, Pomezia, Rome, Italy
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy
| | - Christian Steinkühler
- Research and Development, Italfarmaco Group, Via dei Lavoratori 54, 20092, Cinisello Balsamo, Italy
| | - Paola Gallinari
- Exiris S.r.l., Tecnopolo Castel, Romano, Via Castel Romano 100, 00128, Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
- Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. de Aldo Moro n. 5, 00185, Rome, Italy
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7
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Sun J, Zhu W, Luan M, Xing Y, Feng Z, Zhu J, Ma X, Wang Y, Jia Y. Positive GLI1/INHBA feedback loop drives tumor progression in gastric cancer. Cancer Sci 2024; 115:2301-2317. [PMID: 38676428 PMCID: PMC11247559 DOI: 10.1111/cas.16193] [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: 02/08/2024] [Revised: 04/02/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
GLI1, a key transcription factor of the Hedgehog (Hh) signaling pathway, plays an important role in the development of cancer. However, the function and mechanisms by which GLI1 regulates gene transcription are not fully understood in gastric cancer (GC). Here, we found that GLI1 induced the proliferation and metastasis of GC cells, accompanied by transcriptional upregulation of INHBA. This increased INHBA expression exerted a promoting activity on Smads signaling and then transcriptionally activated GLI1 expression. Notably, our results demonstrate that disrupting the interaction between GLI1 and INHBA could inhibit GC tumorigenesis in vivo. More intriguingly, we confirmed the N6-methyladenosine (m6A) activation mechanism of the Helicobacter pylori/FTO/YTHDF2/GLI1 pathway in GC cells. In conclusion, our study confirmed that the GLI1/INHBA positive feedback loop influences GC progression and revealed the mechanism by which H. pylori upregulates GLI1 expression through m6A modification. This positive GLI1/INHBA feedback loop suggests a novel noncanonical mechanism of GLI1 activity in GC and provides potential therapeutic targets for GC treatment.
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Affiliation(s)
- Jingguo Sun
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wenshuai Zhu
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Muhua Luan
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
| | - Yuanxin Xing
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhaotian Feng
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jingyu Zhu
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xiaoli Ma
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yunshan Wang
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yanfei Jia
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, China
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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8
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Kapteijn MY, Lanting VR, Kaptein FHJ, Guman NAM, Laghmani EH, Kuipers TB, Mei H, Goeman JJ, Mulder FI, van Duinen SG, Taphoorn MJB, Dirven L, Broekman MLD, van Es N, Klok FA, Koekkoek JAF, Versteeg HH, Buijs JT. RNA-sequencing to discover genes and signaling pathways associated with venous thromboembolism in glioblastoma patients: A case-control study. Thromb Res 2023; 232:27-34. [PMID: 37918288 DOI: 10.1016/j.thromres.2023.10.018] [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: 07/27/2023] [Revised: 10/08/2023] [Accepted: 10/26/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Glioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms remain incompletely understood. OBJECTIVES To identify tumor-expressed genes and signaling pathways that associate with glioblastoma-related VTE by using next generation RNA-sequencing (RNA-Seq). METHODS The tumor gene expression profile of 23 glioblastoma patients with VTE and 23 glioblastoma patients without VTE was compared using an unpaired analysis. Ingenuity Pathway Analysis (IPA) core analysis was performed on the top 50 differentially expressed genes to explore associated functions and pathways. Based on full RNA-Seq data, molecular glioblastoma subtypes were determined by performing cluster analysis. RESULTS Of the 19,327 genes, 1246 (6.4 %) were differentially expressed between glioblastoma patients with and without VTE (unadjusted P < 0.05). The most highly overexpressed gene was GLI1, a classical target gene in the Sonic Hedgehog (Shh) signaling pathway (log2 fold change: 3.7; unadjusted P < 0.0001, adjusted P = 0.219). In line, Shh signaling was among the top canonical pathways and processes associated with VTE. The proportion of patients with the proneural/neural glioblastoma subtype was higher among those with VTE than controls. CONCLUSION Shh signaling may be involved in the development of glioblastoma-related VTE.
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Affiliation(s)
- Maaike Y Kapteijn
- Einthoven Laboratory for Vascular and Regenerative Medicine, Div. of Thrombosis & Hemostasis, Dept. of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Vincent R Lanting
- Amsterdam University Medical Center location University of Amsterdam, Department of Vascular Medicine, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, the Netherlands; Tergooi Hospital, Department of Internal Medicine, Hilversum, the Netherlands
| | - Fleur H J Kaptein
- Einthoven Laboratory for Vascular and Regenerative Medicine, Div. of Thrombosis & Hemostasis, Dept. of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Noori A M Guman
- Amsterdam University Medical Center location University of Amsterdam, Department of Vascular Medicine, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, the Netherlands; Tergooi Hospital, Department of Internal Medicine, Hilversum, the Netherlands
| | - El Houari Laghmani
- Einthoven Laboratory for Vascular and Regenerative Medicine, Div. of Thrombosis & Hemostasis, Dept. of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Thomas B Kuipers
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Hailiang Mei
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Jelle J Goeman
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Frits I Mulder
- Amsterdam University Medical Center location University of Amsterdam, Department of Vascular Medicine, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, the Netherlands; Tergooi Hospital, Department of Internal Medicine, Hilversum, the Netherlands
| | - Sjoerd G van Duinen
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Martin J B Taphoorn
- Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands; Department of Neurology, Haaglanden Medical Center, The Hague, the Netherlands
| | - Linda Dirven
- Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands; Department of Neurology, Haaglanden Medical Center, The Hague, the Netherlands
| | - Marike L D Broekman
- Department of Neurosurgery, Leiden University Medical Center, Leiden, the Netherlands; Department of Neurosurgery, Haaglanden Medical Center, Den Haag, the Netherlands
| | - Nick van Es
- Amsterdam University Medical Center location University of Amsterdam, Department of Vascular Medicine, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, the Netherlands
| | - Frederikus A Klok
- Einthoven Laboratory for Vascular and Regenerative Medicine, Div. of Thrombosis & Hemostasis, Dept. of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Johan A F Koekkoek
- Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands; Department of Neurology, Haaglanden Medical Center, The Hague, the Netherlands
| | - Henri H Versteeg
- Einthoven Laboratory for Vascular and Regenerative Medicine, Div. of Thrombosis & Hemostasis, Dept. of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Jeroen T Buijs
- Einthoven Laboratory for Vascular and Regenerative Medicine, Div. of Thrombosis & Hemostasis, Dept. of Medicine, Leiden University Medical Center, Leiden, the Netherlands.
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9
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Joshi G, Basu A. Epigenetic control of cell signalling in cancer stem cells. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 383:67-88. [PMID: 38359971 DOI: 10.1016/bs.ircmb.2023.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
The self-renewing cancer stem cells (CSCs) represent one of the distinct cell populations occurring in a tumour that can differentiate into multiple lineages. This group of sparsely abundant cells play a vital role in tumour survival and resistance to different treatments during cancer. The lack of exclusive markers associated with CSCs makes diagnosis and prognosis in cancer patients extremely difficult. This calls for the identification of unique regulators and markers for CSCs. Various signalling pathways like the Wnt/β-catenin pathway, Hedgehog pathway, Notch pathway, and TGFβ/BMP play a major role in the regulation and maintenance of CSCs. Epigenetic regulatory mechanisms add another layer of complexity to control these signalling pathways. In this chapter, we discuss about the role of epigenetic mechanisms in regulating the cellular signalling pathways in CSCs. The epigenetic regulatory mechanisms such as DNA methylation, histone modification and microRNAs can modulate the diverse effectors of signalling pathways and consequently the growth, differentiation and tumorigenicity of CSCs. In the end, we briefly discuss the therapeutic potential of targeting these epigenetic regulators and their target genes in CSCs.
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Affiliation(s)
- Gaurav Joshi
- Institute of Molecular Biology (IMB), Mainz, Germany.
| | - Amitava Basu
- Institute of Molecular Biology (IMB), Mainz, Germany.
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10
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Lauko A, Volovetz J, Turaga SM, Bayik D, Silver DJ, Mitchell K, Mulkearns-Hubert EE, Watson DC, Desai K, Midha M, Hao J, McCortney K, Steffens A, Naik U, Ahluwalia MS, Bao S, Horbinski C, Yu JS, Lathia JD. SerpinB3 drives cancer stem cell survival in glioblastoma. Cell Rep 2022; 40:111348. [PMID: 36103817 PMCID: PMC9513382 DOI: 10.1016/j.celrep.2022.111348] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 06/22/2022] [Accepted: 08/22/2022] [Indexed: 12/11/2022] Open
Abstract
Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs.
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Affiliation(s)
- Adam Lauko
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA; Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Josephine Volovetz
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA
| | - Soumya M Turaga
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
| | - Defne Bayik
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
| | - Daniel J Silver
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
| | - Kelly Mitchell
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
| | - Erin E Mulkearns-Hubert
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA
| | - Dionysios C Watson
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA; Division of Hematology/Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Kiran Desai
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
| | - Manav Midha
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
| | - Jing Hao
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Kathleen McCortney
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Alicia Steffens
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ulhas Naik
- Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | | | - Shideng Bao
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Craig Horbinski
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Neurosurgery, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Jennifer S Yu
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44106, USA; Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Justin D Lathia
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA; Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44106, USA.
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11
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Canonical Hedgehog Pathway and Noncanonical GLI Transcription Factor Activation in Cancer. Cells 2022; 11:cells11162523. [PMID: 36010600 PMCID: PMC9406872 DOI: 10.3390/cells11162523] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 01/12/2023] Open
Abstract
The Hedgehog signaling pathway is one of the fundamental pathways required for development and regulation of postnatal regeneration in a variety of tissues. The pathway has also been associated with cancers since the identification of a mutation in one of its components, PTCH, as the cause of Basal Cell Nevus Syndrome, which is associated with several cancers. Our understanding of the pathway in tumorigenesis has expanded greatly since that initial discovery over two decades ago. The pathway has tumor-suppressive and oncogenic functions depending on the context of the cancer. Furthermore, noncanonical activation of GLI transcription factors has been reported in a number of tumor types. Here, we review the roles of canonical Hedgehog signaling pathway and noncanonical GLI activation in cancers, particularly epithelial cancers, and discuss an emerging concept of the distinct outcomes that these modes have on cancer initiation and progression.
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12
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Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies. Biomedicines 2022; 10:biomedicines10061308. [PMID: 35740330 PMCID: PMC9220281 DOI: 10.3390/biomedicines10061308] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy.
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13
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Transcription Factors with Targeting Potential in Gliomas. Int J Mol Sci 2022; 23:ijms23073720. [PMID: 35409080 PMCID: PMC8998804 DOI: 10.3390/ijms23073720] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/23/2022] [Accepted: 03/26/2022] [Indexed: 12/18/2022] Open
Abstract
Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. Transcription factors (TFs) are master regulators of gene expression programs, which ultimately shape cell fate and homeostasis. A variety of TFs have been detected to be aberrantly expressed in brain tumors, being highly implicated in critical pathological aspects and progression of gliomas. Herein, we describe a selection of oncogenic (GLI-1/2/3, E2F1–8, STAT3, and HIF-1/2) and tumor suppressor (NFI-A/B, TBXT, MYT1, and MYT1L) TFs that are deregulated in gliomas and are subsequently associated with tumor development, progression, and migratory potential. We further discuss the current targeting options against these TFs, including chemical (Bortezomib) and natural (Plumbagin) compounds, small molecules, and inhibitors, and address their potential implications in glioma therapy.
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14
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Onishi H, Nakamura K, Yanai K, Nagai S, Nakayama K, Oyama Y, Fujimura A, Ozono K, Yamasaki A. Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review). Oncol Rep 2022; 47:93. [DOI: 10.3892/or.2022.8304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/25/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Katsuya Nakamura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kosuke Yanai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Shuntaro Nagai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kazunori Nakayama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Yasuhiro Oyama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akiko Fujimura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Keigo Ozono
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akio Yamasaki
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
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15
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Stevanovic M, Kovacevic-Grujicic N, Mojsin M, Milivojevic M, Drakulic D. SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation. World J Stem Cells 2021; 13:1417-1445. [PMID: 34786152 PMCID: PMC8567447 DOI: 10.4252/wjsc.v13.i10.1417] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/15/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
- Chair Biochemistry and Molecular Biology, Faculty of Biology, University of Belgrade, Belgrade 11158, Serbia
- Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Belgrade 11000, Serbia.
| | - Natasa Kovacevic-Grujicic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Milena Milivojevic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
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16
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Henao-Restrepo J, Caro-Urrego YA, Barrera-Arenas LM, Arango-Viana JC, Bermudez-Munoz M. Expression of activator proteins of SHH/GLI and PI3K/Akt/mTORC1 signaling pathways in human gliomas is associated with high grade tumors. Exp Mol Pathol 2021; 122:104673. [PMID: 34371011 DOI: 10.1016/j.yexmp.2021.104673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/25/2021] [Accepted: 08/03/2021] [Indexed: 01/15/2023]
Abstract
Recent findings have demonstrated a synergic crosstalk between SHH/GLI and PI3K/Akt/mTORC1 signaling in glioblastoma progression cells in vitro and in tumors in mice, but it is not known if this also occurs in human gliomas. We then aimed to investigate the expression of key proteins of these pathways in different human gliomas. The expression of PTEN, phospho-Akt (Ser473), phospho-S6K1 (Thr389), SHH, GLI1, GLI2 and GLI3 was assessed by immunohistochemistry in gliomas and in control brain tissues. The pattern of expression of each protein was established according to glioma type, glioma grade and to cell type; the relative expression of each protein was used to perform statistical analyses. We found that the expression of proteins of both signaling pathways differs between normal brain and glioma tissues. For instance, normal astrocytes had a different protein expression pattern compared with reactive and tumoral astrocytes. Interestingly, we detected a recurrent pattern of expression of GLI3 in oligodendrocytes and of phospho-S6K1 in mitotic neoplastic cells. We also identified differences of cell signaling according to glioma type: oligodendrogliomas and ependymomas are related with the expression of SHH/GLI proteins. Finally, we detected that high grade gliomas statistically correlate with the expression of GLI1 and GLI2, and that GLI1, GLI2, phospho-Akt and phospho-S6K1 are more expressed in patients with less survival, suggesting that activation of these cell signaling influences glioma outcome and patient survival. In summary, our results show that proteins of PI3K/Akt/mTORC1 and SHH/GLI pathways are differentially expressed in human gliomas according to tumor type and grade, and suggest that the activation of these signaling networks is associated with glioma progression.
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Affiliation(s)
- Julián Henao-Restrepo
- Institute of Biology, Faculty of Exact and Natural Sciences, University of Antioquia, Calle 67 #53-108, 050010 Medellín, Colombia.
| | - Yudys Anggelly Caro-Urrego
- Department of Pathology, Faculty of Medicine, University of Antioquia, Cra. 51d #62-29, 050010 Medellín, Colombia
| | - Lina Marcela Barrera-Arenas
- Grupo de Investigaciones Biomédicas, Health Sciences Faculty, University Corporation Remington, Calle 51 #51-27, Medellín, Colombia.
| | - Juan Carlos Arango-Viana
- Department of Pathology, Faculty of Medicine, University of Antioquia, Cra. 51d #62-29, 050010 Medellín, Colombia.
| | - Maria Bermudez-Munoz
- Institute of Biology, Faculty of Exact and Natural Sciences, University of Antioquia, Calle 67 #53-108, 050010 Medellín, Colombia.
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17
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Alves ALV, Gomes INF, Carloni AC, Rosa MN, da Silva LS, Evangelista AF, Reis RM, Silva VAO. Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives. Stem Cell Res Ther 2021; 12:206. [PMID: 33762015 PMCID: PMC7992331 DOI: 10.1186/s13287-021-02231-x] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 02/15/2021] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma (GBM) is the highest-grade form of glioma, as well as one of the most aggressive types of cancer, exhibiting rapid cellular growth and highly invasive behavior. Despite significant advances in diagnosis and therapy in recent decades, the outcomes for high-grade gliomas (WHO grades III-IV) remain unfavorable, with a median overall survival time of 15–18 months. The concept of cancer stem cells (CSCs) has emerged and provided new insight into GBM resistance and management. CSCs can self-renew and initiate tumor growth and are also responsible for tumor cell heterogeneity and the induction of systemic immunosuppression. The idea that GBM resistance could be dependent on innate differences in the sensitivity of clonogenic glial stem cells (GSCs) to chemotherapeutic drugs/radiation prompted the scientific community to rethink the understanding of GBM growth and therapies directed at eliminating these cells or modulating their stemness. This review aims to describe major intrinsic and extrinsic mechanisms that mediate chemoradioresistant GSCs and therapies based on antineoplastic agents from natural sources, derivatives, and synthetics used alone or in synergistic combination with conventional treatment. We will also address ongoing clinical trials focused on these promising targets. Although the development of effective therapy for GBM remains a major challenge in molecular oncology, GSC knowledge can offer new directions for a promising future.
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Affiliation(s)
- Ana Laura V Alves
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Izabela N F Gomes
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Adriana C Carloni
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Marcela N Rosa
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Luciane S da Silva
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Adriane F Evangelista
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's PT Government Associate Laboratory, 4806-909, Braga, Portugal
| | - Viviane Aline O Silva
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil.
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18
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Biserova K, Jakovlevs A, Uljanovs R, Strumfa I. Cancer Stem Cells: Significance in Origin, Pathogenesis and Treatment of Glioblastoma. Cells 2021; 10:cells10030621. [PMID: 33799798 PMCID: PMC8000844 DOI: 10.3390/cells10030621] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/27/2021] [Accepted: 03/09/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)—tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics—are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
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Affiliation(s)
- Karina Biserova
- Faculty of Residency, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
- Correspondence:
| | - Arvids Jakovlevs
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia; (A.J.); (R.U.); (I.S.)
| | - Romans Uljanovs
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia; (A.J.); (R.U.); (I.S.)
| | - Ilze Strumfa
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia; (A.J.); (R.U.); (I.S.)
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19
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Tirrò E, Massimino M, Romano C, Martorana F, Pennisi MS, Stella S, Pavone G, Di Gregorio S, Puma A, Tomarchio C, Vitale SR, Manzella L, Vigneri P. Prognostic and Therapeutic Roles of the Insulin Growth Factor System in Glioblastoma. Front Oncol 2021; 10:612385. [PMID: 33604294 PMCID: PMC7885861 DOI: 10.3389/fonc.2020.612385] [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: 09/30/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common primary brain malignancy and is often resistant to conventional treatments due to its extensive cellular heterogeneity. Thus, the overall survival of GBM patients remains extremely poor. Insulin-like growth factor (IGF) signaling entails a complex system that is a key regulator of cell transformation, growth and cell-cycle progression. Hence, its deregulation is frequently involved in the development of several cancers, including brain malignancies. In GBM, differential expression of several IGF system components and alterations of this signaling axis are linked to significantly worse prognosis and reduced responsiveness to temozolomide, the most commonly used pharmacological agent for the treatment of the disease. In the present review we summarize the biological role of the IGF system in the pathogenesis of GBM and comprehensively discuss its clinical significance and contribution to the development of resistance to standard chemotherapy and experimental treatments.
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Affiliation(s)
- Elena Tirrò
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Michele Massimino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Chiara Romano
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Federica Martorana
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy.,Medical Oncology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Maria Stella Pennisi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Stefania Stella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Giuliana Pavone
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy.,Medical Oncology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Sandra Di Gregorio
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Adriana Puma
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Cristina Tomarchio
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Silvia Rita Vitale
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy.,Medical Oncology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
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20
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Javed Z, Javed Iqbal M, Rasheed A, Sadia H, Raza S, Irshad A, Koch W, Kukula-Koch W, Głowniak-Lipa A, Cho WC, Sharifi-Rad J. Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer. Front Oncol 2021; 10:607607. [PMID: 33489917 PMCID: PMC7817854 DOI: 10.3389/fonc.2020.607607] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.
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Affiliation(s)
- Zeeshan Javed
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Muhammad Javed Iqbal
- Department of Biotechnology, Faculty of Sciences, University of Sialkot, Sialkot, Pakistan
| | - Amna Rasheed
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Haleema Sadia
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan
| | - Shahid Raza
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Asma Irshad
- Department of Life Sciences, University of Management and Technology, Lahore, Pakistan
| | - Wojciech Koch
- Chair and Department of Food and Nutrition, Medical University of Lublin, Lublin, Poland
| | | | - Anna Głowniak-Lipa
- Department of Cosmetology, University of Information Technology and Management in Rzeszów, Rzeszów, Poland
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
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21
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Ferreira Mendes JM, de Faro Valverde L, Torres Andion Vidal M, Paredes BD, Coelho P, Allahdadi KJ, Coletta RD, Souza BSDF, Rocha CAG. Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma. Int J Mol Sci 2020; 21:E6487. [PMID: 32899449 PMCID: PMC7555130 DOI: 10.3390/ijms21186487] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/29/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023] Open
Abstract
(1) Background: Activation of the PI3K-AKT pathway controls most hallmarks of cancer, and the hedgehog (HH) pathway has been associated with oral squamous cell carcinoma (OSCC) development and progression. We hypothesized that fibroblast-derived insulin-like growth factor-1 (IGF-1) acts in oral squamous cell carcinoma (OSCC) cells, leading to the non-canonical activation of the HH pathway, maintaining AKT activity and promoting tumor aggressiveness. (2) Methods: Primary fibroblasts (MF1) were genetically engineered for IGF-1 overexpression (MF1-IGF1) and CRISPR/Cas9-mediated IGF1R silencing was performed in SCC-4 cells. SCC-4 cells were co-cultured with fibroblasts or incubated with fibroblast conditioned medium (CM) or rIGF-1 for functional assays and the evaluation of AKT and HH pathways. (3) Results: Gene expression analysis confirmed IGF-1 overexpression in MF1-IGF1 and the absence of IGF-1 expression in SCC-4, while elevated IGF1R expression was detected. IGF1R silencing was associated with decreased survival of SCC-4 cells. Ihh was expressed in both MF1 and MF1-IGF1, and increased levels of GLI1 mRNA were observed in SCC-4 after stimulation with CM-MF1. Activation of both PI3K-AKT and the HH pathway (GLI1, Ihh and SMO) were identified in SCC-4 cells cultured in the presence of MF1-IGF1-CM. rIGF-1 promoted tumor cell proliferation, migration, invasion and tumorsphere formation, whereas CM-MF1 significantly stimulated angiogenesis. (4) Conclusions: IGF-1 exerts pro-tumorigenic effects by stimulating SCC-4 cell proliferation, migration, invasion and stemness. AKT and HH pathways were activated by IGF-1 in SCC-4, reinforcing its influence on the regulation of these signaling pathways.
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Affiliation(s)
- Jéssica Mariane Ferreira Mendes
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia 40296-710, Brazil; (J.M.F.M.); (L.d.F.V.); (M.T.A.V.); (P.C.)
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Bahia 41253-190, Brazil; (B.D.P.); (K.J.A.)
| | - Ludmila de Faro Valverde
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia 40296-710, Brazil; (J.M.F.M.); (L.d.F.V.); (M.T.A.V.); (P.C.)
| | - Manuela Torres Andion Vidal
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia 40296-710, Brazil; (J.M.F.M.); (L.d.F.V.); (M.T.A.V.); (P.C.)
| | - Bruno Diaz Paredes
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Bahia 41253-190, Brazil; (B.D.P.); (K.J.A.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, Brazil
| | - Paulo Coelho
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia 40296-710, Brazil; (J.M.F.M.); (L.d.F.V.); (M.T.A.V.); (P.C.)
| | - Kyan James Allahdadi
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Bahia 41253-190, Brazil; (B.D.P.); (K.J.A.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, Brazil
| | - Ricardo Della Coletta
- Department of Oral Diagnosis, School of Dentistry, Campinas State University (UNICAMP), Piracicaba, São Paulo 13414-903, Brazil;
| | - Bruno Solano de Freitas Souza
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia 40296-710, Brazil; (J.M.F.M.); (L.d.F.V.); (M.T.A.V.); (P.C.)
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Bahia 41253-190, Brazil; (B.D.P.); (K.J.A.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, Brazil
| | - Clarissa Araújo Gurgel Rocha
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia 40296-710, Brazil; (J.M.F.M.); (L.d.F.V.); (M.T.A.V.); (P.C.)
- Department of Pathology, School of Medicine and School of Dentistry, Federal University of Bahia (UFBA), Salvador, Bahia 40110-909, Brazil
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22
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Chen KC, Chen PH, Ho KH, Shih CM, Chou CM, Cheng CH, Lee CC. IGF-1-enhanced miR-513a-5p signaling desensitizes glioma cells to temozolomide by targeting the NEDD4L-inhibited Wnt/β-catenin pathway. PLoS One 2019; 14:e0225913. [PMID: 31805126 PMCID: PMC6894868 DOI: 10.1371/journal.pone.0225913] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 11/14/2019] [Indexed: 12/20/2022] Open
Abstract
Temozolomide (TMZ) is a first-line alkylating agent for glioblastoma multiforme (GBM). Clarifying the mechanisms inducing TMZ insensitivity may be helpful in improving its therapeutic effectiveness against GBM. Insulin-like growth factor (IGF)-1 signaling and micro (mi)RNAs are relevant in mediating GBM progression. However, their roles in desensitizing GBM cells to TMZ are still unclear. We aimed to identify IGF-1-mediated miRNA regulatory networks that elicit TMZ insensitivity for GBM. IGF-1 treatment attenuated TMZ cytotoxicity via WNT/β-catenin signaling, but did not influence glioma cell growth. By miRNA array analyses, 93 upregulated and 148 downregulated miRNAs were identified in IGF-1-treated glioma cells. miR-513a-5p from the miR-513a-2 gene locus was upregulated by IGF-1-mediated phosphoinositide 3-kinase (PI3K) signaling. Its elevated levels were also observed in gliomas versus normal cells, in array data of The Cancer Genome Atlas (TCGA), and the GSE61710, GSE37366, and GSE41032 datasets. In addition, lower levels of neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin protein ligase that inhibits WNT signaling, were found in gliomas by analyzing cells, arrays, and RNA sequencing data of TCGA glioma patients. Furthermore, a negative correlation was identified between miR-513a-5p and NEDD4L in glioma. NEDD4L was also validated as a direct target gene of miR-513a-5p, and it was reduced by IGF-1 treatment. Overexpression of NEDD4L inhibited glioma cell viability and reversed IGF-1-repressed TMZ cytotoxicity. In contrast, miR-513a-5p significantly affected NEDD4L-inhibited WNT signaling and reduced TMZ cytotoxicity. These findings demonstrate a distinct role of IGF-1 signaling through miR-513a-5p-inhibited NEDD4L networks in influencing GBM's drug sensitivity to TMZ.
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Affiliation(s)
- Ku-Chung Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Peng-Hsu Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Hao Ho
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chwen-Ming Shih
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Ming Chou
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chia-Hsiung Cheng
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chin-Cheng Lee
- Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
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23
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Izadpanah S, Shabani P, Aghebati-Maleki A, Baghbanzadeh A, Fotouhi A, Bisadi A, Aghebati-Maleki L, Baradaran B. Prospects for the involvement of cancer stem cells in the pathogenesis of osteosarcoma. J Cell Physiol 2019; 235:4167-4182. [PMID: 31709547 DOI: 10.1002/jcp.29344] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 08/26/2019] [Indexed: 12/31/2022]
Abstract
Osteosarcoma (OS) is one of the most common bone tumors in children and adolescents that cause a high rate of mortality in this age group and tends to be metastatic, in spite of chemotherapy and surgery. The main reason for this can be returned to a small group of malignant cells called cancer stem cells (CSCs). OS-CSCs play a key role in the resistance to treatment and relapse and metastasis through self-renewal and differentiation abilities. In this review, we intend to go through the different aspects of this malignant disease, including the cancer stem cell-phenotype, methods for isolating CSCs, signaling pathways, and molecular markers in this disease, and drugs showing resistance in treatment efforts of OS.
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Affiliation(s)
- Sama Izadpanah
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parastoo Shabani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Fotouhi
- Department of Orthopedic Surgery, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Bisadi
- Department of Orthopedic Surgery, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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24
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Volnitskiy A, Shtam T, Burdakov V, Kovalev R, Konev A, Filatov M. Abnormal activity of transcription factors gli in high-grade gliomas. PLoS One 2019; 14:e0211980. [PMID: 30730955 PMCID: PMC6366868 DOI: 10.1371/journal.pone.0211980] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 01/24/2019] [Indexed: 12/11/2022] Open
Abstract
Malignant transformation is associated with loss of cell differentiation, anaplasia. Transcription factors gli, required for embryonic development, may be involved in this process. We studied the activity of transcription factors gli in high-grade gliomas and their role in maintenance of stem cell state and glioma cell survival. 20 glioma cell lines and a sample of a normal adult brain tissue were used in the present study. We found the expression of gli target genes, including GLI1 and FOXM1, in all tested glioma cell lines, but not in the normal tissue. Interestingly, the expression of gli target genes in some glioma cell lines was observed together with a high level of their transcriptional repressor, Gli3R. Knockdown of GLI3 in one of these lines resulted in decrease of gli target gene expression. These data suggest that Gli3R does not prevent the gli target genes transcription, and gli3 acts in glioma cells more as an activator, than a repressor of transcription. We observed that gli regulated the expression of such genes, as SOX2 or OCT4 that maintain stem cell state, and TET1, involving in DNA demethylation. Treatment with GANT61 or siRNA against GLI1, GLI2, or GLI3 could result in complete glioma cell death, while cyclopamine had a weaker and line-specific effect on glioma cell survival. Thus, the gli transcription factors are abnormally active in high-grade gliomas, regulate expression of genes, maintaining the stem cell state, and contribute to glioma cell survival.
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Affiliation(s)
- Andrey Volnitskiy
- Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Gatchina, Russia
| | - Tatiana Shtam
- Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Gatchina, Russia
- N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Pesochnyj, Leningradskaya, Russia
| | - Vladimir Burdakov
- Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Gatchina, Russia
| | - Roman Kovalev
- Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Gatchina, Russia
| | - Alexander Konev
- Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Gatchina, Russia
| | - Michael Filatov
- Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Gatchina, Russia
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25
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Huang D, Wang Y, Xu L, Chen L, Cheng M, Shi W, Xiong H, Zalli D, Luo S. GLI2 promotes cell proliferation and migration through transcriptional activation of ARHGEF16 in human glioma cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:247. [PMID: 30305138 PMCID: PMC6180656 DOI: 10.1186/s13046-018-0917-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 09/25/2018] [Indexed: 01/02/2023]
Abstract
BACKGROUND The Hedgehog (Hh) signaling pathway plays critical roles in modulating embryogenesis and maintaining tissue homeostasis, with glioma-associated oncogene (GLI) transcription factors being the main mediators. Aberrant activation of this pathway is associated with various human malignancies including glioblastoma, although the mechanistic details are not well understood. METHODS We performed a microarray analysis of genes that are differentially expressed in glioblastoma U87 cells overexpressing GLI2A, the active form of GLI2, relative to the control cells. Chromatin immunoprecipitation and dual-luciferase assays were used to determine whether Rho guanine nucleotide exchange factor 16 (ARHGEF16) is a downstream target of GLI2. Then, transwell migration, EdU and soft-agar colony formation assays were employed to test effects of ARHGEF16 on glioma cancer cell migration and proliferation, and the effects of GLI2/ARHGEF16 signaling on tumor growth were examined in vivo. Finally, we performed yeast two-hybrid assay, Co-IP and GST-pull down to identify factors that mediate effects of ARHGEF16. RESULTS We found that ARHGEF16 mRNA level was upregulated in U87 cells overexpressing GLI2A relative to control cells. GLI2 binds to the ARHGEF16 promoter and activates gene transcription. Glioma cells U87 and U118 overexpressing ARHGEF16 showed enhanced migration and proliferation relative to the control cells, while knockdown of ARHGEF16 in H4 cells led to decreased cell proliferation compared to the control H4 cells. In contrast to the promoting effect of GLI2A overexpression on glioma xenograft growth, both GLI2 inhibition and ARHGEF16 knockdown retarded tumor growth. Cytoskeleton-associated protein 5 (CKAP5) was identified as an interaction protein of ARHGEF16, which is important for the stimulatory effects of ARHGEF16 on glioma cell migration and proliferation. CONCLUSIONS These results suggest that therapeutic strategies targeting the GLI2/ARHGEF16/CKAP5 signaling axis could inhibit glioma progression and recurrence.
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Affiliation(s)
- Dengliang Huang
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China
| | - Yiting Wang
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China
| | - Linlin Xu
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China
| | - Limin Chen
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China
| | - Minzhang Cheng
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China
| | - Wei Shi
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China
| | - Huanting Xiong
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China
| | - Detina Zalli
- School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, UK
| | - Shiwen Luo
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China. .,Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, Nanchang, 330006, Jiangxi, China.
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26
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Liu P, Zhang R, Yu W, Ye Y, Cheng Y, Han L, Dong L, Chen Y, Wei X, Yu J. FGF1 and IGF1-conditioned 3D culture system promoted the amplification and cancer stemness of lung cancer cells. Biomaterials 2017; 149:63-76. [PMID: 29017078 DOI: 10.1016/j.biomaterials.2017.09.030] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 09/20/2017] [Accepted: 09/25/2017] [Indexed: 12/21/2022]
Abstract
Lung cancer stem cells (LCSCs) are considered as the cellular origins of metastasis and relapse of lung cancer. However, routine two-dimensional culture system (2D-culture) hardly mimics the growth and functions of LCSCs in vivo and therefore significantly decreases the stemness activity of LCSCs. In this study, we constructed a special BME-based three-dimensional culture system (3D-culture) to amplify LCSCs in human lung adenocarcinoma cell line A549 cells and found 3D-culture promoted the enrichment and amplification of LCSCs in A549 cells displaying higher proliferation potential and invasion activity, but lower apoptosis. The expression and secretion levels of FGF1 and IGF1 were dramatically elevated in 3D-culture compared to 2D-culture. After growing in FGF1 and IGF1-conditioned 3D-culture, the proportion of LCSCs with specific stemness phenotypes in A549 cells significantly increased compared to that in conventional 3D suspension culture system. Further results indicated that FGF1 and IGF1 promoted the amplification and cancer stemness of LCSCs dependent on MAPK signaling pathway. Our data firstly established a growth factors-conditioned 3D-culture for LCSCs and demonstrated the effects of FGF1 and IGF1 in promoting the enrichment and amplification of LCSCs which might provide a feasible cell model in vitro for both mechanism study and translational research on lung cancer.
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Affiliation(s)
- Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Rui Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China
| | - Yingnan Ye
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yanan Cheng
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Lei Han
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Li Dong
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yongzi Chen
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xiyin Wei
- Public Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China.
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27
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Arun S, Ravisankar S, Vanisree AJ. Implication of connexin30 on the stemness of glioma: connexin30 reverses the malignant phenotype of glioma by modulating IGF-1R, CD133 and cMyc. J Neurooncol 2017; 135:473-485. [PMID: 28875331 DOI: 10.1007/s11060-017-2608-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 08/20/2017] [Indexed: 01/24/2023]
Abstract
Gap-junctional intercellular communication (GJIC) plays a major role in the malignant growth of glioma. Although the mechanistic aspects of GJIC have been extensively studied, the role of connexins in the regulation of the malignant behavior of glioma stem cells (GSCs) remains unclear. In our previous studies, we have shown that connexin30 can interfere with the insulin-like growth factor 1 receptor (IGF-1R), which is known for self-renewal and pluripotency. Following our earlier in vitro observation, in this work, we aimed to study the consequence of this influence of Cx30 on IGF-1R by evaluating the marker of GSCs, CD133 and oncoprotein, cMyc. We strengthened our basis by examining human glioma samples of different grades as well as rat C6 xenografts (Cx30-transfected and -non-transfected C6 cells) along with the sphere formation assays in vitro. Investigation of stemness-related CD133 and cMyc in human samples and rat xenografts exhibited a reciprocal relationship between Cx30 and IGF-1R in the low and high grades (HG) of glioma. Cx30 was completely abolished in HG; levels of IGF-1R, CD133 and cMyc expression were positively correlated with HG. Cx30 transfection could attenuate the malignant burden of glioma in rat xenografts. Cx30 transfection also altered the tumor sphere formation of C6 glioma cells in vitro, an important property of GSCs, and there was a significant reduction of CD133 and cMyc expression by Cx30 both in vitro and in vivo. These factors indicate that dysfunction of Cx30 plays a crucial role in the prevention of the stemness of glioma, and the exploitation of this feature will help in the management of glioma.
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Affiliation(s)
- Sankaradoss Arun
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600 025, India
| | - Shantha Ravisankar
- Department of Neuropathology, Tamil Nadu Multi-Specialty Hospital, Chennai, Tamil Nadu, 600 003, India
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28
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Kijewska M, Kocyk M, Kloss M, Stepniak K, Korwek Z, Polakowska R, Dabrowski M, Gieryng A, Wojtas B, Ciechomska IA, Kaminska B. The embryonic type of SPP1 transcriptional regulation is re-activated in glioblastoma. Oncotarget 2017; 8:16340-16355. [PMID: 28030801 PMCID: PMC5369967 DOI: 10.18632/oncotarget.14092] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 12/16/2016] [Indexed: 11/25/2022] Open
Abstract
Osteopontin (SPP1, a secreted phosphoprotein 1) is primarily involved in immune responses, tissue remodelling and biomineralization. However, it is also overexpressed in many cancers and regulates tumour progression by increasing migration, invasion and cancer stem cell self-renewal. Mechanisms of SPP1 overexpression in gliomas are poorly understood. We demonstrate overexpression of two out of five SPP1 isoforms in glioblastoma (GBM) and differential isoform expression in glioma cell lines. Up-regulated SPP1 expression is associated with binding of the GLI1 transcription factor to the promoter and OCT4 (octamer-binding transcription factor 4) to the first SPP1 intron of the SPP1 gene in human glioma cells but not in non-transformed astrocytes. GLI1 knockdown reduced SPP1 mRNA and protein levels in glioma cells. GLI1 and OCT4 are known regulators of stem cell pluripotency. GBMs contain rare cells that express stem cell markers and display ability to self-renew. We reveal that SPP1 is overexpressed in glioma initiating cells defined by high rhodamine 123 efflux, sphere forming capacity and stemness marker expression. Forced differentiation of human glioma spheres reduced SPP1 expression. Knockdown of SPP1, GLI1 or CD44 with siRNAs diminished sphere formation. C6 glioma cells stably depleted of Spp1 displayed reduced sphere forming capacity and downregulated stemness marker expression. Overexpression of the wild type Spp1, but not Spp1 lacking a Cd44 binding domain, rescued cell ability to form spheres. Our findings show re-activation of the embryonic-type transcriptional regulation of SPP1 in malignant gliomas and point to the importance of SPP1-CD44 interactions in self-renewal and pluripotency glioma initiating cells.
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Affiliation(s)
- Magdalena Kijewska
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Marta Kocyk
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Michal Kloss
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Karolina Stepniak
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Zbigniew Korwek
- Laboratory of Molecular Bases of Aging, The Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | | | - Michal Dabrowski
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Anna Gieryng
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Bartosz Wojtas
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Iwona A Ciechomska
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
| | - Bozena Kaminska
- Laboratory of Molecular Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
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29
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The Roles of Insulin-Like Growth Factors in Mesenchymal Stem Cell Niche. Stem Cells Int 2017; 2017:9453108. [PMID: 28298931 PMCID: PMC5337393 DOI: 10.1155/2017/9453108] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 12/22/2016] [Accepted: 01/18/2017] [Indexed: 12/12/2022] Open
Abstract
Many tissues contain adult mesenchymal stem cells (MSCs), which may be used in tissue regeneration therapies. However, the MSC availability in most tissues is limited which demands expansion in vitro following isolation. Like many developing cells, the state of MSCs is affected by the surrounding microenvironment, and mimicking this natural microenvironment that supports multipotent or differentiated state in vivo is essential to understand for the successful use of MSC in regenerative therapies. Many researchers are, therefore, optimizing cell culture conditions in vitro by altering growth factors, extracellular matrices, chemicals, oxygen tension, and surrounding pH to enhance stem cells self-renewal or differentiation. Insulin-like growth factors (IGFs) system has been demonstrated to play an important role in stem cell biology to either promote proliferation and self-renewal or enhance differentiation onset and outcome, depending on the cell culture conditions. In this review, we will describe the importance of IGFs, IGF-1 and IGF-2, in development and in the MSC niche and how they affect the pluripotency or differentiation towards multiple lineages of the three germ layers.
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30
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Zhang X, Hua R, Wang X, Huang M, Gan L, Wu Z, Zhang J, Wang H, Cheng Y, Li J, Guo W. Identification of stem-like cells and clinical significance of candidate stem cell markers in gastric cancer. Oncotarget 2016; 7:9815-31. [PMID: 26769843 PMCID: PMC4891086 DOI: 10.18632/oncotarget.6890] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Accepted: 12/29/2015] [Indexed: 12/14/2022] Open
Abstract
The existence of gastric cancer stem cells (CSCs) has not been definitively proven and specific cell surface markers for identifying gastric CSCs have largely not been identified. Our research aimed to isolate potential gastric CSCs and clarify their clinical significance, while defining markers for GCSC identification and verification. Here, we report that spheroid cells possess stem cell-like properties, and overexpress certain stem cell markers. CD133 or CD44-positive cells also exhibit properties of CSCs. The expression of Oct4, Sox2, Gli1, CD44, CD133, p-AKT, and p-ERK was significantly higher in metastatic lesions compared to that in primary lesions. Elevated expression of some of these proteins was correlated with a more aggressive phenotype and poorer prognosis, including Oct4, Sox2, Gli1, CD44, and p-ERK. Multivariate Cox proportional hazards model analysis showed that only CD44 is an independent factor. Knockdown of CD44 down-regulated the stem cell-like properties, which was accompanied by the down-regulation of p-ERK and Oct4. Oct4 overexpression could reverse the decreased CSCs properties induced by CD44 knockdown. Taken together, our research revealed that spheroid cell culture, and CD133 or CD44-labeled FACS methods can be used to isolate gastric CSCs. Some CSC markers have clinical significance in predicting the prognosis. CD44 is an independent prognostic factor and maintains the properties of CSCs in CD44-p-ERK-Oct4 positive feedback loop.
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Affiliation(s)
- Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Ruixi Hua
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaofeng Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Mingzhu Huang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Lu Gan
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Zhenhua Wu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Jiejun Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Hongqiang Wang
- Department of Cancer Chemotherapy Center, Zhoushan Hospital, Zhejiang, China
| | - Yufan Cheng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Cancer Hospital of Fudan University, Shanghai, China
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31
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Gao YF, Wang ZB, Zhu T, Mao CX, Mao XY, Li L, Yin JY, Zhou HH, Liu ZQ. A critical overview of long non-coding RNA in glioma etiology 2016: an update. Tumour Biol 2016; 37:14403-14413. [DOI: 10.1007/s13277-016-5307-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 09/05/2016] [Indexed: 12/31/2022] Open
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32
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Kelley K, Knisely J, Symons M, Ruggieri R. Radioresistance of Brain Tumors. Cancers (Basel) 2016; 8:cancers8040042. [PMID: 27043632 PMCID: PMC4846851 DOI: 10.3390/cancers8040042] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 03/10/2016] [Accepted: 03/24/2016] [Indexed: 12/21/2022] Open
Abstract
Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation.
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Affiliation(s)
- Kevin Kelley
- Radiation Medicine Department, Hofstra Northwell School of Medicine, Northwell Health, Manhasset, NY 11030, USA.
| | - Jonathan Knisely
- Radiation Medicine Department, Hofstra Northwell School of Medicine, Northwell Health, Manhasset, NY 11030, USA.
| | - Marc Symons
- The Feinstein Institute for Molecular Medicine, Hofstra Northwell School of Medicine, Northwell Health, Manhasset, NY 11030, USA.
| | - Rosamaria Ruggieri
- Radiation Medicine Department, Hofstra Northwell School of Medicine, Northwell Health, Manhasset, NY 11030, USA.
- The Feinstein Institute for Molecular Medicine, Hofstra Northwell School of Medicine, Northwell Health, Manhasset, NY 11030, USA.
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33
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Yan GN, Lv YF, Guo QN. Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets. Cancer Lett 2016; 370:268-74. [DOI: 10.1016/j.canlet.2015.11.003] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 11/03/2015] [Accepted: 11/03/2015] [Indexed: 12/15/2022]
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34
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The hedgehog antagonist HHIP as a favorable prognosticator in glioblastoma. Tumour Biol 2015; 37:3979-86. [PMID: 26482617 DOI: 10.1007/s13277-015-3442-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 04/08/2015] [Indexed: 01/19/2023] Open
Abstract
Inactivation of hedgehog-interacting protein (HHIP) and overexpression of Gli1 play vital roles in the development of diverse human cancers. The aim of this study is to examine the association of HHIP and Gli1 with the clinicopathologic features and prognosis of patients with glioblastoma (GBM). The expression of HHIP and Gli1 in 103 patients with GBM and 32 control patients was investigated by immunohistochemistry. Statistical analysis was utilized to evaluate the association of HHIP as well as Gli1 with clinicopathological characteristics and prognosis of patients. HHIP and Gli1 were dysregulated in GBM. Spearman's rank analysis showed that HHIP and Gli1 had an inverse correlation (r = -0.386, P = 0.000). Expression of HHIP was significantly correlated with age (P = 0.000), gender (P = 0.003), seizure (P = 0.013), resection degree (P = 0.033), adjuvant treatment (P = 0.030), and O(6)-methylguanine-DNA methyltransferase (MGMT) methylation (P = 0.021), while Gli1 expression was significantly correlated with age (P = 0.002), gender (P = 0.033), Karnofsky performance status (KPS) score (P = 0.028), resection degree (P = 0.000), adjuvant treatment (P = 0.014), and MGMT methylation (P = 0.030). Kaplan-Meier method showed that patients with low Gli1 expression had longer overall survival (OS) than those with high Gli1 expression (P = 0.000) and the OS of the patients with HHIP-positive GBM was significantly longer than that of the patients with HHIP-negative GBM (P = 0.000). Univariate and multivariate analyses confirmed that HHIP expression and Gli1 expression were independent prognostic factors. Our data suggested that expression of HHIP could be considered as significant prognostic marker for patients with GBM.
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35
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Persano L, Zagoura D, Louisse J, Pistollato F. Role of Environmental Chemicals, Processed Food Derivatives, and Nutrients in the Induction of Carcinogenesis. Stem Cells Dev 2015; 24:2337-52. [DOI: 10.1089/scd.2015.0081] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Luca Persano
- Istituto di Riceca Pediatrica Città della Speranza—IRP, Padova, Italy
- Department of Woman and Child Health, University of Padova, Padova, Italy
| | - Dimitra Zagoura
- Laboratory of Biology, University of Athens School of Medicine, Athens, Greece
| | - Jochem Louisse
- Division of Toxicology, Wageningen University, Wageningen, the Netherlands
| | - Francesca Pistollato
- Center for Nutrition & Health, Universidad Europea del Atlantico (UEA), Santander, Spain
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36
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Rovida E, Stecca B. Mitogen-activated protein kinases and Hedgehog-GLI signaling in cancer: A crosstalk providing therapeutic opportunities? Semin Cancer Biol 2015; 35:154-67. [PMID: 26292171 DOI: 10.1016/j.semcancer.2015.08.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 08/07/2015] [Accepted: 08/10/2015] [Indexed: 01/07/2023]
Abstract
The Hedgehog-GLI (HH-GLI) signaling is of critical importance during embryonic development, where it regulates a number of cellular processes, including patterning, proliferation and differentiation. Its aberrant activation has been linked to several types of cancer. HH-GLI signaling is triggered by binding of ligands to the transmembrane receptor patched and is subsequently mediated by transcriptional effectors belonging to the GLI family, whose function is fine tuned by a series of molecular interactions and modifications. Several HH-GLI inhibitors have been developed and are in clinical trials. Similarly, the mitogen-activated protein kinases (MAPK) are involved in a number of biological processes and play an important role in many diseases including cancer. Inhibiting molecules targeting MAPK signaling, especially those elicited by the MEK1/2-ERK1/2 pathway, have been developed and are moving into clinical trials. ERK1/2 may be activated as a consequence of aberrant activation of upstream signaling molecules or during development of drug resistance following treatment with kinase inhibitors such as those for PI3K or BRAF. Evidence of a crosstalk between HH-GLI and other oncogenic signaling pathways has been reported in many tumor types, as shown by recent reviews. Here we will focus on the interaction between HH-GLI and the final MAPK effectors ERK1/2, p38 and JNK in cancer in view of its possible implications for cancer therapy. Several reports highlight the existence of a consistent crosstalk between HH signaling and MAPK, especially with the MEK1/2-ERK1/2 pathway, and this fact should be taken into consideration for designing optimal treatment and prevent tumor relapse.
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Affiliation(s)
- Elisabetta Rovida
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Sezione di Patologia, Università degli Studi di Firenze, Firenze, Italy
| | - Barbara Stecca
- Laboratory of Tumor Cell Biology, Core Research Laboratory-Istituto Toscano Tumori (CRL-ITT), Florence, Italy; Department of Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
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37
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Cherepanov SA, Baklaushev VP, Gabashvili AN, Shepeleva II, Chekhonin VP. [Hedgehog signaling in the pathogenesis of neuro-oncology diseases]. BIOMEDITSINSKAIA KHIMIIA 2015; 61:332-342. [PMID: 26215410 DOI: 10.18097/pbmc20156103332] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2025]
Abstract
The review summarizes current knowledge on the Hedgehog signaling pathway, its role in normal embryogenesis and/or initiation and progression of neuro-oncological diseases, especially of high-grade gliomas, the most malignant neuroepithelial tumors. The main proteins forming the Hedgehog signaling pathway include Shh, PTCH1, SMO, HHIP, SUFU and GLI1 isoforms. Effects of other signaling pathways on the family of transcription factors GLI and other proteins are described. The review summarizes modern data about the impact of the Hedgehog signaling pathway on proliferation, migration activity and invasiveness, and also on tumor neoangiogenesis and tumor cell chemoresistance. The role of the Hedgehog signaling pathway in origin of cancer stem cells and epithelial-mesenchymal transition is also analyzed. Some prospects for new anticancer drugs acting on components of the Hedgehog signaling pathway inhibitors are demonstrated.
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Affiliation(s)
- S A Cherepanov
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - V P Baklaushev
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - A N Gabashvili
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - I I Shepeleva
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - V P Chekhonin
- Pirogov Russian National Research Medical University, Moscow, Russia
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38
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Denduluri SK, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed MK, Ye J, Wei Q, Wang J, Zhao L, Luu HH. Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis 2015; 2:13-25. [PMID: 25984556 PMCID: PMC4431759 DOI: 10.1016/j.gendis.2014.10.004] [Citation(s) in RCA: 239] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 10/15/2014] [Indexed: 12/18/2022] Open
Abstract
One of the greatest obstacles to current cancer treatment efforts is the development of drug resistance by tumors. Despite recent advances in diagnostic practices and surgical interventions, many neoplasms demonstrate poor response to adjuvant or neoadjuvant radiation and chemotherapy. As a result, the prognosis for many patients afflicted with these aggressive cancers remains bleak. The insulin-like growth factor (IGF) signaling axis has been shown to play critical role in the development and progression of various tumors. Many basic science and translational studies have shown that IGF pathway modulators can have promising effects when used to treat various malignancies. There also exists a substantial body of recent evidence implicating IGF signaling dysregulation in the dwindling response of tumors to current standard-of-care therapy. By better understanding both the IGF-dependent and -independent mechanisms by which pathway members can influence drug sensitivity, we can eventually aim to use modulators of IGF signaling to augment the effects of current therapy. This review summarizes and synthesizes numerous recent investigations looking at the role of the IGF pathway in drug resistance. We offer a brief overview of IGF signaling and its general role in neoplasia, and then delve into detail about the many types of human cancer that have been shown to have IGF pathway involvement in resistance and/or sensitization to therapy. Ultimately, our hope is that such a compilation of evidence will compel investigators to carry out much needed studies looking at combination treatment with IGF signaling modulators to overcome current therapy resistance.
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Affiliation(s)
- Sahitya K. Denduluri
- The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
| | - Olumuyiwa Idowu
- The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
| | - Zhongliang Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China
| | - Zhan Liao
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, Xiang-Ya Hospital of Central South University, Changsha 410008, China
| | - Zhengjian Yan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China
| | - Maryam K. Mohammed
- The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
| | - Jixing Ye
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
- School of Bioengineering, Chongqing University, Chongqing, China
| | - Qiang Wei
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China
| | - Jing Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China
| | - Lianggong Zhao
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, the Second Affiliated Hospital of Lanzhou University, Lanzhou, Gansu 730000, China
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
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Jia Y, Wang Y, Xie J. The Hedgehog pathway: role in cell differentiation, polarity and proliferation. Arch Toxicol 2015; 89:179-91. [PMID: 25559776 PMCID: PMC4630008 DOI: 10.1007/s00204-014-1433-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 12/04/2014] [Indexed: 02/07/2023]
Abstract
Hedgehog (Hh) is first described as a genetic mutation that has "spiked" phenotype in the cuticles of Drosophila in later 1970s. Since then, Hh signaling has been implicated in regulation of differentiation, proliferation, tissue polarity, stem cell population and carcinogenesis. The first link of Hh signaling to cancer was established through discovery of genetic mutations of Hh receptor gene PTCH1 being responsible for Gorlin syndrome in 1996. It was later shown that Hh signaling is associated with many types of cancer, including skin, leukemia, lung, brain and gastrointestinal cancers. Another important milestone for the Hh research field is the FDA approval for the clinical use of Hh inhibitor Erivedge/Vismodegib for treatment of locally advanced and metastatic basal cell carcinomas. However, recent clinical trials of Hh signaling inhibitors in pancreatic, colon and ovarian cancer all failed, indicating a real need for further understanding of Hh signaling in cancer. In this review, we will summarize recent progress in the Hh signaling mechanism and its role in human cancer.
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Affiliation(s)
- Yanfei Jia
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong, University, Jinan, China
- Division of Hematology and Oncology, Department of Pediatrics, Wells Center for Pediatric Research, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
| | - Yunshan Wang
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong, University, Jinan, China
| | - Jingwu Xie
- Division of Hematology and Oncology, Department of Pediatrics, Wells Center for Pediatric Research, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
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40
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Goffart N, Dedobbeleer M, Rogister B. Glioblastoma stem cells: new insights in therapeutic strategies. FUTURE NEUROLOGY 2014. [DOI: 10.2217/fnl.14.56] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
ABSTRACT Despite notable achievements in glioblastoma diagnosis and treatment, the prognosis of glioblastoma patients remains poor and reflects the failure of current therapeutic modalities. In this context, innovative therapeutic strategies have recently been developed to specifically target glioblastoma stem cells, a subpopulation of tumor cells involved in experimental tumorigenesis and known to be critical for tumor recurrence and therapeutic resistance. The current review summarizes the different trails which make glioblastoma stem cells resistant to treatments, mainly focusing on radio-, chemo- and immunotherapy. This broad overview might actually help to set up new bases for glioblastoma therapy in order to better fight tumor relapses and to improve the patients’ prognosis.
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Affiliation(s)
- Nicolas Goffart
- Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium
| | - Matthias Dedobbeleer
- Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium
| | - Bernard Rogister
- Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium
- Department of Neurology, CHU & University of Liège, Liège, Belgium
- GIGA-Development, Stem Cells & Regenerative Medicine, University of Liège, Liège, Belgium
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41
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Bakry OA, Samaka RM, Shoeib MAM, Megahed DM. Immunolocalization of glioma-associated oncogene homolog 1 in non melanoma skin cancer. Ultrastruct Pathol 2014; 39:135-46. [PMID: 25350271 DOI: 10.3109/01913123.2014.970723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Glioma-associated oncogene homolog (GLI)1 is involved in controlling cell proliferation and angiogenesis. The aim of this work was to explore its possible role in non-melanoma skin cancer pathogenesis through its immunohistochemical (IHC) expression in skin biopsies of these diseases and correlating this expression with the clinico-pathological parameters of the studied cases. Seventy-six cutaneous specimens were studied; 30 cases with basal cell carcinoma (BCC), 30 cases with squamous cell carcinoma (SCC) and 16 normal skin samples, from age- and gender-matched subjects, as a control group. GLI1 was expressed in all BCC cases and in 60% of SCC cases. All SCC cases showed cytoplasmic, while 70% of BCC cases showed nucleocytoplasmic immunoreactivity. It was over expressed in BCC and SCC compared to normal skin (p = 0.01 and 0.0006, respectively). Higher Histo (H) score in BCC cases was significantly associated with female gender (p = 0.04), multiple lesions, desmoplastic stromal reaction and stromal angiogenesis (p < 0.001 for all). Higher H score in SCC cases was significantly associated with scalp location, nodular type, recurrent lesions, high tumor grade, lymphovascular invasion (p = 0.004 for all), inflammatory stromal reaction (p = 0.01), lymph node involvement and absence of calcification (p = 0.001 for both). In conclusion, GLI1 may play a role in BCC pathogenesis through its role in cell proliferation, migration, and angiogenesis. Its upregulation and cytoplasmic localization in SCC may suggest that its role in tumor pathogenesis is through mechanisms other than Hedgehog pathway activation. Further studies are needed to clarify the exact molecular basis of its oncogenic action.
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Affiliation(s)
- Ola Ahmed Bakry
- Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufiya University , Shibeen El Kom , Egypt and
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Wang YY, Zhang T, Li SW, Qian TY, Fan X, Peng XX, Ma J, Wang L, Jiang T. Mapping p53 mutations in low-grade glioma: a voxel-based neuroimaging analysis. AJNR Am J Neuroradiol 2014; 36:70-6. [PMID: 25104286 DOI: 10.3174/ajnr.a4065] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND PURPOSE Brain tumor location has proved to be a prognostic factor that may be associated with features of neoplastic origin. Mutation of p53 is an atypical genetic change that occurs during tumorigenesis. Thus, a potential correlation may exist between tumor location and p53 status. The purpose of the current study was to identify anatomic characteristics of mutant p53 expression by using quantitative neuroimaging analyses. MATERIALS AND METHODS Preoperative MR images from 182 patients with histologically confirmed low-grade gliomas were retrospectively analyzed. All tumors were manually marked and registered to the standard space. Using a voxel-based lesion-symptom mapping analysis, we located brain regions associated with a high occurrence of p53 mutation and corrected them by using a permutation test. The acquired clusters were further included as a factor in survival analyses. RESULTS Statistical analysis demonstrated that the left medial temporal lobe and right anterior temporal lobe were specifically associated with high expression of mutant p53. Kaplan-Meier curves showed that tumors located in these regions were associated with significantly worse progression-free survival compared with tumors occurring elsewhere. CONCLUSIONS Our voxel-level imaging analysis provides new evidence that genetic changes during cancer may have anatomic specificity. Additionally, the current study suggests that tumor location identified on structural MR images could potentially be used for customized presurgical outcome prediction.
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Affiliation(s)
- Y Y Wang
- From the Beijing Neurosurgical Institute (Y.Y.W., T.J.) Departments of Neurosurgery (Y.Y.W., T.Z., X.F., L.W., T.J.)
| | - T Zhang
- Departments of Neurosurgery (Y.Y.W., T.Z., X.F., L.W., T.J.)
| | - S W Li
- Neuroradiology (S.W.L., J.M.), Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - T Y Qian
- Siemens Healthcare (T.Y.Q.), MR Collaboration NE Asia, Beijing, China
| | - X Fan
- Departments of Neurosurgery (Y.Y.W., T.Z., X.F., L.W., T.J.)
| | - X X Peng
- Department of Epidemiology and Biostatistics (X.X.P.), School of Public Health and Family Medicine, Capital Medical University, Beijing, China
| | - J Ma
- Neuroradiology (S.W.L., J.M.), Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - L Wang
- Departments of Neurosurgery (Y.Y.W., T.Z., X.F., L.W., T.J.) China National Clinical Research Center for Neurological Diseases (L.W.), Beijing, China
| | - T Jiang
- From the Beijing Neurosurgical Institute (Y.Y.W., T.J.) Departments of Neurosurgery (Y.Y.W., T.Z., X.F., L.W., T.J.) Beijing Institute for Brain Disorders (T.J.), Beijing, China.
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Abstract
The hedgehog (Hh) signaling pathway is well established as being evolutionarily conserved across vertebrates, and is involved in organogenesis, hematopoiesis, embryogenesis and homeostasis of adult tissues. At a microscopic level, the Hh signaling pathway controls the proliferation, apoptosis, cell-cycle and differentiation programs of stem and progenitor cells. Increasing evidence suggests that aberrant activation of the Hh signaling pathway is related to neoplasm, including solid tumors and hematologic malignancies. Currently the Hh signaling pathway has become one of the most studied potential therapeutic targets in hematological malignancies. In this review, we focus on findings related to Hh signaling in the initiation, maintenance, progression and chemoresistance of hematological malignancies, looking forward to better targeted treatment strategies.
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Affiliation(s)
- Lingyun Geng
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong , P. R. China
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Malaguarnera R, Belfiore A. The emerging role of insulin and insulin-like growth factor signaling in cancer stem cells. Front Endocrinol (Lausanne) 2014; 5:10. [PMID: 24550888 PMCID: PMC3912738 DOI: 10.3389/fendo.2014.00010] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 01/21/2014] [Indexed: 12/20/2022] Open
Abstract
Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth, and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT) and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the evidences indicating that IGF signaling enhances the expression of transcription factors implicated in the EMT program and has extensive cross-talk with specific pathways involved in cell pluripotency and stemness maintenance. In turn, EMT and cell stemness activate positive feed-back mechanisms causing up-regulation of various IGF signaling components. These findings may have novel translational implications.
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Affiliation(s)
- Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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New molecules and old drugs as emerging approaches to selectively target human glioblastoma cancer stem cells. BIOMED RESEARCH INTERNATIONAL 2014; 2014:126586. [PMID: 24527434 PMCID: PMC3909978 DOI: 10.1155/2014/126586] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 12/04/2013] [Indexed: 02/07/2023]
Abstract
Despite relevant progress obtained by multimodal treatment, glioblastoma (GBM), the most aggressive primary brain tumor, is still incurable. The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs), since these cells appear to represent the determinants of resistance to current standard therapies. The goal of most ongoing studies is to identify drugs able to affect CSCs biology, either inducing selective toxicity or differentiating this tumor cell population into nontumorigenic cells. Moreover, the therapeutic approach for GBM could be improved interfering with chemo- or radioresistance mechanisms, microenvironment signals, and the neoangiogenic process. During the last years, molecular targeted compounds such as sorafenib and old drugs, like metformin, displayed interesting efficacy in preclinical studies towards several tumors, including GBM, preferentially affecting CSC viability. In this review, the latest experimental results, controversies, and prospective application concerning these promising anticancer drugs will be discussed.
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Erdreich-Epstein A, Robison N, Ren X, Zhou H, Xu J, Davidson TB, Schur M, Gilles FH, Ji L, Malvar J, Shackleford GM, Margol AS, Krieger MD, Judkins AR, Jones DTW, Pfister SM, Kool M, Sposto R, Asgharzadeh S, Asgharazadeh S. PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas. Clin Cancer Res 2013; 20:827-36. [PMID: 24300787 DOI: 10.1158/1078-0432.ccr-13-2053] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
PURPOSE We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. EXPERIMENTAL DESIGN AND RESULTS Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets, PID1 mRNA was lower in glioblastomas (GBM), the most malignant gliomas, compared with other astrocytomas, oligodendrogliomas and nontumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared with classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients whose tumors had higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in patients with glioma and GBM. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolaization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT, and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization. CONCLUSIONS These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors.
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Affiliation(s)
- Anat Erdreich-Epstein
- Authors' Affiliations: Departments of Pediatrics, Pathology, Radiology, and Neurosurgery, at the Saban Research Institute at Children's Hospital Los Angeles, Norris Comprehensive Cancer Center; Departments of Preventive Medicine and Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California; Division of Pediatric Neurooncology at the German Cancer Research Center DKFZ; and Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
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Du WZ, Feng Y, Wang XF, Piao XY, Cui YQ, Chen LC, Lei XH, Sun X, Liu X, Wang HB, Li XF, Yang DB, Sun Y, Zhao ZF, Jiang T, Li YL, Jiang CL. Curcumin suppresses malignant glioma cells growth and induces apoptosis by inhibition of SHH/GLI1 signaling pathway in vitro and vivo. CNS Neurosci Ther 2013; 19:926-36. [PMID: 24165291 DOI: 10.1111/cns.12163] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 07/14/2013] [Accepted: 07/15/2013] [Indexed: 01/06/2023] Open
Abstract
AIMS To study the role of curcumin on glioma cells via the SHH/GLI1 pathway in vitro and vivo. METHODS The effects of curcumin on proliferation, migration, apoptosis, SHH/GLI1 signaling, and GLI1 target genes expression were evaluated in multiple glioma cell lines in vitro. A U87-implanted nude mice model was used to study the role of curcumin on tumor volume and the suppression efficacy of GLI1. RESULTS Curcumin showed cytotoxic effects on glioma cell lines in vitro. Both mRNA and protein levels of SHH/GLI1 signaling (Shh, Smo, GLI1) were downregulated in a dose- and time-dependent manner. Several GLI1-dependent target genes (CyclinD1, Bcl-2, Foxm1) were also downregulated. Curcumin treatment prevented GLI1 translocating into the cell nucleus and reduced the concentration of its reporter. Curcumin suppressed cell proliferation, colony formation, migration, and induced apoptosis which was mediated partly through the mitochondrial pathway after an increase in the ratio of Bax to Bcl2. Intraperitoneal injection of curcumin in vivo reduced tumor volume, GLI1 expression, the number of positively stained cells, and prolonged the survival period compared with the control group. CONCLUSION This study shows that curcumin holds a great promise for SHH/GLI1 targeted therapy against gliomas.
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Affiliation(s)
- Wen-Zhong Du
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Xie J, Bartels CM, Barton SW, Gu D. Targeting hedgehog signaling in cancer: research and clinical developments. Onco Targets Ther 2013; 6:1425-35. [PMID: 24143114 PMCID: PMC3797650 DOI: 10.2147/ott.s34678] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Since its first description in Drosophila by Drs Nusslein-Volhard and Wieschaus in 1980, hedgehog (Hh) signaling has been implicated in regulation of cell differentiation, proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of Gorlin syndrome in 1996 by two independent teams. Later, it was shown that Hh signaling may be involved in many types of cancer, including skin, leukemia, lung, brain, and gastrointestinal cancers. In early 2012, the US Food and Drug Administration approved the clinical use of Hh inhibitor Erivedge/vismodegib for treatment of locally advanced and metastatic basal cell carcinomas. With further investigation, it is possible to see more clinical applications of Hh signaling inhibitors. In this review, we will summarize major advances in the last 3 years in our understanding of Hh signaling activation in human cancer, and recent developments in preclinical and clinical studies using Hh signaling inhibitors.
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Affiliation(s)
- Jingwu Xie
- Wells Center for Pediatric Research, Division of Hematology and Oncology, Department of Pediatrics, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN, USA
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Osuka S, Sampetrean O, Shimizu T, Saga I, Onishi N, Sugihara E, Okubo J, Fujita S, Takano S, Matsumura A, Saya H. IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. Stem Cells 2013; 31:627-40. [PMID: 23335250 DOI: 10.1002/stem.1328] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 12/20/2012] [Indexed: 01/07/2023]
Abstract
Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.
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Affiliation(s)
- Satoru Osuka
- Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Filbin MG, Dabral SK, Pazyra-Murphy MF, Ramkissoon S, Kung AL, Pak E, Chung J, Theisen MA, Sun Y, Franchetti Y, Sun Y, Shulman DS, Redjal N, Tabak B, Beroukhim R, Wang Q, Zhao J, Dorsch M, Buonamici S, Ligon KL, Kelleher JF, Segal RA. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nat Med 2013; 19:1518-23. [PMID: 24076665 DOI: 10.1038/nm.3328] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 08/06/2013] [Indexed: 01/17/2023]
Abstract
In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.
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Affiliation(s)
- Mariella Gruber Filbin
- 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [4] Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
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