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Begagić E, Bečulić H, Džidić-Krivić A, Kadić Vukas S, Hadžić S, Mekić-Abazović A, Šegalo S, Papić E, Muchai Echengi E, Pugonja R, Kasapović T, Kavgić D, Nuhović A, Juković-Bihorac F, Đuričić S, Pojskić M. Understanding the Significance of Hypoxia-Inducible Factors (HIFs) in Glioblastoma: A Systematic Review. Cancers (Basel) 2024; 16:2089. [PMID: 38893207 PMCID: PMC11171068 DOI: 10.3390/cancers16112089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/25/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND The study aims to investigate the role of hypoxia-inducible factors (HIFs) in the development, progression, and therapeutic potential of glioblastomas. METHODOLOGY The study, following PRISMA guidelines, systematically examined hypoxia and HIFs in glioblastoma using MEDLINE (PubMed), Web of Science, and Scopus. A total of 104 relevant studies underwent data extraction. RESULTS Among the 104 studies, global contributions were diverse, with China leading at 23.1%. The most productive year was 2019, accounting for 11.5%. Hypoxia-inducible factor 1 alpha (HIF1α) was frequently studied, followed by hypoxia-inducible factor 2 alpha (HIF2α), osteopontin, and cavolin-1. Commonly associated factors and pathways include glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) receptors, vascular endothelial growth factor (VEGF), phosphoinositide 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway, and reactive oxygen species (ROS). HIF expression correlates with various glioblastoma hallmarks, including progression, survival, neovascularization, glucose metabolism, migration, and invasion. CONCLUSION Overcoming challenges such as treatment resistance and the absence of biomarkers is critical for the effective integration of HIF-related therapies into the treatment of glioblastoma with the aim of optimizing patient outcomes.
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Affiliation(s)
- Emir Begagić
- Department of General Medicine, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Hakija Bečulić
- Department of Neurosurgery, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina;
- Department of Anatomy, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Amina Džidić-Krivić
- Department of Neurology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina (S.K.V.)
| | - Samra Kadić Vukas
- Department of Neurology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina (S.K.V.)
| | - Semir Hadžić
- Department of Physiology, Faculty of Medicine, University of Tuzla, 75000 Tuzla, Bosnia and Herzegovina
| | - Alma Mekić-Abazović
- Department of Oncology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Sabina Šegalo
- Department of Laboratory Technologies, Faculty of Health Studies, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina; (S.Š.); (E.P.)
| | - Emsel Papić
- Department of Laboratory Technologies, Faculty of Health Studies, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina; (S.Š.); (E.P.)
| | - Emmanuel Muchai Echengi
- College of Health Sciences, School of Medicine, Kenyatta University, Nairobi 43844-00100, Kenya
| | - Ragib Pugonja
- Department of Anatomy, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Tarik Kasapović
- Department of Physiology, Faculty of Medicine, University of Tuzla, 75000 Tuzla, Bosnia and Herzegovina
| | - Dalila Kavgić
- Department of Physiology, Faculty of Medicine, University of Tuzla, 75000 Tuzla, Bosnia and Herzegovina
| | - Adem Nuhović
- Department of General Medicine, School of Medicine, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina;
| | - Fatima Juković-Bihorac
- Department of Pathology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina
- Department of Pathology, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina;
| | - Slaviša Đuričić
- Department of Pathology, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina;
| | - Mirza Pojskić
- Department of Neurosurgery, University Hospital Marburg, 35033 Marburg, Germany
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Shah S, Mansour HM, Aguilar TM, Lucke-Wold B. Advances in Anti-Cancer Drug Development: Metformin as Anti-Angiogenic Supplemental Treatment for Glioblastoma. Int J Mol Sci 2024; 25:5694. [PMID: 38891882 PMCID: PMC11171521 DOI: 10.3390/ijms25115694] [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: 04/27/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin's possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.
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Affiliation(s)
- Siddharth Shah
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
| | - Hadeel M. Mansour
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
| | - Tania M. Aguilar
- College of Medicine at Chicago, University of Illinois, Chicago, IL 60612, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
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Wang H, Kaplan FS, Pignolo RJ. The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification. Biomolecules 2024; 14:147. [PMID: 38397384 PMCID: PMC10887042 DOI: 10.3390/biom14020147] [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: 12/11/2023] [Revised: 01/16/2024] [Accepted: 01/23/2024] [Indexed: 02/25/2024] Open
Abstract
Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (ACVR1, also known as ALK2) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1α inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1α and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1α and the mTOR pathways into clinical interventions for FOP and other forms of HO.
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Affiliation(s)
- Haitao Wang
- Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Frederick S. Kaplan
- Department of Orthopaedic Surgery, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Medicine, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA
- The Center for Research in FOP and Related Disorders, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert J. Pignolo
- Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Medicine, Divisions of Endocrinology, Hospital Internal Medicine, Rochester, MN 55905, USA
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Romagnoli R, De Ventura T, Manfredini S, Baldini E, Supuran CT, Nocentini A, Brancale A, Bortolozzi R, Manfreda L, Viola G. Design, synthesis, and biological investigation of selective human carbonic anhydrase II, IX, and XII inhibitors using 7-aryl/heteroaryl triazolopyrimidines bearing a sulfanilamide scaffold. J Enzyme Inhib Med Chem 2023; 38:2270180. [PMID: 37850364 PMCID: PMC10586084 DOI: 10.1080/14756366.2023.2270180] [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: 07/17/2023] [Accepted: 10/07/2023] [Indexed: 10/19/2023] Open
Abstract
A novel library of human carbonic anhydrase (hCA) inhibitors based on the 2-sulfanilamido[1,2,4]triazolo[1,5-a]pyrimidine skeleton modified at its 7-position was prepared by an efficient convergent procedure. These derivatives were evaluated in vitro for their inhibition properties against a representative panel of hCA isoforms (hCA I, II, IV, IX, and XII). The target tumour-associated isoforms hCA IX and XII were potently inhibited with KIs in the low nanomolar range of 5-96 nM and 4-72 nM, respectively. Compounds 1d, 1j, 1v, and 1x were the most potent hCA IX inhibitors with KIs of 5.1, 8.6, 4.7, and 5.1 nM, respectively. Along with derivatives 1d and 1j, compounds 1r and 1ab potently inhibited hCA XII isoform with KIs in a single-digit nanomolar range of 8.8, 5.4, 4.3, and 9.0 nM, respectively. Compounds 1e, 1m, and 1p exhibited the best selectivity against hCA IX and hCA XII isoforms over off-target hCA II, with selectivity indexes ranging from 5 to 14.
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Affiliation(s)
- Romeo Romagnoli
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy
| | - Tiziano De Ventura
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy
| | - Stefano Manfredini
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Erika Baldini
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Claudiu T. Supuran
- Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy
| | - Alessio Nocentini
- Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy
| | - Andrea Brancale
- Vysoká Škola Chemicko-Technologická v Praze, Prague, Czech Republic
| | - Roberta Bortolozzi
- Department of Woman’s and Child’s Health, Hemato-Oncology Lab, University of Padova, Padova, Italy
- Department of Pharmaceutical and Pharmacological Sciences, Section of Pharmacology, University of Padova, Padova, Italy
- Laboratory of Experimental Pharmacology, Istituto di Ricerca Pediatrica (IRP), Padova, Italy
| | - Lorenzo Manfreda
- Department of Woman’s and Child’s Health, Hemato-Oncology Lab, University of Padova, Padova, Italy
- Laboratory of Experimental Pharmacology, Istituto di Ricerca Pediatrica (IRP), Padova, Italy
| | - Giampietro Viola
- Department of Woman’s and Child’s Health, Hemato-Oncology Lab, University of Padova, Padova, Italy
- Laboratory of Experimental Pharmacology, Istituto di Ricerca Pediatrica (IRP), Padova, Italy
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Dowling AL, Walbridge S, Ertekin C, Namagiri S, Camacho K, Chowdhury A, Bryant JP, Kohut E, Heiss JD, Brown DA, Kumbar SG, Banasavadi-Siddegowda YK. FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres. Cells 2023; 12:2562. [PMID: 37947640 PMCID: PMC10647221 DOI: 10.3390/cells12212562] [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: 08/15/2023] [Revised: 10/24/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023] Open
Abstract
Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions, including apoptosis and autophagy. In this study, we tested the role of FKBP38 in glioblastoma tumor biology. Expression of FKBP38 was upregulated in the patient-derived primary glioblastoma neurospheres (GBMNS), compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNSs and increased the caspase 3/7 activity, indicating that FKBP38 is required for the survival of GBMNSs. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed, implying that FKBP38 regulates the self-renewal of GBMNSs. Additionally, the transient knockdown of FKBP38 increased the LC3-II/I ratio, suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNSs is mediated through the JNK/C-Jun-PTEN-AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest that targeting FKBP38 imparts an anti-glioblastoma effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for glioblastoma therapy.
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Affiliation(s)
- Aimee L. Dowling
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Stuart Walbridge
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Celine Ertekin
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Sriya Namagiri
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Krystal Camacho
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Ashis Chowdhury
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Jean-Paul Bryant
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Eric Kohut
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - John D. Heiss
- Clinical Neurology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Desmond A. Brown
- Neurosurgical Oncology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Sangamesh G. Kumbar
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT 06030, USA;
| | - Yeshavanth Kumar Banasavadi-Siddegowda
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
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Herrmann A, Meyer AK, Braunschweig L, Wagenfuehr L, Markert F, Kolitsch D, Vukicevic V, Hartmann C, Siebert M, Ehrhart-Bornstein M, Hermann A, Storch A. Notch is Not Involved in Physioxia-Mediated Stem Cell Maintenance in Midbrain Neural Stem Cells. Int J Stem Cells 2023; 16:293-303. [PMID: 37105558 PMCID: PMC10465337 DOI: 10.15283/ijsc22168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 02/10/2023] [Accepted: 03/17/2023] [Indexed: 04/29/2023] Open
Abstract
Background and Objectives The physiological oxygen tension in fetal brains (∼3%, physioxia) is beneficial for the maintenance of neural stem cells (NSCs). Sensitivity to oxygen varies between NSCs from different fetal brain regions, with midbrain NSCs showing selective susceptibility. Data on Hif-1α/Notch regulatory interactions as well as our observations that Hif-1α and oxygen affect midbrain NSCs survival and proliferation prompted our investigations on involvement of Notch signalling in physioxia-dependent midbrain NSCs performance. Methods and Results Here we found that physioxia (3% O2) compared to normoxia (21% O2) increased proliferation, maintained stemness by suppression of spontaneous differentiation and supported cell cycle progression. Microarray and qRT-PCR analyses identified significant changes of Notch related genes in midbrain NSCs after long-term (13 days), but not after short-term physioxia (48 hours). Consistently, inhibition of Notch signalling with DAPT increased, but its stimulation with Dll4 decreased spontaneous differentiation into neurons solely under normoxic but not under physioxic conditions. Conclusions Notch signalling does not influence the fate decision of midbrain NSCs cultured in vitro in physioxia, where other factors like Hif-1α might be involved. Our findings on how physioxia effects in midbrain NSCs are transduced by alternative signalling might, at least in part, explain their selective susceptibility to oxygen.
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Affiliation(s)
- Anne Herrmann
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Anne K. Meyer
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Lena Braunschweig
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Lisa Wagenfuehr
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Franz Markert
- Department of Neurology, University of Rostock, Rostock, Germany
| | - Deborah Kolitsch
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Vladimir Vukicevic
- Molecular Endocrinology, Medical Clinic III, University Clinic Dresden, Technische Universität Dresden, Dresden, Germany
| | - Christiane Hartmann
- Translational Neurodegeneration Section Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
| | - Marlen Siebert
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
| | - Monika Ehrhart-Bornstein
- Molecular Endocrinology, Medical Clinic III, University Clinic Dresden, Technische Universität Dresden, Dresden, Germany
| | - Andreas Hermann
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
- Translational Neurodegeneration Section Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany
| | - Alexander Storch
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany
- Department of Neurology, University of Rostock, Rostock, Germany
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany
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Sharma P, Aaroe A, Liang J, Puduvalli VK. Tumor microenvironment in glioblastoma: Current and emerging concepts. Neurooncol Adv 2023; 5:vdad009. [PMID: 36968288 PMCID: PMC10034917 DOI: 10.1093/noajnl/vdad009] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Glioblastoma (GBM) tumor microenvironment (TME) is a highly heterogeneous and complex system, which in addition to cancer cells, consists of various resident brain and immune cells as well as cells in transit through the tumor such as marrow-derived immune cells. The TME is a dynamic environment which is heavily influenced by alterations in cellular composition, cell-to-cell contact and cellular metabolic products as well as other chemical factors, such as pH and oxygen levels. Emerging evidence suggests that GBM cells appear to reprogram their the TME, and hijack microenvironmental elements to facilitate rapid proliferation, invasion, migration, and survival thus generating treatment resistance. GBM cells interact with their microenvironment directly through cell-to-cell by interaction mediated by cell-surface molecules, or indirectly through apocrine or paracrine signaling via cytokines, growth factors, and extracellular vehicles. The recent discovery of neuron-glioma interfaces and neurotransmitter-based interactions has uncovered novel mechanisms that favor tumor cell survival and growth. Here, we review the known and emerging evidence related to the communication between GBM cells and various components of its TME, discuss models for studying the TME and outline current studies targeting components of the TME for therapeutic purposes.
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Affiliation(s)
- Pratibha Sharma
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ashley Aaroe
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jiyong Liang
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Vinay K Puduvalli
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Castellan M, Guarnieri A, Fujimura A, Zanconato F, Battilana G, Panciera T, Sladitschek HL, Contessotto P, Citron A, Grilli A, Romano O, Bicciato S, Fassan M, Porcù E, Rosato A, Cordenonsi M, Piccolo S. Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in Glioblastoma. NATURE CANCER 2021; 2:174-188. [PMID: 33644767 PMCID: PMC7116831 DOI: 10.1038/s43018-020-00150-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/28/2020] [Indexed: 02/07/2023]
Abstract
Glioblastoma (GBM) is a devastating human malignancy. GBM stem-like cells (GSCs) drive tumor initiation and progression. Yet, the molecular determinants defining GSCs in their native state in patients remain poorly understood. Here we used single cell datasets and identified GSCs at the apex of the differentiation hierarchy of GBM. By reconstructing the GSCs' regulatory network, we identified the YAP/TAZ coactivators as master regulators of this cell state, irrespectively of GBM subtypes. YAP/TAZ are required to install GSC properties in primary cells downstream of multiple oncogenic lesions, and required for tumor initiation and maintenance in vivo in different mouse and human GBM models. YAP/TAZ act as main roadblock of GSC differentiation and their inhibition irreversibly lock differentiated GBM cells into a non-tumorigenic state, preventing plasticity and regeneration of GSC-like cells. Thus, GSC identity is linked to a key molecular hub integrating genetics and microenvironmental inputs within the multifaceted biology of GBM.
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Affiliation(s)
| | | | - Atsushi Fujimura
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | | | - Giusy Battilana
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | - Tito Panciera
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | | | | | - Anna Citron
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | - Andrea Grilli
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Oriana Romano
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Silvio Bicciato
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Matteo Fassan
- Department of Medicine - Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy
| | - Elena Porcù
- Department of Woman and Children Health, University of Padua, Padua, Italy
| | - Antonio Rosato
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | - Stefano Piccolo
- Department of Molecular Medicine, University of Padua, Padua, Italy.
- IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
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Choudhuri KSR, Mishra S. Structural basis of BMP-2 and BMP-7 interactions with antagonists Gremlin-1 and Noggin in Glioblastoma tumors. J Comput Chem 2020; 41:2544-2561. [PMID: 32935366 DOI: 10.1002/jcc.26407] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/03/2020] [Accepted: 08/02/2020] [Indexed: 12/27/2022]
Abstract
In Glioblastoma (GBM) brain tumors, both Gremlin-1 and Noggin are reported to bind to BMP and inhibit BMP-signaling, thereby allowing the cell to maintain tumorous morphology. Enlisting the interfacial residues important for protein-protein complex formation between BMPs (BMP-2 and BMP-7) and antagonists (Gremlin-1 and Noggin), we analyzed the structural basis of their interactions. We found possible key mutations that destabilize these complexes, which may prevent GBM development. It was also observed that when the interfacial residues were either mutated to histidine or tryptophan, it led to higher destabilization energy values. Besides, our study of the Noggin interactive model of BMP-2 suggested preferential binding at binding site II over binding site I. In the case of Gremlin-1 and BMPs, our research, along with few previous studies, indicates a close-ended cis-trans interactive model.
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Affiliation(s)
| | - Seema Mishra
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
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10
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Ruiz-Garcia H, Alvarado-Estrada K, Schiapparelli P, Quinones-Hinojosa A, Trifiletti DM. Engineering Three-Dimensional Tumor Models to Study Glioma Cancer Stem Cells and Tumor Microenvironment. Front Cell Neurosci 2020; 14:558381. [PMID: 33177991 PMCID: PMC7596188 DOI: 10.3389/fncel.2020.558381] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/24/2020] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma (GBM) is the most common and devastating primary brain tumor, leading to a uniform fatality after diagnosis. A major difficulty in eradicating GBM is the presence of microscopic residual infiltrating disease remaining after multimodality treatment. Glioma cancer stem cells (CSCs) have been pinpointed as the treatment-resistant tumor component that seeds ultimate tumor progression. Despite the key role of CSCs, the ideal preclinical model to study the genetic and epigenetic landmarks driving their malignant behavior while simulating an accurate interaction with the tumor microenvironment (TME) is still missing. The introduction of three-dimensional (3D) tumor platforms, such as organoids and 3D bioprinting, has allowed for a better representation of the pathophysiologic interactions between glioma CSCs and the TME. Thus, these technologies have enabled a more detailed study of glioma biology, tumor angiogenesis, treatment resistance, and even performing high-throughput screening assays of drug susceptibility. First, we will review the foundation of glioma biology and biomechanics of the TME, and then the most up-to-date insights about the applicability of these new tools in malignant glioma research.
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Affiliation(s)
- Henry Ruiz-Garcia
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, United States.,Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, United States
| | | | - Paula Schiapparelli
- Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, United States
| | | | - Daniel M Trifiletti
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, United States.,Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, United States
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11
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Mazurek M, Litak J, Kamieniak P, Kulesza B, Jonak K, Baj J, Grochowski C. Metformin as Potential Therapy for High-Grade Glioma. Cancers (Basel) 2020; 12:E210. [PMID: 31952173 PMCID: PMC7016983 DOI: 10.3390/cancers12010210] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open
Abstract
Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy.
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Affiliation(s)
- Marek Mazurek
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Jakub Litak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
- Department of Immunology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Piotr Kamieniak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Bartłomiej Kulesza
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Katarzyna Jonak
- Department of Foregin Languages, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Cezary Grochowski
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
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12
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The Multiple Roles of Peptidyl Prolyl Isomerases in Brain Cancer. Biomolecules 2018; 8:biom8040112. [PMID: 30314361 PMCID: PMC6316532 DOI: 10.3390/biom8040112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023] Open
Abstract
Peptidyl prolyl isomerases (PPIases) are broadly expressed enzymes that accelerate the cis-trans isomerization of proline peptide bonds. The most extensively studied PPIase family member is protein interacting with never in mitosis A1 (PIN1), which isomerizes phosphorylated serine/threonine–proline bonds. By catalyzing this specific cis-trans isomerization, PIN1 can alter the structure of its target proteins and modulate their activities in a number of different ways. Many proteins are targets of proline-directed phosphorylation and thus PIN1-mediated isomerization of proline bonds represents an important step in the regulation of a variety of cellular mechanisms. Numerous other proteins in addition to PIN1 are endowed with PPIase activity. These include other members of the parvulin family to which PIN1 belongs, such as PIN4, as well as several cyclophilins and FK506-binding proteins. Unlike PIN1, however, these other PPIases do not isomerize phosphorylated serine/threonine–proline bonds and have different substrate specificities. PIN1 and other PPIases are overexpressed in many types of cancer and have been implicated in various oncogenic processes. This review will discuss studies providing evidence for multiple roles of PIN1 and other PPIases in glioblastoma and medulloblastoma, the most frequent adult and pediatric primary brain tumors.
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A synthetic BMP-2 mimicking peptide induces glioblastoma stem cell differentiation. Biochim Biophys Acta Gen Subj 2017; 1861:2282-2292. [PMID: 28687190 DOI: 10.1016/j.bbagen.2017.07.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 06/09/2017] [Accepted: 07/03/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Glioblastoma (GBM) is the most aggressive type of primary brain tumor, characterized by the intrinsic resistance to chemotherapy due to the presence of a highly aggressive Cancer Stem Cell (CSC) sub-population. In this context, Bone Morphogenetic Proteins (BMPs) have been demonstrated to induce CSC differentiation and to sensitize GBM cells to treatments. METHODS The BMP-2 mimicking peptide, named GBMP1a, was synthesized on solid-phase by Fmoc chemistry. Structural characterization and prediction of receptor binding were obtained by Circular Dicroism (CD) and NRM analyses. Activation of BMP signalling was evaluated by a luciferase reporter assay and western blot. Pro-differentiating effects of GBMP1a were verified by immunostaining and neurosphere assay in primary glioblastoma cultures. RESULTS CD and NMR showed that GBMP1a correctly folds into expected tridimensional structures and predicted its binding to BMPR-IA to the same epitope as in the native complex. Reporter analysis disclosed that GBMP1a is able to activate BMP signalling in GBM cells. Moreover, BMP-signalling activation was specifically dependent on smad1/5/8 phosphorylation. Finally, we confirmed that GBMP1a treatment is sufficient to enhance osteogenic differentiation of Mesenchymal Stem Cells and to induce astroglial differentiation of glioma stem cells (GSCs) in vitro. CONCLUSIONS GBMP1a was demonstrated to be a good inducer of GSC differentiation, thus being considered a potential anti-cancer tool to be further developed for GBM treatment. GENERAL SIGNIFICANCE These data highlight the role of BMP-mimicking peptides as potential anti-cancer agents against GBM and stimulate the further development of GBMP1a-based structures in order to enhance its stability and activity.
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Karsy M, Guan J, Jensen R, Huang LE, Colman H. The Impact of Hypoxia and Mesenchymal Transition on Glioblastoma Pathogenesis and Cancer Stem Cells Regulation. World Neurosurg 2015; 88:222-236. [PMID: 26724617 DOI: 10.1016/j.wneu.2015.12.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 12/01/2015] [Accepted: 12/01/2015] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor with potential for wide dissemination and resistance to standard treatments. Although GBM represents a single histopathologic diagnosis under current World Health Organization criteria, data from multiplatform molecular profiling efforts, including The Cancer Genome Atlas, indicate that multiple subgroups with distinct markers and biology exist. It remains unclear whether treatment resistance differs based on subgroup. Recent evidence suggests that hypoxia, or absence of normal tissue oxygenation, is important in generating tumor resistance through a signaling cascade driven by hypoxia-inducible factors and vascular endothelial growth factor. Hypoxia can result in isolation of tumor cells from therapeutic agents and activation of downstream tumor protective mechanisms. In addition, there are links between hypoxia and the phenomenon of mesenchymal transition in gliomas. Mesenchymal transformation in gliomas resembles at many levels the epithelial-mesenchymal transition that has been described in other solid tumors in which epithelial cells lose their epithelial characteristics and take on a more mesenchymal phenotype, but the mesenchymal transition in brain tumors is also distinct, perhaps related to the unique cell types and cellular organization in the brain and brain tumors. Cancer stem cells, which are specific cell populations involved in self-renewal, differentiation, and GBM pathophysiology, are also importantly regulated by hypoxia signaling pathways. In this review, we discuss the interplay of hypoxia and mesenchymal signaling in GBM including the key pathway regulators and downstream genes, the effect of these processes in regulation of the tumor microenvironment and cancer stem cells, and their role in treatment resistance.
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Affiliation(s)
- Michael Karsy
- Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA
| | - Jian Guan
- Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA
| | - Randy Jensen
- Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA; Huntsman Cancer Institute, Salt Lake City, Utah, USA
| | - L Eric Huang
- Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Howard Colman
- Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA; Huntsman Cancer Institute, Salt Lake City, Utah, USA.
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15
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García de Vinuesa A, Abdelilah-Seyfried S, Knaus P, Zwijsen A, Bailly S. BMP signaling in vascular biology and dysfunction. Cytokine Growth Factor Rev 2015; 27:65-79. [PMID: 26823333 DOI: 10.1016/j.cytogfr.2015.12.005] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The vascular system is critical for developmental growth, tissue homeostasis and repair but also for tumor development. Bone morphogenetic protein (BMP) signaling has recently emerged as a fundamental pathway of the endothelium by regulating cardiovascular and lymphatic development and by being causative for several vascular dysfunctions. Two vascular disorders have been directly linked to impaired BMP signaling: pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia. Endothelial BMP signaling critically depends on the cellular context, which includes among others vascular heterogeneity, exposure to flow, and the intertwining with other signaling cascades (Notch, WNT, Hippo and hypoxia). The purpose of this review is to highlight the most recent findings illustrating the clear need for reconsidering the role of BMPs in vascular biology.
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Affiliation(s)
- Amaya García de Vinuesa
- Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands
| | - Salim Abdelilah-Seyfried
- Institute of Biochemistry and Biology, Potsdam University, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam, Germany; Institute of Molecular Biology, Hannover Medical School, Carl-Neuberg Straße 1, D-30625 Hannover, Germany
| | - Petra Knaus
- Institute for Chemistry and Biochemistry, Freie Universitaet Berlin, Berlin, Germany
| | - An Zwijsen
- VIB Center for the Biology of Disease, Leuven, Belgium; KU Leuven, Department of Human Genetics, Leuven, Belgium
| | - Sabine Bailly
- Institut National de la Santé et de la Recherche Médicale (INSERM, U1036), Grenoble F-38000, France; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble F-38000, France; Université Grenoble-Alpes, Grenoble F-38000, France.
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16
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Inhibition of PI3K Signalling Selectively Affects Medulloblastoma Cancer Stem Cells. BIOMED RESEARCH INTERNATIONAL 2015; 2015:973912. [PMID: 26557719 PMCID: PMC4628705 DOI: 10.1155/2015/973912] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 07/26/2015] [Indexed: 01/07/2023]
Abstract
Medulloblastoma is the most common malignant brain tumor of childhood. Although survival has slowly increased in the past years, the prognosis of these patients remains unfavourable. In this context, it has been recently shown that the intracellular signaling pathways activated during embryonic cerebellar development are deregulated in MDB. One of the most important is PI3K/AKT/mTOR, implicated in cell proliferation, survival, growth, and protein synthesis. Moreover, a fraction of MDB cells has been shown to posses stemlike features, to express typical neuronal precursor markers (Nestin and CD133), and to be maintained by the hypoxic cerebellar microenvironment. This subpopulation of MDB cells is considered to be responsible for treatment resistance and recurrence. In this study, we evaluated the effects of PI3K/AKT pathway inhibition on primary cultures of MDB and particularly on the cancer stem cell (CSC) population (CD133+). PI3K inhibition was able to counteract MDB cell growth and to promote differentiation of stemlike MDB cells. Moreover, PI3K/AKT pathway suppression induced dramatic cell death through activation of the mitochondrial proapoptotic cascade. Finally, analysis on the stem cells fraction revealed that the MDB CSC population is more sensitive to PI3K targeting compared to the whole cancerous population and its nonstem cell counterpart.
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17
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Transforming growth factor β and bone morphogenetic protein actions in brain tumors. FEBS Lett 2015; 589:1588-97. [PMID: 25957771 DOI: 10.1016/j.febslet.2015.04.058] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 04/28/2015] [Accepted: 04/29/2015] [Indexed: 01/05/2023]
Abstract
Members of the transforming growth factor β (TGF-β) family are implicated in the biology of several cancers. Here we focus on malignancies of the brain and examine the TGFβ and the bone morphogenetic protein (BMP) signaling branches of the family. These pathways exhibit context-dependent actions during tumorigenesis, acting either as tumor suppressors or as pro-tumorigenic agents. In the brain, the TGF-βs associate with oncogenic development and progression to the more malignant state. Inversely, the BMPs suppress tumorigenic potential by acting as agents that induce tumor cell differentiation. The latter has been best demonstrated in grade IV astrocytomas, otherwise known as glioblastoma multiforme. We discuss how the actions of TGF-βs and BMPs on cancer stem cells may explain their effects on tumor progression, and try to highlight intricate mechanisms that may link tumor cell differentiation to invasion. The focus on TGF-β and BMP and their actions in brain malignancies provides a rich territory for mechanistic understanding of tumor heterogeneity and suggests ways for improved therapeutic intervention, currently being addressed by clinical trials.
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18
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Seystahl K, Tritschler I, Szabo E, Tabatabai G, Weller M. Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma. Neuro Oncol 2014; 17:254-65. [PMID: 25165192 DOI: 10.1093/neuonc/nou218] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) pathways have a major role in the pathogenesis of glioblastoma, notably immunosuppression, migration, and angiogenesis, but their interactions have remained poorly understood. METHODS We characterized TGF-β pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-β-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data. RESULTS Glioma cells exhibit heterogeneous patterns of constitutive TGF-β pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-β pathway activity depends on the type I TGF-β receptor, ALK-5, and accounts for up to 69% of constitutive VEGF release, which is positively regulated by SMAD2/3 and negatively regulated by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces VEGF release in most cell lines in a SMAD- and ALK-5-dependent manner. There is no correlation between the fold induction of VEGF secretion induced by TGF-β compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-β and pSMAD2 levels and a stimulatory effect when TGF-β is abundant. CONCLUSIONS TGF-β regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3, and SMAD1/5/8 signaling. This crosstalk between the TGF-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastoma.
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Affiliation(s)
- Katharina Seystahl
- Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Isabel Tritschler
- Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Emese Szabo
- Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Ghazaleh Tabatabai
- Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Michael Weller
- Department of Neurology, University Hospital Zurich, Zurich, Switzerland
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Reguera-Nuñez E, Roca C, Hardy E, de la Fuente M, Csaba N, Garcia-Fuentes M. Implantable controlled release devices for BMP-7 delivery and suppression of glioblastoma initiating cells. Biomaterials 2014; 35:2859-67. [DOI: 10.1016/j.biomaterials.2013.12.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/08/2013] [Indexed: 01/04/2023]
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20
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Baracca A, Sgarbi G, Padula A, Solaini G. Glucose plays a main role in human fibroblasts adaptation to hypoxia. Int J Biochem Cell Biol 2013; 45:1356-65. [DOI: 10.1016/j.biocel.2013.03.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 03/01/2013] [Accepted: 03/12/2013] [Indexed: 01/22/2023]
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21
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Galeffi F, Turner DA. Exploiting metabolic differences in glioma therapy. Curr Drug Discov Technol 2013; 9:280-93. [PMID: 22339075 DOI: 10.2174/157016312803305906] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Revised: 09/30/2011] [Accepted: 02/11/2012] [Indexed: 12/20/2022]
Abstract
Brain function depends upon complex metabolic interactions amongst only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolysis and metabolism associated with synthesis of critical intermediates, hence are less susceptible to lack of oxygen. Astrocytoma and higher grade glioma cells demonstrate both basic metabolic mechanisms of astrocytes as well as tumors in general, e.g. they show a high glycolytic rate, lactate extrusion, ability to proliferate even under hypoxia, and opportunistic use of mechanisms to enhance metabolism and blood vessel generation, and suppression of cell death pathways. There may be differences in metabolism between neurons, normal astrocytes and astrocytoma cells, providing therapeutic opportunities against astrocytomas, including a wide range of enzyme and transporter differences, regulation of hypoxia-inducible factor (HIF), glutamate uptake transporters and glutamine utilization, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of NADPH for lipid synthesis, utilizing differential regulation of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate dehydrogenase, lactate dehydrogenase, malate-aspartate NADH shuttle) and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone, and are starting to be implemented in clinical trials.
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22
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Persano L, Rampazzo E, Basso G, Viola G. Glioblastoma cancer stem cells: Role of the microenvironment and therapeutic targeting. Biochem Pharmacol 2013; 85:612-622. [DOI: 10.1016/j.bcp.2012.10.001] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Revised: 10/01/2012] [Accepted: 10/01/2012] [Indexed: 12/22/2022]
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23
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Rampazzo E, Persano L, Pistollato F, Moro E, Frasson C, Porazzi P, Della Puppa A, Bresolin S, Battilana G, Indraccolo S, Te Kronnie G, Argenton F, Tiso N, Basso G. Wnt activation promotes neuronal differentiation of glioblastoma. Cell Death Dis 2013; 4:e500. [PMID: 23429286 PMCID: PMC4098797 DOI: 10.1038/cddis.2013.32] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
One of the biggest challenges in tumour research is the possibility to reprogram cancer
cells towards less aggressive phenotypes. In this study, we reprogrammed primary
Glioblastoma multiforme (GBM)-derived cells towards a more differentiated and less
oncogenic phenotype by activating the Wnt pathway in a hypoxic microenvironment. Hypoxia
usually correlates with malignant behaviours in cancer cells, but it has been recently
involved, together with Wnt signalling, in the differentiation of embryonic and neural
stem cells. Here, we demonstrate that treatment with Wnt ligands, or overexpression of
β-catenin, mediate neuronal differentiation and halt proliferation in
primary GBM cells. An hypoxic environment cooperates with Wnt-induced differentiation, in
line with our finding that hypoxia inducible factor-1α
(HIF-1α) is instrumental and required to sustain the expression of
β-catenin transcriptional partners TCF-1 and LEF-1. In addition, we also
found that Wnt-induced GBM cell differentiation inhibits Notch signalling, and thus gain
of Wnt and loss of Notch cooperate in the activation of a pro-neuronal differentiation
program. Intriguingly, the GBM sub-population enriched of cancer stem cells
(CD133+ fraction) is the primary target of the pro-differentiating
effects mediated by the crosstalk between HIF-1α, Wnt, and Notch
signalling. By using zebrafish transgenics and mutants as model systems to visualize and
manipulate in vivo the Wnt pathway, we confirm that Wnt pathway activation is
able to promote neuronal differentiation and inhibit Notch signalling of primary human GBM
cells also in this in vivo set-up. In conclusion, these findings shed light on an
unsuspected crosstalk between hypoxia, Wnt and Notch signalling in GBM, and suggest the
potential to manipulate these microenvironmental signals to blunt GBM malignancy.
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Affiliation(s)
- E Rampazzo
- Department of Woman and Child Health, University of Padova, Padova, Italy
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Zhu RJ, Wu MQ, Li ZJ, Zhang Y, Liu KY. Hematopoietic recovery following chemotherapy is improved by BADGE-induced inhibition of adipogenesis. Int J Hematol 2012; 97:58-72. [PMID: 23264188 DOI: 10.1007/s12185-012-1233-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Revised: 11/22/2012] [Accepted: 11/26/2012] [Indexed: 12/18/2022]
Abstract
This study was designed to investigate the role of increased adipocytes in the bone marrow (BM) niche induced by high-dose chemotherapy in hematopoietic recovery. Arabinosylcytosine (Ara-C) was administered to adult C57BL/6J mice to induce adipogenesis in the BM. We investigated the effects of adipogenesis on hematopoietic recovery following chemotherapy, using the peroxisome proliferator-activated receptor gamma inhibitor, bisphenol A diglycidyl ether (BADGE). Adipocyte hyperplasia could be induced by Ara-C treatment in BM and inhibited by BADGE. The accelerated recovery of leukocyte counts, increased colony forming units, and a higher proportion of Ki67(+)CD45(+) BM cells and Ki67(+)Lin(-)Sca1(+)c-kit(+) hematopoietic stem cells were observed in the long bone marrow of adipocyte-inhibited mice, as well as an increase in the number of CD45(+) BM cells in the tail fatty marrow compared to controls. Adipocytes participated in creating a distinctive niche for hematopoietic cells. In addition, lower expression of stromal cell-derived factor-1α and hypoxia-inducible factor-1 alpha were detected in the BADGE-treated group. These results indicate that hematopoietic recovery is improved following chemotherapy in adipogenesis-inhibited mice. In addition, adipocytes may create an individual niche that affects the proliferation and migration of hematopoietic cells in vitro and in vivo.
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Affiliation(s)
- Rong-Jia Zhu
- Peking University People's Hospital and Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, 11 Xizhimen South Street, Xicheng District, Beijing, China
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BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression. Cell Death Dis 2012; 3:e412. [PMID: 23076220 PMCID: PMC3481140 DOI: 10.1038/cddis.2012.153] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common brain tumour, characterized by a central and partially necrotic (i.e., hypoxic) core enriched in cancer stem cells (CSCs). We previously showed that the most hypoxic and immature (i.e., CSCs) GBM cells were resistant to Temozolomide (TMZ) in vitro, owing to a particularly high expression of O6-methylguanine-DNA-methyltransferase (MGMT), the most important factor associated to therapy resistance in GBM. Bone morphogenetic proteins (BMPs), and in particular BMP2, are known to promote differentiation and growth inhibition in GBM cells. For this reason, we investigated whether a BMP2-based treatment would increase TMZ response in hypoxic drug-resistant GBM-derived cells. Here we show that BMP2 induced strong differentiation of GBM stem-like cells and subsequent addition of TMZ caused dramatic increase of apoptosis. Importantly, we correlated these effects to a BMP2-induced downregulation of both hypoxia-inducible factor-1α (HIF-1α) and MGMT. We report here a novel mechanism involving the HIF-1α-dependent regulation of MGMT, highlighting the existence of a HIF-1α/MGMT axis supporting GBM resistance to therapy. As confirmed from this evidence, over-stabilization of HIF-1α in TMZ-sensitive GBM cells abolished their responsiveness to it. In conclusion, we describe a HIF-1α-dependent regulation of MGMT and suggest that BMP2, by down-modulating the HIF-1α/MGMT axis, should increase GBM responsiveness to chemotherapy, thus opening the way to the development of future strategies for GBM treatment.
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Laibe S, Lagarde A, Ferrari A, Monges G, Birnbaum D, Olschwang S. A seven-gene signature aggregates a subgroup of stage II colon cancers with stage III. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2012; 16:560-5. [PMID: 22917480 DOI: 10.1089/omi.2012.0039] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Colorectal cancer is one of the most common cancers in the world. Histological staging is efficient, but combination with molecular markers may improve tumor classification. Gene expression profiles have been defined as prognosis predictors among stage II and III tumors, but their implementation in medical practice remains controversial. Stage II tumors have been recognized as a heterogeneous group, and high-risk morphologic features have been used to justify adjuvant chemotherapy. We propose here the investigation of clinical features and expression profiles from stage II and stage III colon carcinomas without DNA mismatch repair defects. Two series of 130 and 66 colon cancer samples were obtained. Expression profiles were established on oligonucleotide microarrays and processed in the R/Bioconductor environment. Hierarchical, then supervised, analyses were successively performed by applying a data-sampling approach. A molecular signature of seven genes was found to cluster stage III tumors with adjusted p values lower than 10(-10). A subgroup of stage II tumors aggregated this cluster in both series. No correlation was found with disease severity, but the function of the discriminating genes suggests that tumors have been classified according to their putative response to adjuvant targeted or classic therapies. Further pharmacogenetic studies might verify this observation.
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Affiliation(s)
- Sophy Laibe
- Tumor Biology Department, Institut Paoli-Calmettes, Marseille, France
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Yang L, Lin C, Wang L, Guo H, Wang X. Hypoxia and hypoxia-inducible factors in glioblastoma multiforme progression and therapeutic implications. Exp Cell Res 2012; 318:2417-26. [PMID: 22906859 DOI: 10.1016/j.yexcr.2012.07.017] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 07/20/2012] [Accepted: 07/24/2012] [Indexed: 02/05/2023]
Abstract
Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in humans, with a uniformly poor prognosis. Hypoxia is a predominant feature in GBM and its microenvironment; it is associated with the tumor growth, progression and resistance to conventional therapy of cancers. Hypoxia-inducible factors (HIFs) are the master regulators of the transcriptional response to hypoxia in tumor cells and their microenvironment. Numerous studies indicated that hypoxia and HIFs played pivotal roles in the initiation, progression, therapy resistance and recurrence of GBM and maintained the phenotype of glioma stem cells (GSCs), which makes the prognosis of GBM patients worse. This review summarized the current research advance of hypoxia and HIFs in GBM progression and therapeutic implications, which will provide a better understanding of the contribution of hypoxia and HIFs to GBM initiation and progression and highlight that HIFs might be taken as the attractive molecular target approaches for GBM therapeutics.
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Affiliation(s)
- Liuqi Yang
- Laboratory of Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
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Kockar F, Yildrim H, Sagkan RI, Hagemann C, Soysal Y, Anacker J, Hamza AA, Vordermark D, Flentje M, Said HM. Hypoxia and cytokines regulate carbonic anhydrase 9 expression in hepatocellular carcinoma cells in vitro. World J Clin Oncol 2012; 3:82-91. [PMID: 22724087 PMCID: PMC3380102 DOI: 10.5306/wjco.v3.i6.82] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 05/30/2012] [Accepted: 06/05/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression of carbonic anhydrase (CA) 9 in human hepatocellular carcinoma (HCC) cells.
METHODS: We studied CA9 protein, CA9 mRNA and hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Hep3B cells exposed in different parallel approaches. In one of these approaches, HCC cells were exposed to extreme in vitro hypoxia (24 h 0.1% O2) without or with interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) stimulation for the same hypoxic exposure time or exposed to normoxic oxygenation conditions without or with cytokine stimulation.
RESULTS: The tumour cell line analysed showed a strong hypoxic CA9 mRNA expression pattern in response to prolonged severe hypoxia with cell-line specific patterns and a marked induction of CA9 protein in response to severe hypoxia. These results were paralleled by the results for HIF-1α protein under identical oxygenation conditions with a similar expression tendency to that displayed during the CA9 protein expression experimental series. Continuous stimulation with the cytokines, IL-1, IL-6, TNF-α and TGF-β, under normoxic conditions significantly increased the carbonic anhydrase 9 expression level at both the protein and mRNA level, almost doubling the CA9 mRNA and CA9 and HIF-1α protein expression levels found under hypoxia. The findings from these experiments indicated that hypoxia is a positive regulator of CA9 expression in HCC, and the four signal transduction pathways, IL-1, IL-6, TNF-α and TGF-β, positively influence CA9 expression under both normoxic and hypoxic conditions.
CONCLUSION: These findings may potentially be considered in the design of anti- cancer therapeutic approaches involving hypoxia-induced or cytokine stimulatory effects on expression. In addition, they provide evidence of the stimulatory role of the examined cytokine families resulting in an increase in CA9 expression under different oxygenation conditions in human cancer, especially HCC, and on the role of the CA9 gene as a positive disease regulator in human cancer.
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Affiliation(s)
- Feray Kockar
- Feray Kockar, Hatice Yildrim, Department of Biology, Faculty of Art and Science, Balikesir University, 10145 Balikesir, Turkey
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Persano L, Rampazzo E, Della Puppa A, Pistollato F, Basso G. The three-layer concentric model of glioblastoma: cancer stem cells, microenvironmental regulation, and therapeutic implications. ScientificWorldJournal 2011; 11:1829-41. [PMID: 22125441 PMCID: PMC3217608 DOI: 10.1100/2011/736480] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 09/29/2011] [Indexed: 12/15/2022] Open
Abstract
Tumors arising in the central nervous system are thought to
originate from a sub-population of cells named cancer stem cells
(CSCs) or tumor initiating cells (TICs) that possess an immature
phenotype, combined with self-renewal and chemotherapy resistance
capacity. Moreover, in the last years, these cells have been
identified in particular brain tumor niches fundamental for
supporting their characteristics. In this paper, we report studies
from many authors demonstrating that hypoxia or the so called
“hypoxic niche” plays a crucial role in controlling CSC molecular
and phenotypic profile. We recently investigated the relationship
existing between Glioblastoma (GBM) stem cells and their niche,
defining the theory of three-concentric layers model for GBM mass.
According to this model, GBM stem cells reside preferentially
within the hypoxic core of the tumour mass, while more
differentiated cells are mainly localized along the peripheral and
vascularized part of the tumour. This GBM model provides
explanation of the effects mediated by the tumour microenvironment
on the phenotypic and molecular regulation of GBM stem cells,
describing their spatial distribution in the tumor bulk. Moreover,
we discuss the possible clinical implications of the creation of
this model for future GBM patient management and novel therapeutic
strategies development.
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Affiliation(s)
- Luca Persano
- Oncohematology Laboratory, Department of Paediatrics, University of Padova, Via Giustiniani 3, Padova 35128, Italy.
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From cell death to viral replication: the diverse functions of the membrane-associated FKBP38. Curr Opin Pharmacol 2011; 11:348-53. [PMID: 21514222 DOI: 10.1016/j.coph.2011.03.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 03/25/2011] [Accepted: 03/30/2011] [Indexed: 01/27/2023]
Abstract
FKBP38 is in many ways an exceptional member of the FK506-binding proteins. The calmodulin-regulated activity of FKBP38 for instance is unique within this protein family. The activated FKBP38 participates in apoptosis signaling by inhibiting the anti-apoptotic Bcl-2. Beyond this role in programmed cell death, FKBP38 seems to be involved in very different cellular processes that do not necessarily depend on the FKBP domain. These functions involve regulation of the kinase mTOR, regulation of neural tube formation, regulation of cellular hypoxia response, but also Hepatitis C virus replication. Pharmacological targeting of FKBP38 might therefore prove a successful strategy for intervention in different FKBP38-dependent processes, including programmed cell death in cancer or neurodegenerative diseases.
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Pistollato F, Rampazzo E, Persano L, Abbadi S, Frasson C, Denaro L, D'Avella D, Panchision DM, Della Puppa A, Scienza R, Basso G. Interaction of hypoxia-inducible factor-1α and Notch signaling regulates medulloblastoma precursor proliferation and fate. Stem Cells 2011; 28:1918-29. [PMID: 20827750 DOI: 10.1002/stem.518] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Medulloblastoma (MDB) is the most common brain malignancy of childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. Although interaction between hypoxia-inducible factor-1α (HIF-1α) and Notch signaling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here, we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133(+) and nestin(+) precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion.
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Affiliation(s)
- Francesca Pistollato
- SSD Clinical and Experimental Hematology, Department of Paediatrics, University of Padova, Padova, Italy
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Pistollato F, Abbadi S, Rampazzo E, Persano L, Della Puppa A, Frasson C, Sarto E, Scienza R, D'avella D, Basso G. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells 2010; 28:851-62. [PMID: 20309962 DOI: 10.1002/stem.415] [Citation(s) in RCA: 206] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Glioblastoma multiforme (GBM) are highly proliferative tumors currently treated by surgical removal, followed by radiotherapy and chemotherapy, which are counteracted by intratumoral hypoxia. Here we exploited image guided surgery to sample multiple intratumoral areas to define potential cellular heterogeneity in correlation to the oxygen tension gradient within the GBM mass. Our results indicate that more immature cells are localized in the inner core and in the intermediate layer of the tumor mass, whereas more committed cells, expressing glial fibrillary acidic protein and beta-III-tubulin, are distributed along the peripheral and neo-vascularized area, where Smad1/5/8 and Stat3 result to be activated. Moreover, GBM stem cells, identified with the stem cell marker CD133, express high level of DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) known to be involved in chemotherapy resistance and highly expressed in the inner core of the tumor mass. Importantly, these cells and, particularly, CD133(+) cells result to be resistant to temozolomide (TMZ), the most used oral alkylating agent for the treatment of GBM, which specifically causes apoptosis only in GBM cells derived from the peripheral layer of the tumor mass. These results indicate a correlation between the intratumoral hypoxic gradient, the tumor cell phenotype, and the tumor resistance to chemotherapy leading to a novel concentric model of tumor stem cell niche, which may be useful to define the real localization of the chemoresistant GBM tumor cells in order to design more effective treatment strategies.
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Affiliation(s)
- Francesca Pistollato
- Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, 3-35128 Padova, Italy.
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Fatoo A, Nanaszko MJ, Allen BB, Mok CL, Bukanova EN, Beyene R, Moliterno JA, Boockvar JA. Understanding the role of tumor stem cells in glioblastoma multiforme: a review article. J Neurooncol 2010; 103:397-408. [DOI: 10.1007/s11060-010-0406-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2010] [Accepted: 09/06/2010] [Indexed: 02/06/2023]
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Argyriou P, Papageorgiou SG, Panteleon V, Psyrri A, Bakou V, Pappa V, Spathis A, Economopoulou P, Papageorgiou E, Economopoulos T, Rontogianni D. Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1→HIF-1α pathway. Ann Hematol 2010; 90:315-22. [DOI: 10.1007/s00277-010-1070-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Accepted: 08/25/2010] [Indexed: 12/21/2022]
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35
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Pistollato F, Abbadi S, Rampazzo E, Viola G, Della Puppa A, Cavallini L, Frasson C, Persano L, Panchision DM, Basso G. Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma. Biochem Pharmacol 2010; 80:1517-27. [PMID: 20705058 DOI: 10.1016/j.bcp.2010.08.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Revised: 08/03/2010] [Accepted: 08/03/2010] [Indexed: 02/04/2023]
Abstract
Glioblastoma multiforme (GBM) are highly proliferative brain tumors characterized by a hypoxic microenvironment which controls GBM stem cell maintenance. Tumor hypoxia promotes also elevated glycolytic rate; thus, limiting glucose metabolism is a potential approach to inhibit tumor growth. Here we investigate the effects mediated by 2-deoxyglucose (2-DG), a glucose analogue, on primary GBM-derived cells maintained under hypoxia. Our results indicate that hypoxia protects GBM cells from the apoptotic effect elicited by 2-DG, which raises succinate dehydrogenase activity thus promoting succinate level decrease. As a consequence hypoxia inducible factor-1α (HIF-1α) degradation occurs and this induces GBM cells to acquire a neuronal committed phenotype. By adding succinate these effects are reverted, as succinate stabilizes HIF-1α and increases GBM stem cell fraction particularly under hypoxia, thus preserving the tumor stem cell niche. 2-DG inhibits anaerobic glycolysis altering GBM cell phenotype by forcing tumor cells into mitochondrial metabolism and by inducing differentiation.
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Affiliation(s)
- Francesca Pistollato
- Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Via Giustiniani 3, Padova 35128, Italy
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Pistollato F, Persano L, Rampazzo E, Basso G. L-Proline as a modulator of ectodermal differentiation in ES cells. Focus on "L-Proline induces differentiation of ES cells: a novel role for an amino acid in the regulation of pluripotent cells in culture. Am J Physiol Cell Physiol 2010; 298:C979-81. [PMID: 20219949 DOI: 10.1152/ajpcell.00072.2010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Wu Y, Zhao W, Zhao J, Zhang Y, Qin W, Pan J, Bauman WA, Blitzer RD, Cardozo C. REDD1 is a major target of testosterone action in preventing dexamethasone-induced muscle loss. Endocrinology 2010; 151:1050-9. [PMID: 20032058 PMCID: PMC2840688 DOI: 10.1210/en.2009-0530] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Glucocorticoids are a well-recognized and common cause of muscle atrophy that can be prevented by testosterone. However, the molecular mechanisms underlying such protection have not been described. Thus, the global effects of testosterone on dexamethasone-induced changes in gene expression were evaluated in rat gastrocnemius muscle using DNA microarrays. Gene expression was analyzed after 7-d administration of dexamethasone, dexamethasone plus testosterone, or vehicle. Dexamethasone changed expression of 876 probe sets by at least 2-fold. Among these, 474 probe sets were changed by at least 2-fold in the opposite direction in the dexamethasone plus testosterone group (genes in opposition). Major biological themes represented by genes in opposition included IGF-I signaling, myogenesis and muscle development, and cell cycle progression. Testosterone completely prevented the 22-fold increase in expression of the mammalian target of rapamycin (mTOR) inhibitor regulated in development and DNA damage responses 1 (REDD1), and attenuated dexamethasone induced increased expression of eIF4E binding protein 1, Forkhead box O1, and the p85 regulatory subunit of the IGF-I receptor but prevented decreased expression of IRS-1. Testosterone attenuated increases in REDD1 protein in skeletal muscle and L6 myoblasts and prevented dephosphorylation of p70S6 kinase at the mTOR-dependent site Thr389 in L6 myoblast cells. Effects of testosterone on REDD1 mRNA levels occurred within 1 h, required the androgen receptor, were blocked by bicalutamide, and were due to inhibition of transcriptional activation of REDD1 by dexamethasone. These data suggest that testosterone blocks dexamethasone-induced changes in expression of REDD1 and other genes that collectively would otherwise down-regulate mTOR activity and hence also down-regulate protein synthesis.
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Affiliation(s)
- Yong Wu
- Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, 953 Southern Boulevard, Bronx, New York 10468, USA
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