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1
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Ivanova YI, Nunes AC, Cruz V, Selting K, Harley BAC. Radiation Damage to a Three-Dimensional Hydrogel Model of the Brain Perivascular Niche. Tissue Eng Part C Methods 2025. [PMID: 40329812 DOI: 10.1089/ten.tec.2025.0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025] Open
Abstract
Glioblastoma (GBM) is a highly aggressive and recurrent brain cancer characterized by diffuse metastasis at the tumor margins. Radiation therapy is a standard component of current treatment and offers potential for improved patient outcomes. While radiation therapy targets GBM cells in the tumor margins, it may also significantly damage adjacent noncancerous tissues, leading to reduced quality of life and potentially creating a tumor-supportive microenvironment. The perivascular niche (PVN) in the tumor margins is believed to play a significant role in regulating the glioblastoma stem cell subpopulation as well as serving as a site for cancer recurrence and migration. Understanding the impact of radiation on the PVN can better inform radiation schemes and improve our understanding of GBM recurrence, but is difficult in vivo. Here, we adapt a previously developed three-dimensional hydrogel model of the brain PVN to investigate the impact of radiation dosage and delivery rate on PVN properties in vitro. Effects of radiation on vessel architecture can be measured in this hydrogel-based model, suggesting an approach that can provide insight into the effects of radiation on a shorter time scale relative to in vivo experiments.
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Affiliation(s)
- Yoanna I Ivanova
- Department of Bioengineering, University of Illinois, Urbana, Illinois, USA
| | - Alison C Nunes
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Val Cruz
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Kimberly Selting
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Brendan A C Harley
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
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2
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Ivanova Y, Nunes A, Cruz V, Selting K, Harley B. Radiation damage to a three-dimensional hydrogel model of the brain perivascular niche. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.20.639287. [PMID: 40060667 PMCID: PMC11888163 DOI: 10.1101/2025.02.20.639287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/18/2025]
Abstract
Glioblastoma (GBM) is a highly aggressive and recurrent brain cancer characterized by diffuse metastasis at the tumor margins. Radiation therapy is a standard component of current treatment and offers potential for improved patient outcomes. While radiation therapy targets GBM cells in the tumor margins, it may also significantly damage adjacent non-cancerous tissues, leading to reduced quality of life and potentially creating a tumor-supportive microenvironment. The perivascular niche (PVN) in the tumor margins is believed to play a significant role in regulating the glioblastoma stem cell subpopulation as well as serving as a site for cancer recurrence and migration. Understanding the impact of radiation on the PVN can better inform radiation schemes and improve our understanding of GBM recurrence, but is difficult in vivo. Here we adapt a previously developed three-dimensional hydrogel model of the brain perivascular niche to investigate the impact of radiation dosage and delivery rate on perivascular niche properties in vitro. Effects of radiation on vessel architecture can be measured in this hydrogel-based model, suggesting an approach that can provide insight into the effects of radiation on a shorter time scale relative to in vivo experiments.
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Affiliation(s)
- Y.I. Ivanova
- Dept. of Bioengineering, University of Illinois at Urbana-Champaign Urbana, IL 61801
| | - A.C. Nunes
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign Urbana, IL 61801
| | - V. Cruz
- Dept. of Materials Science and Engineering, University of Illinois at Urbana-Champaign Urbana, IL 61801
| | - K. Selting
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign Urbana, IL 61801
- Dept. of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign Urbana, IL 61801
| | - B.A.C. Harley
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign Urbana, IL 61801
- Dept. of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign Urbana, IL 61801
- Dept. of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign Urbana, IL 61801
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3
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Pun S, Prakash A, Demaree D, Krummel DP, Sciumè G, Sengupta S, Barrile R. Rapid Biofabrication of an Advanced Microphysiological System Mimicking Phenotypical Heterogeneity and Drug Resistance in Glioblastoma. Adv Healthc Mater 2024; 13:e2401876. [PMID: 39101329 PMCID: PMC11616263 DOI: 10.1002/adhm.202401876] [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: 05/20/2024] [Revised: 07/10/2024] [Indexed: 08/06/2024]
Abstract
Microphysiological systems (MPSs) reconstitute tissue interfaces and organ functions, presenting a promising alternative to animal models in drug development. However, traditional materials like polydimethylsiloxane (PDMS) often interfere by absorbing hydrophobic molecules, affecting drug testing accuracy. Additive manufacturing, including 3D bioprinting, offers viable solutions. GlioFlow3D, a novel microfluidic platform combining extrusion bioprinting and stereolithography (SLA) is introduced. GlioFlow3D integrates primary human cells and glioblastoma (GBM) lines in hydrogel-based microchannels mimicking vasculature, within an SLA resin framework using cost-effective materials. The study introduces a robust protocol to mitigate SLA resin cytotoxicity. Compared to PDMS, GlioFlow3D demonstrated lower small molecule absorption, which is relevant for accurate testing of small molecules like Temozolomide (TMZ). Computational modeling is used to optimize a pumpless setup simulating interstitial fluid flow dynamics in tissues. Co-culturing GBM with brain endothelial cells in GlioFlow3D showed enhanced CD133 expression and TMZ resistance near vascular interfaces, highlighting spatial drug resistance mechanisms. This PDMS-free platform promises advanced drug testing, improving preclinical research and personalized therapy by elucidating complex GBM drug resistance mechanisms influenced by the tissue microenvironment.
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Affiliation(s)
- Sirjana Pun
- Department of Biomedical EngineeringUniversity of CincinnatiCincinnatiOH45221USA
| | - Anusha Prakash
- Department of Biomedical EngineeringUniversity of CincinnatiCincinnatiOH45221USA
- AbbvieWorcesterMassachusetts01605USA
| | - Dalee Demaree
- Department of Biomedical EngineeringUniversity of CincinnatiCincinnatiOH45221USA
- Thermo Fisher ScientificWalthamMassachusetts02451USA
| | - Daniel Pomeranz Krummel
- Department of NeurologyUniversity of CincinnatiCincinnatiOH45219USA
- Department of NeurosurgeryUniversity of North CarolinaChapel HillNC27599USA
| | - Giuseppe Sciumè
- Institute of Mechanics and Engineering‐12 MUniversity of BordeauxBordeaux33607France
| | - Soma Sengupta
- Department of NeurologyUniversity of CincinnatiCincinnatiOH45219USA
- Department of NeurosurgeryUniversity of North CarolinaChapel HillNC27599USA
- Department of NeurologyUniversity of North CarolinaChapel HillNC27599‐7025USA
- Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillNC27599‐7295USA
| | - Riccardo Barrile
- Department of Biomedical EngineeringUniversity of CincinnatiCincinnatiOH45221USA
- Center for Stem Cells and Organoid Medicine (CuSTOM)Cincinnati Children's Hospital Medical CenterCincinnatiOH45229USA
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4
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Sojka C, Sloan SA. Gliomas: a reflection of temporal gliogenic principles. Commun Biol 2024; 7:156. [PMID: 38321118 PMCID: PMC10847444 DOI: 10.1038/s42003-024-05833-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/18/2024] [Indexed: 02/08/2024] Open
Abstract
The hijacking of early developmental programs is a canonical feature of gliomas where neoplastic cells resemble neurodevelopmental lineages and possess mechanisms of stem cell resilience. Given these parallels, uncovering how and when in developmental time gliomagenesis intersects with normal trajectories can greatly inform our understanding of tumor biology. Here, we review how elapsing time impacts the developmental principles of astrocyte (AS) and oligodendrocyte (OL) lineages, and how these same temporal programs are replicated, distorted, or circumvented in pathological settings such as gliomas. Additionally, we discuss how normal gliogenic processes can inform our understanding of the temporal progression of gliomagenesis, including when in developmental time gliomas originate, thrive, and can be pushed towards upon therapeutic coercion.
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Affiliation(s)
- Caitlin Sojka
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Steven A Sloan
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
- Emory Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
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5
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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: 28] [Impact Index Per Article: 7.0] [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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6
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Hira VV, Molenaar RJ, Breznik B, Lah T, Aronica E, Van Noorden CJ. Immunohistochemical Detection of Neural Stem Cells and Glioblastoma Stem Cells in the Subventricular Zone of Glioblastoma Patients. J Histochem Cytochem 2021; 69:349-364. [PMID: 33596115 PMCID: PMC8091546 DOI: 10.1369/0022155421994679] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 01/25/2021] [Indexed: 02/08/2023] Open
Abstract
Glioblastoma usually recurs after therapy consisting of surgery, radiotherapy, and chemotherapy. Recurrence is at least partly caused by glioblastoma stem cells (GSCs) that are maintained in intratumoral hypoxic peri-arteriolar microenvironments, or niches, in a slowly dividing state that renders GSCs resistant to radiotherapy and chemotherapy. Because the subventricular zone (SVZ) is a major niche for neural stem cells (NSCs) in the brain, we investigated whether GSCs are present in the SVZ at distance from the glioblastoma tumor. We characterized the SVZ of brains of seven glioblastoma patients using fluorescence immunohistochemistry and image analysis. NSCs were identified by CD133 and SOX2 but not CD9 expression, whereas GSCs were positive for all three biomarkers. NSCs were present in all seven samples and GSCs in six out of seven samples. The SVZ in all samples were hypoxic and expressed the same relevant chemokines and their receptors as GSC niches in glioblastoma tumors: stromal-derived factor-1α (SDF-1α), C-X-C receptor type 4 (CXCR4), osteopontin, and CD44. In conclusion, in glioblastoma patients, GSCs are present at distance from the glioblastoma tumor in the SVZ. These findings suggest that GSCs in the SVZ niche are protected against radiotherapy and chemotherapy and protected against surgical resection due to their distant localization and thus may contribute to tumor recurrence after therapy.
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Affiliation(s)
- Vashendriya V.V. Hira
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Remco J. Molenaar
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Tamara Lah
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Eleonora Aronica
- Department of Neuropathology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Cornelis J.F. Van Noorden
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
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7
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Prager BC, Bhargava S, Mahadev V, Hubert CG, Rich JN. Glioblastoma Stem Cells: Driving Resilience through Chaos. Trends Cancer 2020; 6:223-235. [PMID: 32101725 PMCID: PMC8779821 DOI: 10.1016/j.trecan.2020.01.009] [Citation(s) in RCA: 252] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/22/2019] [Accepted: 01/07/2020] [Indexed: 12/21/2022]
Abstract
Glioblastoma is an aggressive and heterogeneous tumor in which glioblastoma stem cells (GSCs) are at the apex of an entropic hierarchy and impart devastating therapy resistance. The high entropy of GSCs is driven by a permissive epigenetic landscape and a mutational landscape that revokes crucial cellular checkpoints. The GSC population encompasses a complex array of diverse microstates that are defined and maintained by a wide variety of attractors including the complex tumor ecosystem and therapeutic intervention. Constant dynamic transcriptional fluctuations result in a highly adaptable and heterogeneous entity primed for therapy evasion and survival. Analyzing the transcriptional, epigenetic, and metabolic landscapes of GSC dynamics in the context of a stochastically fluctuating tumor network will provide novel strategies to target resistant populations of GSCs in glioblastoma.
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Affiliation(s)
- Briana C Prager
- Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, 92037, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA; Case Western Reserve University Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Shruti Bhargava
- Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, 92037, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
| | - Vaidehi Mahadev
- Department of Neurosurgery, University of Texas Health San Antonio, San Antonio, TX, USA
| | | | - Jeremy N Rich
- Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, 92037, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA.
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8
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Wolf KJ, Chen J, Coombes J, Aghi MK, Kumar S. Dissecting and rebuilding the glioblastoma microenvironment with engineered materials. NATURE REVIEWS. MATERIALS 2019; 4:651-668. [PMID: 32647587 PMCID: PMC7347297 DOI: 10.1038/s41578-019-0135-y] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/24/2019] [Indexed: 05/15/2023]
Abstract
Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer. Several decades of research have provided great insight into GBM progression; however, the prognosis remains poor with a median patient survival time of ~ 15 months. The tumour microenvironment (TME) of GBM plays a crucial role in mediating tumour progression and thus is being explored as a therapeutic target. Progress in the development of treatments targeting the TME is currently limited by a lack of model systems that can accurately recreate the distinct extracellular matrix composition and anatomic features of the brain, such as the blood-brain barrier and axonal tracts. Biomaterials can be applied to develop synthetic models of the GBM TME to mimic physiological and pathophysiological features of the brain, including cellular and ECM composition, mechanical properties, and topography. In this Review, we summarize key features of the GBM microenvironment and discuss different strategies for the engineering of GBM TME models, including 2D and 3D models featuring chemical and mechanical gradients, interfaces and fluid flow. Finally, we highlight the potential of engineered TME models as platforms for mechanistic discovery and drug screening as well as preclinical testing and precision medicine.
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Affiliation(s)
- Kayla J. Wolf
- University of California, Berkeley – University of California, San Francisco Graduate Program in Bioengineering, Berkeley, California, 94720, USA
- Department of Bioengineering, University of California, Berkeley, Berkeley, California, 94720, USA
| | - Joseph Chen
- Department of Bioengineering, University of California, Berkeley, Berkeley, California, 94720, USA
| | - Jason Coombes
- Department of Bioengineering, University of California, Berkeley, Berkeley, California, 94720, USA
- Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Manish K. Aghi
- Department of Neurosurgery, University of California San Francisco (UCSF), San Francisco, California, 94158
| | - Sanjay Kumar
- University of California, Berkeley – University of California, San Francisco Graduate Program in Bioengineering, Berkeley, California, 94720, USA
- Department of Bioengineering, University of California, Berkeley, Berkeley, California, 94720, USA
- Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, California, 94720, USA
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9
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Hira VVV, Breznik B, Vittori M, Loncq de Jong A, Mlakar J, Oostra RJ, Khurshed M, Molenaar RJ, Lah T, Van Noorden CJF. Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies. J Histochem Cytochem 2019; 68:33-57. [PMID: 31566074 DOI: 10.1369/0022155419878416] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma is the most aggressive primary brain tumor. Slowly dividing and therapy-resistant glioblastoma stem cells (GSCs) reside in protective peri-arteriolar niches and are held responsible for glioblastoma recurrence. Recently, we showed similarities between GSC niches and hematopoietic stem cell (HSC) niches in bone marrow. Acute myeloid leukemia (AML) cells hijack HSC niches and are transformed into therapy-resistant leukemic stem cells (LSCs). Current clinical trials are focussed on removal of LSCs out of HSC niches to differentiate and to become sensitized to chemotherapy. In the present study, we elaborated further on these similarities by immunohistochemical analyses of 17 biomarkers in paraffin sections of human glioblastoma and human bone marrow. We found all 17 biomarkers to be expressed both in hypoxic peri-arteriolar HSC niches in bone marrow and hypoxic peri-arteriolar GSC niches in glioblastoma. Our findings implicate that GSC niches are being formed in glioblastoma as a copy of HSC niches in bone marrow. These similarities between HSC niches and GSC niches provide a theoretic basis for the development of novel strategies to force GSCs out of their niches, in a similar manner as in AML, to induce GSC differentiation and proliferation to render them more sensitive to anti-glioblastoma therapies.
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Affiliation(s)
- Vashendriya V V Hira
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Miloš Vittori
- Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Annique Loncq de Jong
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Jernej Mlakar
- Institute of Pathology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Roelof-Jan Oostra
- Department of Medical Biology, Section Clinical Anatomy and Embryology, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Mohammed Khurshed
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Remco J Molenaar
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
| | - Tamara Lah
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Cornelis J F Van Noorden
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.,Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC at the Academic Medical Center, Amsterdam, The Netherlands
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10
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Xiao Y, Kim D, Dura B, Zhang K, Yan R, Li H, Han E, Ip J, Zou P, Liu J, Chen AT, Vortmeyer AO, Zhou J, Fan R. Ex vivo Dynamics of Human Glioblastoma Cells in a Microvasculature-on-a-Chip System Correlates with Tumor Heterogeneity and Subtypes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1801531. [PMID: 31016107 PMCID: PMC6468969 DOI: 10.1002/advs.201801531] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 12/24/2018] [Indexed: 05/03/2023]
Abstract
The perivascular niche (PVN) plays an essential role in brain tumor stem-like cell (BTSC) fate control, tumor invasion, and therapeutic resistance. Here, a microvasculature-on-a-chip system as a PVN model is used to evaluate the ex vivo dynamics of BTSCs from ten glioblastoma patients. BTSCs are found to preferentially localize in the perivascular zone, where they exhibit either the lowest motility, as in quiescent cells, or the highest motility, as in the invasive phenotype, with migration over long distance. These results indicate that PVN is a niche for BTSCs, while the microvascular tracks may serve as a path for tumor cell migration. The degree of colocalization between tumor cells and microvessels varies significantly across patients. To validate these results, single-cell transcriptome sequencing (10 patients and 21 750 single cells in total) is performed to identify tumor cell subtypes. The colocalization coefficient is found to positively correlate with proneural (stem-like) or mesenchymal (invasive) but not classical (proliferative) tumor cells. Furthermore, a gene signature profile including PDGFRA correlates strongly with the "homing" of tumor cells to the PVN. These findings demonstrate that the model can recapitulate in vivo tumor cell dynamics and heterogeneity, representing a new route to study patient-specific tumor cell functions.
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Affiliation(s)
- Yang Xiao
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
| | - Dongjoo Kim
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
| | - Burak Dura
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
| | - Kerou Zhang
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
| | - Runchen Yan
- School of Computer ScienceCarnegie Mellon UniversityPittsburghPA15213USA
| | - Huamin Li
- Applied Math ProgramYale UniversityNew HavenCT06520USA
| | - Edward Han
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
| | - Joshua Ip
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
| | - Pan Zou
- Department of NeurosurgeryYale School of MedicineNew HavenCT06520USA
| | - Jun Liu
- Department of NeurosurgeryYale School of MedicineNew HavenCT06520USA
| | - Ann Tai Chen
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
| | - Alexander O. Vortmeyer
- Department of PathologyIndiana University Health Pathology LaboratoryIndianapolisIN46202USA
| | - Jiangbing Zhou
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
- Department of NeurosurgeryYale School of MedicineNew HavenCT06520USA
- Yale Comprehensive Cancer CenterNew HavenCT06520USA
| | - Rong Fan
- Department of Biomedical EngineeringYale UniversityNew HavenCT06520USA
- Yale Comprehensive Cancer CenterNew HavenCT06520USA
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11
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Xiao Y, Kim D, Dura B, Zhang K, Yan R, Li H, Han E, Ip J, Zou P, Liu J, Chen AT, Vortmeyer AO, Zhou J, Fan R. Ex vivo Dynamics of Human Glioblastoma Cells in a Microvasculature-on-a-Chip System Correlates with Tumor Heterogeneity and Subtypes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1801531. [PMID: 31016107 DOI: 10.1101/400739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 12/24/2018] [Indexed: 05/21/2023]
Abstract
The perivascular niche (PVN) plays an essential role in brain tumor stem-like cell (BTSC) fate control, tumor invasion, and therapeutic resistance. Here, a microvasculature-on-a-chip system as a PVN model is used to evaluate the ex vivo dynamics of BTSCs from ten glioblastoma patients. BTSCs are found to preferentially localize in the perivascular zone, where they exhibit either the lowest motility, as in quiescent cells, or the highest motility, as in the invasive phenotype, with migration over long distance. These results indicate that PVN is a niche for BTSCs, while the microvascular tracks may serve as a path for tumor cell migration. The degree of colocalization between tumor cells and microvessels varies significantly across patients. To validate these results, single-cell transcriptome sequencing (10 patients and 21 750 single cells in total) is performed to identify tumor cell subtypes. The colocalization coefficient is found to positively correlate with proneural (stem-like) or mesenchymal (invasive) but not classical (proliferative) tumor cells. Furthermore, a gene signature profile including PDGFRA correlates strongly with the "homing" of tumor cells to the PVN. These findings demonstrate that the model can recapitulate in vivo tumor cell dynamics and heterogeneity, representing a new route to study patient-specific tumor cell functions.
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Affiliation(s)
- Yang Xiao
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
| | - Dongjoo Kim
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
| | - Burak Dura
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
| | - Kerou Zhang
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
| | - Runchen Yan
- School of Computer Science Carnegie Mellon University Pittsburgh PA 15213 USA
| | - Huamin Li
- Applied Math Program Yale University New Haven CT 06520 USA
| | - Edward Han
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
| | - Joshua Ip
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
| | - Pan Zou
- Department of Neurosurgery Yale School of Medicine New Haven CT 06520 USA
| | - Jun Liu
- Department of Neurosurgery Yale School of Medicine New Haven CT 06520 USA
| | - Ann Tai Chen
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
| | - Alexander O Vortmeyer
- Department of Pathology Indiana University Health Pathology Laboratory Indianapolis IN 46202 USA
| | - Jiangbing Zhou
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
- Department of Neurosurgery Yale School of Medicine New Haven CT 06520 USA
- Yale Comprehensive Cancer Center New Haven CT 06520 USA
| | - Rong Fan
- Department of Biomedical Engineering Yale University New Haven CT 06520 USA
- Yale Comprehensive Cancer Center New Haven CT 06520 USA
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12
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Sattiraju A, Mintz A. Pericytes in Glioblastomas: Multifaceted Role Within Tumor Microenvironments and Potential for Therapeutic Interventions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:65-91. [PMID: 31147872 DOI: 10.1007/978-3-030-16908-4_2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glioblastoma (GBM) is an aggressive and lethal disease that often results in a poor prognosis. Unlike most solid tumors, GBM is characterized by diffuse infiltrating margins, extensive angiogenesis, hypoxia, necrosis, and clonal heterogeneity. Recurrent disease is an unavoidable consequence for many patients as standard treatment options such as surgery, radiotherapy, and chemotherapy have proven to be insufficient in causing long-term survival benefits. Systemic delivery of promising drugs is hindered due to the blood-brain barrier and non-uniform perfusion within GBM tissue. In recent years, many investigations have highlighted the role of GBM stem cells (GSCs) and their microenvironment in the initiation and maintenance of tumor tissue. Preclinical and early clinical studies to target GSCs and microenvironmental components are currently underway. Of these strategies, immunotherapy using checkpoint inhibitors and redirected cytotoxic T cells have shown promising results in early investigations. But, GBM microenvironment is heterogenous and recent investigations have shown cell populations within this microenvironment to be plastic. These studies underline the importance of identifying the role of and targeting multiple cell populations within the GBM microenvironment which could have a synergistic effect when combined with novel therapies. Pericytes are multipotent perivascular cells that play a vital role within the GBM microenvironment by assisting in tumor initiation, survival, and progression. Due to their role in regulating the blood-brain barrier permeability, promoting angiogenesis, tumor growth, clearing extracellular matrix for infiltrating GBM cells and in helping GBM cells evade immune surveillance, pericytes could be ideal therapeutic targets for stymieing or exploiting their role within the GBM microenvironment. This chapter will introduce hallmarks of GBM and elaborate on the contributions of pericytes to these hallmarks by examining recent findings. In addition, the chapter also highlights the therapeutic value of targeting pericytes, while discussing conventional and novel GBM therapies and obstacles to their efficacy.
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Affiliation(s)
- Anirudh Sattiraju
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Akiva Mintz
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA.
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13
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Morikawa S, Iribar H, Gutiérrez-Rivera A, Ezaki T, Izeta A. Pericytes in Cutaneous Wound Healing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:1-63. [DOI: 10.1007/978-3-030-16908-4_1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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14
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Sattiraju A, Sai KKS, Mintz A. Glioblastoma Stem Cells and Their Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1041:119-140. [PMID: 29204831 DOI: 10.1007/978-3-319-69194-7_7] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glioblastoma (GBM) is the most common primary malignant astrocytoma associated with a poor patient survival. Apart from arising de novo, GBMs also occur due to progression of slower growing grade III astrocytomas. GBM is characterized by extensive hypoxia, angiogenesis, proliferation and invasion. Standard treatment options such as surgical resection, radiation therapy and chemotherapy have increased median patient survival to 14.6 months in adults but recurrent disease arising from treatment resistant cancer cells often results in patient mortality. These treatment resistant cancer cells have been found to exhibit stem cell like properties. Strategies to identify or target these Glioblastoma Stem Cells (GSC) have proven to be unsuccessful so far. Studies on cancer stem cells (CSC) within GBM and other cancers have highlighted the importance of paracrine signaling networks within their microenvironment on the growth and maintenance of CSCs. The study of GSCs and their communication with various cell populations within their microenvironment is therefore not only important to understand the biology of GBMs but also to predict response to therapies and to identify novel targets which could stymy support to treatment resistant cancer cells and prevent disease recurrence. The purpose of this chapter is to introduce the concept of GSCs and to detail the latest findings indicating the role of various cellular subtypes within their microenvironment on their survival, proliferation and differentiation.
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Affiliation(s)
- Anirudh Sattiraju
- Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | | | - Akiva Mintz
- Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
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15
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Wolf KJ, Lee S, Kumar S. A 3D topographical model of parenchymal infiltration and perivascular invasion in glioblastoma. APL Bioeng 2018; 2. [PMID: 29855630 DOI: 10.1063/1.5021059] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Glioblastoma (GBM) is the most common and invasive primary brain cancer. GBM tumors are characterized by diffuse infiltration, with tumor cells invading slowly through the hyaluronic acid (HA)-rich parenchyma toward vascular beds and then migrating rapidly along microvasculature. Progress in understanding local infiltration, vascular homing, and perivascular invasion is limited by the absence of culture models that recapitulate these hallmark processes. Here, we introduce a platform for GBM invasion consisting of a tumor-like cell reservoir and a parallel open channel "vessel" embedded in the 3D HA-RGD matrix. We show that this simple paradigm is sufficient to capture multi-step invasion and transitions in cell morphology and speed reminiscent of those seen in GBM. Specifically, seeded tumor cells grow into multicellular masses that expand and invade the surrounding HA-RGD matrices while extending long (10-100 μm), thin protrusions resembling those observed for GBM in vivo. Upon encountering the channel, cells orient along the channel wall, adopt a 2D-like morphology, and migrate rapidly along the channel. Structured illumination microscopy reveals distinct cytoskeletal architectures for cells invading through the HA matrix versus those migrating along the vascular channel. Substitution of collagen I in place of HA-RGD supports the same sequence of events but with faster local invasion and a more mesenchymal morphology. These results indicate that topographical effects are generalizable across matrix formulations, but the mechanisms underlying invasion are matrix-dependent. We anticipate that our reductionist paradigm should speed the development of mechanistic hypotheses that could be tested in more complex tumor models.
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Affiliation(s)
- Kayla J Wolf
- University of California, Berkeley - University of California, San Francisco Graduate Program in Bioengineering, Berkeley, California, 94720, USA.,Department of Bioengineering, University of California, Berkeley, Berkeley, California, 94720, USA
| | - Stacey Lee
- University of California, Berkeley - University of California, San Francisco Graduate Program in Bioengineering, Berkeley, California, 94720, USA.,Department of Bioengineering, University of California, Berkeley, Berkeley, California, 94720, USA
| | - Sanjay Kumar
- University of California, Berkeley - University of California, San Francisco Graduate Program in Bioengineering, Berkeley, California, 94720, USA.,Department of Bioengineering, University of California, Berkeley, Berkeley, California, 94720, USA.,Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, California, 94720, USA
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16
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Hira VVV, Wormer JR, Kakar H, Breznik B, van der Swaan B, Hulsbos R, Tigchelaar W, Tonar Z, Khurshed M, Molenaar RJ, Van Noorden CJF. Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins. J Histochem Cytochem 2018; 66:155-173. [PMID: 29297738 DOI: 10.1369/0022155417749174] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In glioblastoma, a fraction of malignant cells consists of therapy-resistant glioblastoma stem cells (GSCs) residing in protective niches that recapitulate hematopoietic stem cell (HSC) niches in bone marrow. We have previously shown that HSC niche proteins stromal cell-derived factor-1α (SDF-1α), C-X-C chemokine receptor type 4 (CXCR4), osteopontin (OPN), and cathepsin K (CatK) are expressed in hypoxic GSC niches around arterioles in five human glioblastoma samples. In HSC niches, HSCs are retained by binding of SDF-1α and OPN to their receptors CXCR4 and CD44, respectively. Protease CatK cleaves SDF-1α to release HSCs out of niches. The aim of the present study was to reproduce the immunohistochemical localization of these GSC markers in 16 human glioblastoma samples with the addition of three novel markers. Furthermore, we assessed the type of blood vessels associated with GSC niches. In total, we found seven GSC niches containing CD133-positive and nestin-positive GSCs as a single-cell layer exclusively around the tunica adventitia of 2% of the CD31-positive and SMA-positive arterioles and not around capillaries and venules. Niches expressed SDF-1α, CXCR4, CatK, OPN, CD44, hypoxia-inducible factor-1α, and vascular endothelial growth factor. In conclusion, we show that GSC niches are present around arterioles and express bone marrow HSC niche proteins.
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Affiliation(s)
- Vashendriya V V Hira
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Jill R Wormer
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Hala Kakar
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Britt van der Swaan
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Renske Hulsbos
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Wikky Tigchelaar
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Zbynek Tonar
- Department of Histology and Embryology and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Mohammed Khurshed
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Remco J Molenaar
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Cornelis J F Van Noorden
- Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
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Abstract
PURPOSE OF REVIEW Brain tumors are composed of primary tumors of the central nervous system, such us glioblastoma (GBM), and secondary metastatic tumors, such as melanoma, non-Hodgkin lymphoma as well as lung and breast cancers. Brain tumors are highly deadly, and unfortunately not many improvements have been achieved to improve the survival of patients with brain tumors. Chemoradiation resistance is one of the most clinically relevant challenges faced in patients with brain tumors. The perivascular niche is one of the most relevant microenvironment hubs in brain tumors. The understanding of the cellular crosstalk established within the brain tumor perivascular niche might provide us with key discoveries of new brain tumor vulnerabilities. RECENT FINDINGS Radio and chemoresistance in GBM and brain metastases is attributed to cancer stem cells (CSCs), which intrinsically modulate several pathways that make them resistant to therapy. Growing evidence, however, highlights the perivascular space as a niche for CSC survival, resistance to therapy, progression and dissemination. Here, I review the latest discoveries on the components and features of brain tumor vascular niches and the possible therapeutic strategies aimed at targeting its vulnerabilities, thus preventing GBM and metastasis chemoradiation resistance and recurrence. SUMMARY Recent discoveries suggest that targeting the brain perivascular niche has the potential of sensitizing brain tumors to therapies and reducing the occurrence of metastases.
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18
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Chen J, Mao S, Li H, Zheng M, Yi L, Lin JM, Lin ZX. The pathological structure of the perivascular niche in different microvascular patterns of glioblastoma. PLoS One 2017; 12:e0182183. [PMID: 28771552 PMCID: PMC5542434 DOI: 10.1371/journal.pone.0182183] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 07/13/2017] [Indexed: 01/22/2023] Open
Abstract
The perivascular niche is critical for intercellular communication between resident cell types in glioblastoma (GBM), and it plays a vital role in maintaining the glioma stem cell (GSC) microenvironment. It is shown in abundant research that different microvascular patterns exist in GBM; and it can be implied that different microvascular patterns are associated with different pathological structures in the perivascular niche. However, the pathological structure of the perivascular niche is still not clear. Here, we investigated the distribution and biological characteristics of different microvascular pattern niches (MVPNs) in GBM by detecting the expression of CD34, CD133, Nestin, α-SMA, GFAP and CD14 in the perivascular niche using multiple -fluorescence. The four basic microvascular patterns are microvascular sprouting (MS), vascular cluster (VC), vascular garland (VG), and glomeruloid vascular proliferation (GVP). By analyzing the proportion of the area of each marker in four types of formations, the results indicated that the expression of CD34, CD133 and Nestin in MS and VC was significantly lower than that in VG and GVP (P<0.05). Furthermore, the results showed that α-SMA expression different in the MS, VC, VG and GVP (P<0.05). However, the expression of GFAP and CD14 in each type of formation exhibited no significant difference (P>0.05). According to the area distributions of different markers, we mapped four precise simulation diagrams to provide an effective foundation for the accurate simulation of glioblastoma in vitro.
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Affiliation(s)
- Jintao Chen
- Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, Tsinghua University, Beijing, China
| | - Sifeng Mao
- Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, Tsinghua University, Beijing, China
| | - Haifang Li
- Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, Tsinghua University, Beijing, China
| | - Mingcheng Zheng
- Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Linglu Yi
- Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, Tsinghua University, Beijing, China
| | - Jin-Ming Lin
- Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, Tsinghua University, Beijing, China
- * E-mail: (JML); (ZXL)
| | - Zhi-xiong Lin
- Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
- * E-mail: (JML); (ZXL)
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19
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Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity. BIOMED RESEARCH INTERNATIONAL 2017. [PMID: 28630875 PMCID: PMC5467280 DOI: 10.1155/2017/9634172] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Glioblastoma is the most aggressive cancer of the brain. The dismal prognosis is largely attributed to the heterogeneous nature of the tumor, which in addition to intrinsic molecular and genetic changes is also influenced by the microenvironmental niche in which the glioma cells reside. The cancer stem cells (CSCs) hypothesis suggests that all cancers arise from CSCs that possess the ability to self-renew and initiate tumor formation. CSCs reside in specialized niches where interaction with the microenvironment regulates their stem cell behavior. The reciprocal interaction between glioma stem cells (GSCs) and cells from the microenvironment, such as endothelial cells, immune cells, and other parenchymal cells, may also promote angiogenesis, invasion, proliferation, and stemness of the GSCs and be likely to have an underappreciated role in their responsiveness to therapy. This crosstalk may also promote molecular transition of GSCs. Hence the inherent plasticity of GSCs can be seen as an adaptive response, changing according to the signaling cue from the niche. Given the association of GSCs with tumor recurrence and treatment sensitivity, understanding this bidirectional crosstalk between GSCs and its niche may provide a framework to identify more effective therapeutic targets and improve treatment outcome.
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20
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Ahmad G, Amiji MM. Cancer stem cell-targeted therapeutics and delivery strategies. Expert Opin Drug Deliv 2016; 14:997-1008. [DOI: 10.1080/17425247.2017.1263615] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Gulzar Ahmad
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
| | - Mansoor M. Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
- Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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21
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Mignogna C, Signorelli F, Vismara MFM, Zeppa P, Camastra C, Barni T, Donato G, Di Vito A. A reappraisal of macrophage polarization in glioblastoma: Histopathological and immunohistochemical findings and review of the literature. Pathol Res Pract 2016; 212:491-9. [DOI: 10.1016/j.prp.2016.02.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/28/2016] [Accepted: 02/23/2016] [Indexed: 12/22/2022]
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22
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Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions. Oncotarget 2016; 6:18282-92. [PMID: 26286961 PMCID: PMC4621891 DOI: 10.18632/oncotarget.4957] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/09/2015] [Indexed: 12/23/2022] Open
Abstract
Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth.
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23
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Glioblastoma Stem Cells Microenvironment: The Paracrine Roles of the Niche in Drug and Radioresistance. Stem Cells Int 2016; 2016:6809105. [PMID: 26880981 PMCID: PMC4736577 DOI: 10.1155/2016/6809105] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 11/09/2015] [Accepted: 11/10/2015] [Indexed: 12/13/2022] Open
Abstract
Among all solid tumors, the high-grade glioma appears to be the most vascularized one. In fact, "microvascular hyperplasia" is a hallmark of GBM. An altered vascular network determines irregular blood flow, so that tumor cells spread rapidly beyond the diffusion distance of oxygen in the tissue, with the consequent formation of hypoxic or anoxic areas, where the bulk of glioblastoma stem cells (GSCs) reside. The response to this event is the induction of angiogenesis, a process mediated by hypoxia inducible factors. However, this new capillary network is not efficient in maintaining a proper oxygen supply to the tumor mass, thereby causing an oxygen gradient within the neoplastic zone. This microenvironment helps GSCs to remain in a "quiescent" state preserving their potential to proliferate and differentiate, thus protecting them by the effects of chemo- and radiotherapy. Recent evidences suggest that responses of glioblastoma to standard therapies are determined by the microenvironment of the niche, where the GSCs reside, allowing a variety of mechanisms that contribute to the chemo- and radioresistance, by preserving GSCs. It is, therefore, crucial to investigate the components/factors of the niche in order to formulate new adjuvant therapies rendering more efficiently the gold standard therapies for this neoplasm.
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24
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Jani A, Shaikh F, Barton S, Willis C, Banerjee D, Mitchell J, Hernandez SL, Hei T, Kadenhe-Chiweshe A, Yamashiro DJ, Connolly EP. High-Dose, Single-Fraction Irradiation Rapidly Reduces Tumor Vasculature and Perfusion in a Xenograft Model of Neuroblastoma. Int J Radiat Oncol Biol Phys 2015; 94:1173-80. [PMID: 26907918 DOI: 10.1016/j.ijrobp.2015.12.367] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 12/15/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023]
Abstract
PURPOSE To characterize the effects of high-dose radiation therapy (HDRT) on neuroblastoma tumor vasculature, including the endothelial cell (EC)-pericyte interaction as a potential target for combined treatment with antiangiogenic agents. METHODS AND MATERIALS The vascular effects of radiation therapy were examined in a xenograft model of high-risk neuroblastoma. In vivo 3-dimensional contrast-enhanced ultrasonography (3D-CEUS) imaging and immunohistochemistry (IHC) were performed. RESULTS HDRT significantly reduced tumor blood volume 6 hours after irradiation compared with the lower doses used in conventionally fractionated radiation. There was a 63% decrease in tumor blood volume after 12-Gy radiation compared with a 24% decrease after 2 Gy. Analysis of tumor vasculature by lectin angiography showed a significant loss of small vessel ends at 6 hours. IHC revealed a significant loss of ECs at 6 and 72 hours after HDRT, with an accompanying loss of immature and mature pericytes at 72 hours. CONCLUSIONS HDRT affects tumor vasculature in a manner not observed at lower doses. The main observation was an early reduction in tumor perfusion resulting from a reduction of small vessel ends with a corresponding loss of endothelial cells and pericytes.
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Affiliation(s)
- Ashish Jani
- Department of Radiation Oncology, Columbia University Medical Center, New York, New York
| | - Fauzia Shaikh
- Department of Radiation Oncology, Columbia University Medical Center, New York, New York
| | - Sunjay Barton
- Department of Radiation Oncology, Columbia University Medical Center, New York, New York
| | - Callen Willis
- Department of Surgery, Columbia University Medical Center, New York, New York
| | - Debarshi Banerjee
- Department of Pediatrics, Columbia University Medical Center, New York, New York
| | - Jason Mitchell
- Department of Surgery, Columbia University Medical Center, New York, New York
| | | | - Tom Hei
- Department of Radiation Oncology, Columbia University Medical Center, New York, New York
| | | | - Darrell J Yamashiro
- Department of Surgery, Columbia University Medical Center, New York, New York; Department of Pediatrics, Columbia University Medical Center, New York, New York; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York
| | - Eileen P Connolly
- Department of Radiation Oncology, Columbia University Medical Center, New York, New York.
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25
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Sun T, Plutynski A, Ward S, Rubin JB. An integrative view on sex differences in brain tumors. Cell Mol Life Sci 2015; 72:3323-42. [PMID: 25985759 PMCID: PMC4531141 DOI: 10.1007/s00018-015-1930-2] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 04/27/2015] [Accepted: 05/11/2015] [Indexed: 02/07/2023]
Abstract
Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations.
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Affiliation(s)
- Tao Sun
- />Department of Pediatrics, Washington University School of Medicine, St Louis, USA
| | - Anya Plutynski
- />Department of Philosophy, Washington University in St Louis, St Louis, USA
| | - Stacey Ward
- />Department of Pediatrics, Washington University School of Medicine, St Louis, USA
| | - Joshua B. Rubin
- />Department of Pediatrics, Washington University School of Medicine, St Louis, USA
- />Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110 USA
- />Campus Box 8208, 660 South Euclid Ave, St Louis, MO 63110 USA
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Hira VVV, Ploegmakers KJ, Grevers F, Verbovšek U, Silvestre-Roig C, Aronica E, Tigchelaar W, Turnšek TL, Molenaar RJ, Van Noorden CJF. CD133+ and Nestin+ Glioma Stem-Like Cells Reside Around CD31+ Arterioles in Niches that Express SDF-1α, CXCR4, Osteopontin and Cathepsin K. J Histochem Cytochem 2015; 63:481-93. [DOI: 10.1369/0022155415581689] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 03/16/2015] [Indexed: 11/22/2022] Open
Abstract
Poor survival of high-grade glioma is at least partly caused by glioma stem-like cells (GSLCs) that are resistant to therapy. GSLCs reside in niches in close vicinity of endothelium. The aim of the present study was to characterize proteins that may be functional in the GSLC niche by performing immunohistochemistry on serial cryostat sections of human high-grade glioma samples. We have found nine niches in five out of five high-grade glioma samples that were all surrounding arterioles with CD31+ endothelial cells and containing cellular structures that were CD133+ and nestin+. All nine niches expressed stromal-derived factor-1α (SDF-1α), its receptor C-X-C chemokine receptor type 4 (CXCR4), osteopontin and cathepsin K. SDF-1α plays a role in homing of CXCR4+ stem cells and leukocytes, whereas osteopontin and cathepsin K promote migration of cancer cells and leukocytes. Leukocyte-related markers, such as CD68, macrophage matrix metalloprotease-9, CD177 and neutrophil elastase were often but not always detected in the niches. We suggest that SDF-1α is involved in homing of CXCR4+ GSLCs and leukocytes and that cathepsin K and osteopontin are involved in the migration of GSLCs out of the niches.
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Affiliation(s)
- Vashendriya V. V. Hira
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Kimberley J. Ploegmakers
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Frederieke Grevers
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Urška Verbovšek
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Carlos Silvestre-Roig
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Eleonora Aronica
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Wikky Tigchelaar
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Tamara Lah Turnšek
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Remco J. Molenaar
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
| | - Cornelis J. F. Van Noorden
- Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands (VVVH, KJP, FG, WT, RJM, CJFVN)
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia (UV, TLT)
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands (CSR, EA)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia (TLT)
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Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol 2014; 25:198-213. [PMID: 25540894 DOI: 10.1016/j.tcb.2014.11.006] [Citation(s) in RCA: 545] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 02/08/2023]
Abstract
The tumor microenvironment (TME) not only plays a pivotal role during cancer progression and metastasis but also has profound effects on therapeutic efficacy. In the case of microenvironment-mediated resistance this can involve an intrinsic response, including the co-option of pre-existing structural elements and signaling networks, or an acquired response of the tumor stroma following the therapeutic insult. Alternatively, in other contexts, the TME has a multifaceted ability to enhance therapeutic efficacy. This review examines recent advances in our understanding of the contribution of the TME during cancer therapy and discusses key concepts that may be amenable to therapeutic intervention.
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Affiliation(s)
- Florian Klemm
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Johanna A Joyce
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Barone A, Sengupta R, Warrington NM, Smith E, Wen PY, Brekken RA, Romagnoli B, Douglas G, Chevalier E, Bauer MP, Dembowsky K, Piwnica-Worms D, Rubin JB. Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma. Oncotarget 2014; 5:9811-22. [PMID: 25238146 PMCID: PMC4259439 DOI: 10.18632/oncotarget.2443] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 09/08/2014] [Indexed: 11/25/2022] Open
Abstract
Glioblastoma recurrence involves the persistence of a subpopulation of cells with enhanced tumor-initiating capacity (TIC) that reside within the perivascular space, or niche (PVN). Anti-angiogenic therapies may prevent the formation of new PVN but have not prevented recurrence in clinical trials, suggesting they cannot abrogate TIC activity. We hypothesized that combining anti-angiogenic therapy with blockade of PVN function would have superior anti-tumor activity. We tested this hypothesis in an established intracranial xenograft model of GBM using a monoclonal antibody specific for murine and human VEGF (mcr84) and a Protein Epitope Mimetic (PEM) CXCR4 antagonist, POL5551. When doses of POL5551 were increased to overcome an mcr84-induced improvement in vascular barrier function, combinatorial therapy significantly inhibited intracranial tumor growth and improved survival. Anti-tumor activity was associated with significant changes in tumor cell proliferation and apoptosis, and a reduction in the numbers of perivascular cells expressing the TIC marker nestin. A direct effect on TICs was demonstrated for POL5551, but not mcr84, in three primary patient-derived GBM isolates. These findings indicate that targeting the structure and function of the PVN has superior anti-tumor effect and provide a strong rationale for clinical evaluation of POL5551 and Avastin in patients with GBM.
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Affiliation(s)
- Amy Barone
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
| | - Rajarshi Sengupta
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
| | - Nicole M. Warrington
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
| | - Erin Smith
- BRIGHT Institute, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
- Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
| | - Patrick Y. Wen
- Center for Neuro-Oncology, Dana Farber/Brigham and Women’s Cancer Center, Brookline Ave, Boston, MA
- Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Brookline Ave, Boston, MA
| | - Rolf A. Brekken
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Harry Hines Blvd. Dallas, TX
| | | | - Garry Douglas
- PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland
| | - Eric Chevalier
- PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland
| | - Michael P. Bauer
- PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland
| | - Klaus Dembowsky
- PolyPhor Ltd, Hegenheimermattweg 125 CH-4123 Allschwil, Switzerland
| | - David Piwnica-Worms
- BRIGHT Institute, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
- Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
- Department of Cell Biology & Physiology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Holcombe Dr., Houston, TX
| | - Joshua B. Rubin
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
- Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO
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29
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Stem cell niches in glioblastoma: a neuropathological view. BIOMED RESEARCH INTERNATIONAL 2014; 2014:725921. [PMID: 24834433 PMCID: PMC4009309 DOI: 10.1155/2014/725921] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 03/22/2014] [Accepted: 03/24/2014] [Indexed: 11/27/2022]
Abstract
Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent.
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