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Wang Y, Siebzehnrubl D, Weller M, Weiss T, Siebzehnrubl FA, Newland B. Vortioxetine: A Potential Drug for Repurposing for Glioblastoma Treatment via a Microsphere Local Delivery System. ACS Biomater Sci Eng 2025; 11:2203-2215. [PMID: 40167528 PMCID: PMC12001186 DOI: 10.1021/acsbiomaterials.5c00068] [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: 01/09/2025] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 04/02/2025]
Abstract
Drug repurposing is an attractive route for finding new therapeutics for brain cancers such as glioblastoma. Local administration of drugs to brain tumors or the postsurgical resection cavity holds promise to deliver a high dose to the target site with minimal off-target effects. Drug delivery systems aim to sustain the release of the drug at the target site but typically exhibit drawbacks such as a poor safety profile, uncontrolled/rapid drug release, or poor control over synthesis parameters/material dimensions. Herein, we analyzed the antidepressant vortioxetine and showed in vitro that it causes a greater loss of viability in glioblastoma cells than it does to normal primary human astrocytes. We developed a new droplet microfluidic-based emulsion method to reproducibly produce vortioxetine-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres with tight size control (36.80 ± 1.96 μm). The drug loading efficiency was around 90% when 9.1% (w/w) drug was loaded into the microspheres, and drug release could be sustained for three to 4 weeks. The vortioxetine microspheres showed robust antiglioblastoma efficacy in both 2D monolayer and 3D spheroid patient-derived glioblastoma cells, highlighting the potential of combining an antidepressant with sustained local delivery as a new therapeutic strategy.
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Affiliation(s)
- Yu Wang
- School
of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom
| | - Dorit Siebzehnrubl
- Cardiff
University School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff CF24 4HQ, United Kingdom
| | - Michael Weller
- Department
of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich 8091, Switzerland
| | - Tobias Weiss
- Department
of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich 8091, Switzerland
| | - Florian A. Siebzehnrubl
- Cardiff
University School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff CF24 4HQ, United Kingdom
| | - Ben Newland
- School
of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom
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2
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Bektas CK, Luo J, Conley B, Le KPN, Lee KB. 3D bioprinting approaches for enhancing stem cell-based neural tissue regeneration. Acta Biomater 2025; 193:20-48. [PMID: 39793745 DOI: 10.1016/j.actbio.2025.01.006] [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: 08/16/2024] [Revised: 12/12/2024] [Accepted: 01/07/2025] [Indexed: 01/13/2025]
Abstract
Three-dimensional (3D) bioprinting holds immense promise for advancing stem cell research and developing novel therapeutic strategies in the field of neural tissue engineering and disease modeling. This paper critically analyzes recent breakthroughs in 3D bioprinting, specifically focusing on its application in these areas. We comprehensively explore the advantages and limitations of various 3D printing methods, the selection and formulation of bioink materials tailored for neural stem cells, and the incorporation of nanomaterials with dual functionality, enhancing the bioprinting process and promoting neurogenesis pathways. Furthermore, the paper reviews the diverse range of stem cells employed in neural bioprinting research, discussing their potential applications and associated challenges. We also introduce the emerging field of 4D bioprinting, highlighting current efforts to develop time-responsive constructs that improve the integration and functionality of bioprinted neural tissues. In short, this manuscript aims to provide a comprehensive understanding of this rapidly evolving field. It underscores the transformative potential of 3D and 4D bioprinting technologies in revolutionizing stem cell research and paving the way for novel therapeutic solutions for neurological disorders and injuries, ultimately contributing significantly to the advancement of regenerative medicine. STATEMENT OF SIGNIFICANCE: This comprehensive review critically examines the current bioprinting research landscape, highlighting efforts to overcome key limitations in printing technologies-improving cell viability post-printing, enhancing resolution, and optimizing cross-linking efficiencies. The continuous refinement of material compositions aims to control the spatiotemporal delivery of therapeutic agents, ensuring better integration of transplanted cells with host tissues. Specifically, the review focuses on groundbreaking advancements in neural tissue engineering. The development of next-generation bioinks, hydrogels, and scaffolds specifically designed for neural regeneration complexities holds the potential to revolutionize treatments for debilitating neural conditions, especially when nanotechnologies are being incorporated. This review offers the readers both a comprehensive analysis of current breakthroughs and an insightful perspective on the future trajectory of neural tissue engineering.
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Affiliation(s)
- Cemile Kilic Bektas
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Jeffrey Luo
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Brian Conley
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Kim-Phuong N Le
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Ki-Bum Lee
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA.
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Maity S, Bhuyan T, Jewell C, Kawakita S, Sharma S, Nguyen HT, Najafabadi AH, Ermis M, Falcone N, Chen J, Mandal K, Khorsandi D, Yilgor C, Choroomi A, Torres E, Mecwan M, John JV, Akbari M, Wang Z, Moniz-Garcia D, Quiñones-Hinojosa A, Jucaud V, Dokmeci MR, Khademhosseini A. Recent Developments in Glioblastoma-On-A-Chip for Advanced Drug Screening Applications. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2405511. [PMID: 39535474 PMCID: PMC11719323 DOI: 10.1002/smll.202405511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/08/2024] [Indexed: 11/16/2024]
Abstract
Glioblastoma (GBM) is an aggressive form of cancer, comprising ≈80% of malignant brain tumors. However, there are no effective treatments for GBM due to its heterogeneity and the presence of the blood-brain barrier (BBB), which restricts the delivery of therapeutics to the brain. Despite in vitro models contributing to the understanding of GBM, conventional 2D models oversimplify the complex tumor microenvironment. Organ-on-a-chip (OoC) models have emerged as promising platforms that recapitulate human tissue physiology, enabling disease modeling, drug screening, and personalized medicine. There is a sudden increase in GBM-on-a-chip models that can significantly advance the knowledge of GBM etiology and revolutionize drug development by reducing animal testing and enhancing translation to the clinic. In this review, an overview of GBM-on-a-chip models and their applications is reported for drug screening and discussed current challenges and potential future directions for GBM-on-a-chip models.
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Affiliation(s)
- Surjendu Maity
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
- Department of Orthopedic Surgery, Duke University School of
Medicine, Duke University, Durham, NC 27705
| | - Tamanna Bhuyan
- Department of Applied Biology, School of Biological
Sciences, University of Science & Technology Meghalaya, Meghalaya, 793101,
India
| | - Christopher Jewell
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Satoru Kawakita
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Saurabh Sharma
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Huu Tuan Nguyen
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | | | - Menekse Ermis
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
- Center of Excellence in Biomaterials and Tissue
Engineering, Middle East Technical University, Ankara, Turkey
| | - Natashya Falcone
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Junjie Chen
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Kalpana Mandal
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Danial Khorsandi
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Can Yilgor
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Auveen Choroomi
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Emily Torres
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Marvin Mecwan
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Johnson V. John
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | - Mohsen Akbari
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
- Laboratoryfor Innovations in Micro Engineering (LiME),
Department of Mechanical Engineering, University of Victoria, Victoria, BC V8P 5C2,
Canada
- Biotechnology Center, Silesian University of Technology,
Akademicka 2A, 44-100 Gliwice, Poland
| | - Zhaohui Wang
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | | | | | - Vadim Jucaud
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
| | | | - Ali Khademhosseini
- Terasaki Institute for Biomedical Innovation, Los Angeles,
CA, 90064 USA
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Jose A, Kulkarni P, Thilakan J, Munisamy M, Malhotra AG, Singh J, Kumar A, Rangnekar VM, Arya N, Rao M. Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine. Mol Cancer 2024; 23:50. [PMID: 38461268 PMCID: PMC10924370 DOI: 10.1186/s12943-023-01916-6] [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: 08/05/2023] [Accepted: 12/15/2023] [Indexed: 03/11/2024] Open
Abstract
Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.
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Affiliation(s)
- Anmi Jose
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Pallavi Kulkarni
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Jaya Thilakan
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Murali Munisamy
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Anvita Gupta Malhotra
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Jitendra Singh
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Vivek M Rangnekar
- Markey Cancer Center and Department of Radiation Medicine, University of Kentucky, Lexington, KY, 40536, USA
| | - Neha Arya
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India.
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Aazmi A, Zhang D, Mazzaglia C, Yu M, Wang Z, Yang H, Huang YYS, Ma L. Biofabrication methods for reconstructing extracellular matrix mimetics. Bioact Mater 2024; 31:475-496. [PMID: 37719085 PMCID: PMC10500422 DOI: 10.1016/j.bioactmat.2023.08.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 09/19/2023] Open
Abstract
In the human body, almost all cells interact with extracellular matrices (ECMs), which have tissue and organ-specific compositions and architectures. These ECMs not only function as cellular scaffolds, providing structural support, but also play a crucial role in dynamically regulating various cellular functions. This comprehensive review delves into the examination of biofabrication strategies used to develop bioactive materials that accurately mimic one or more biophysical and biochemical properties of ECMs. We discuss the potential integration of these ECM-mimics into a range of physiological and pathological in vitro models, enhancing our understanding of cellular behavior and tissue organization. Lastly, we propose future research directions for ECM-mimics in the context of tissue engineering and organ-on-a-chip applications, offering potential advancements in therapeutic approaches and improved patient outcomes.
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Affiliation(s)
- Abdellah Aazmi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, China
| | - Duo Zhang
- Department of Engineering, University of Cambridge, Cambridge, United Kingdom
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 51817, China
| | - Corrado Mazzaglia
- Department of Engineering, University of Cambridge, Cambridge, United Kingdom
| | - Mengfei Yu
- The Affiliated Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Zhen Wang
- Center for Laboratory Medicine, Allergy Center, Department of Transfusion Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Huayong Yang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, China
| | - Yan Yan Shery Huang
- Department of Engineering, University of Cambridge, Cambridge, United Kingdom
| | - Liang Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, China
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Pasupuleti V, Vora L, Prasad R, Nandakumar DN, Khatri DK. Glioblastoma preclinical models: Strengths and weaknesses. Biochim Biophys Acta Rev Cancer 2024; 1879:189059. [PMID: 38109948 DOI: 10.1016/j.bbcan.2023.189059] [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: 08/26/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 12/20/2023]
Abstract
Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy.
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Affiliation(s)
- Vasavi Pasupuleti
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Lalitkumar Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, UK.
| | - Renuka Prasad
- Department of Anatomy, Korea University College of Medicine, Moonsuk Medical Research Building, 516, 5th floor, 73 Inchon-ro, Seongbuk-gu, Seoul 12841, Republic of Korea
| | - D N Nandakumar
- Department of Neurochemistry National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore 560029, India
| | - Dharmendra Kumar Khatri
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India.
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Ahmed T. Biomaterial-based in vitro 3D modeling of glioblastoma multiforme. CANCER PATHOGENESIS AND THERAPY 2023; 1:177-194. [PMID: 38327839 PMCID: PMC10846340 DOI: 10.1016/j.cpt.2023.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/24/2022] [Accepted: 01/04/2023] [Indexed: 02/09/2024]
Abstract
Adult-onset brain cancers, such as glioblastomas, are particularly lethal. People with glioblastoma multiforme (GBM) do not anticipate living for more than 15 months if there is no cure. The results of conventional treatments over the past 20 years have been underwhelming. Tumor aggressiveness, location, and lack of systemic therapies that can penetrate the blood-brain barrier are all contributing factors. For GBM treatments that appear promising in preclinical studies, there is a considerable rate of failure in phase I and II clinical trials. Unfortunately, access becomes impossible due to the intricate architecture of tumors. In vitro, bioengineered cancer models are currently being used by researchers to study disease development, test novel therapies, and advance specialized medications. Many different techniques for creating in vitro systems have arisen over the past few decades due to developments in cellular and tissue engineering. Later-stage research may yield better results if in vitro models that resemble brain tissue and the blood-brain barrier are used. With the use of 3D preclinical models made available by biomaterials, researchers have discovered that it is possible to overcome these limitations. Innovative in vitro models for the treatment of GBM are possible using biomaterials and novel drug carriers. This review discusses the benefits and drawbacks of 3D in vitro glioblastoma modeling systems.
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Affiliation(s)
- Tanvir Ahmed
- Department of Pharmaceutical Sciences, North South University, Bashundhara, Dhaka, 1229, Bangladesh
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Rajan RG, Fernandez-Vega V, Sperry J, Nakashima J, Do LH, Andrews W, Boca S, Islam R, Chowdhary SA, Seldin J, Souza GR, Scampavia L, Hanafy KA, Vrionis FD, Spicer TP. In Vitro and In Vivo Drug-Response Profiling Using Patient-Derived High-Grade Glioma. Cancers (Basel) 2023; 15:3289. [PMID: 37444398 PMCID: PMC10339991 DOI: 10.3390/cancers15133289] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Genomic profiling cannot solely predict the complexity of how tumor cells behave in their in vivo microenvironment and their susceptibility to therapies. The aim of the study was to establish a functional drug prediction model utilizing patient-derived GBM tumor samples for in vitro testing of drug efficacy followed by in vivo validation to overcome the disadvantages of a strict pharmacogenomics approach. METHODS High-throughput in vitro pharmacologic testing of patient-derived GBM tumors cultured as 3D organoids offered a cost-effective, clinically and phenotypically relevant model, inclusive of tumor plasticity and stroma. RNAseq analysis supplemented this 128-compound screening to predict more efficacious and patient-specific drug combinations with additional tumor stemness evaluated using flow cytometry. In vivo PDX mouse models rapidly validated (50 days) and determined mutational influence alongside of drug efficacy. We present a representative GBM case of three tumors resected at initial presentation, at first recurrence without any treatment, and at a second recurrence following radiation and chemotherapy, all from the same patient. RESULTS Molecular and in vitro screening helped identify effective drug targets against several pathways as well as synergistic drug combinations of cobimetinib and vemurafenib for this patient, supported in part by in vivo tumor growth assessment. Each tumor iteration showed significantly varying stemness and drug resistance. CONCLUSIONS Our integrative model utilizing molecular, in vitro, and in vivo approaches provides direct evidence of a patient's tumor response drifting with treatment and time, as demonstrated by dynamic changes in their tumor profile, which may affect how one would address that drift pharmacologically.
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Affiliation(s)
- Robin G. Rajan
- Helene and Stephen Weicholz Cell Therapy Laboratory, Marcus Neuroscience Institute, Boca Raton Regional Hospital, 800 Meadows Road, Boca Raton, FL 33486, USA; (R.G.R.); (S.A.C.); (K.A.H.)
| | - Virneliz Fernandez-Vega
- The Herbert Wertheim UF Scripps Institute Molecular Screening Center, Department of Molecular Medicine, UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, FL 33458, USA; (V.F.-V.); (L.S.)
| | - Jantzen Sperry
- Certis Oncology, 5626 Oberlin Dr. Suite 110, San Diego, CA 92121, USA; (J.S.); (J.N.); (L.H.D.); (W.A.)
| | - Jonathan Nakashima
- Certis Oncology, 5626 Oberlin Dr. Suite 110, San Diego, CA 92121, USA; (J.S.); (J.N.); (L.H.D.); (W.A.)
| | - Long H. Do
- Certis Oncology, 5626 Oberlin Dr. Suite 110, San Diego, CA 92121, USA; (J.S.); (J.N.); (L.H.D.); (W.A.)
| | - Warren Andrews
- Certis Oncology, 5626 Oberlin Dr. Suite 110, San Diego, CA 92121, USA; (J.S.); (J.N.); (L.H.D.); (W.A.)
| | - Simina Boca
- Innovation Center for Biomedical Informatics (ICBI), Departments of Oncology and Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, 2115 Wisconsin Ave NW, Suite G100, Washington, DC 20007, USA;
| | - Rezwanul Islam
- Florida Atlantic University College of Medicine, 777 Glades Road, Boca Raton, FL 33431, USA;
| | - Sajeel A. Chowdhary
- Helene and Stephen Weicholz Cell Therapy Laboratory, Marcus Neuroscience Institute, Boca Raton Regional Hospital, 800 Meadows Road, Boca Raton, FL 33486, USA; (R.G.R.); (S.A.C.); (K.A.H.)
| | - Jan Seldin
- Greiner Bio-One North America, Inc., 4238 Capital Drive, Monroe, NC 28110, USA; (J.S.); (G.R.S.)
| | - Glauco R. Souza
- Greiner Bio-One North America, Inc., 4238 Capital Drive, Monroe, NC 28110, USA; (J.S.); (G.R.S.)
| | - Louis Scampavia
- The Herbert Wertheim UF Scripps Institute Molecular Screening Center, Department of Molecular Medicine, UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, FL 33458, USA; (V.F.-V.); (L.S.)
| | - Khalid A. Hanafy
- Helene and Stephen Weicholz Cell Therapy Laboratory, Marcus Neuroscience Institute, Boca Raton Regional Hospital, 800 Meadows Road, Boca Raton, FL 33486, USA; (R.G.R.); (S.A.C.); (K.A.H.)
- Florida Atlantic University College of Medicine, 777 Glades Road, Boca Raton, FL 33431, USA;
| | - Frank D. Vrionis
- Helene and Stephen Weicholz Cell Therapy Laboratory, Marcus Neuroscience Institute, Boca Raton Regional Hospital, 800 Meadows Road, Boca Raton, FL 33486, USA; (R.G.R.); (S.A.C.); (K.A.H.)
- Florida Atlantic University College of Medicine, 777 Glades Road, Boca Raton, FL 33431, USA;
| | - Timothy P. Spicer
- The Herbert Wertheim UF Scripps Institute Molecular Screening Center, Department of Molecular Medicine, UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, FL 33458, USA; (V.F.-V.); (L.S.)
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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: 101] [Impact Index Per Article: 50.5] [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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Barin N, Balcioglu HE, de Heer I, de Wit M, Lamfers MLM, van Royen ME, French PJ, Accardo A. 3D-Engineered Scaffolds to Study Microtubes and Localization of Epidermal Growth Factor Receptor in Patient-Derived Glioma Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2204485. [PMID: 36207287 DOI: 10.1002/smll.202204485] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/09/2022] [Indexed: 06/16/2023]
Abstract
A major obstacle in glioma research is the lack of in vitro models that can retain cellular features of glioma cells in vivo. To overcome this limitation, a 3D-engineered scaffold, fabricated by two-photon polymerization, is developed as a cell culture model system to study patient-derived glioma cells. Scanning electron microscopy, (live cell) confocal microscopy, and immunohistochemistry are employed to assess the 3D model with respect to scaffold colonization, cellular morphology, and epidermal growth factor receptor localization. Both glioma patient-derived cells and established cell lines successfully colonize the scaffolds. Compared to conventional 2D cell cultures, the 3D-engineered scaffolds more closely resemble in vivo glioma cellular features and allow better monitoring of individual cells, cellular protrusions, and intracellular trafficking. Furthermore, less random cell motility and increased stability of cellular networks is observed for cells cultured on the scaffolds. The 3D-engineered glioma scaffolds therefore represent a promising tool for studying brain cancer mechanobiology as well as for drug screening studies.
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Affiliation(s)
- Nastaran Barin
- Department of Precision and Microsystems Engineering, Delft University of Technology, Mekelweg 2, Delft, 2628 CD, The Netherlands
- Department of Neurology, Erasmus MC Cancer Institute, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands
| | - Hayri E Balcioglu
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands
| | - Iris de Heer
- Department of Neurology, Erasmus MC Cancer Institute, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands
| | - Maurice de Wit
- Department of Neurology, Erasmus MC Cancer Institute, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands
| | - Martine L M Lamfers
- Department of Neurosurgery, Erasmus MC Cancer Institute, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands
| | - Martin E van Royen
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands
| | - Pim J French
- Department of Neurology, Erasmus MC Cancer Institute, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands
| | - Angelo Accardo
- Department of Precision and Microsystems Engineering, Delft University of Technology, Mekelweg 2, Delft, 2628 CD, The Netherlands
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11
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Faisal SM, Comba A, Varela ML, Argento AE, Brumley E, Abel C, Castro MG, Lowenstein PR. The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications. Front Oncol 2022; 12:1005069. [PMID: 36276147 PMCID: PMC9583158 DOI: 10.3389/fonc.2022.1005069] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/20/2022] [Indexed: 11/26/2022] Open
Abstract
Glioblastoma (GBM), an aggressive high-grade glial tumor, is resistant to therapy and has a poor prognosis due to its universal recurrence rate. GBM cells interact with the non-cellular components in the tumor microenvironment (TME), facilitating their rapid growth, evolution, and invasion into the normal brain. Herein we discuss the complexity of the interactions between the cellular and non-cellular components of the TME and advances in the field as a whole. While the stroma of non-central nervous system (CNS) tissues is abundant in fibrillary collagens, laminins, and fibronectin, the normal brain extracellular matrix (ECM) predominantly includes proteoglycans, glycoproteins, and glycosaminoglycans, with fibrillary components typically found only in association with the vasculature. However, recent studies have found that in GBMs, the microenvironment evolves into a more complex array of components, with upregulated collagen gene expression and aligned fibrillary ECM networks. The interactions of glioma cells with the ECM and the degradation of matrix barriers are crucial for both single-cell and collective invasion into neighboring brain tissue. ECM-regulated mechanisms also contribute to immune exclusion, resulting in a major challenge to immunotherapy delivery and efficacy. Glioma cells chemically and physically control the function of their environment, co-opting complex signaling networks for their own benefit, resulting in radio- and chemo-resistance, tumor recurrence, and cancer progression. Targeting these interactions is an attractive strategy for overcoming therapy resistance, and we will discuss recent advances in preclinical studies, current clinical trials, and potential future clinical applications. In this review, we also provide a comprehensive discussion of the complexities of the interconnected cellular and non-cellular components of the microenvironmental landscape of brain tumors to guide the development of safe and effective therapeutic strategies against brain cancer.
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Affiliation(s)
- Syed M. Faisal
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrea Comba
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Maria L. Varela
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Anna E. Argento
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Emily Brumley
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Clifford Abel
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Maria G. Castro
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Pedro R. Lowenstein
- Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
- Dept. of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Pedro R. Lowenstein,
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12
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Sateesh J, Guha K, Dutta A, Sengupta P, Yalamanchili D, Donepudi NS, Surya Manoj M, Sohail SS. A comprehensive review on advancements in tissue engineering and microfluidics toward kidney-on-chip. BIOMICROFLUIDICS 2022; 16:041501. [PMID: 35992641 PMCID: PMC9385224 DOI: 10.1063/5.0087852] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/19/2022] [Indexed: 06/15/2023]
Abstract
This review provides a detailed literature survey on microfluidics and its road map toward kidney-on-chip technology. The whole review has been tailored with a clear description of crucial milestones in regenerative medicine, such as bioengineering, tissue engineering, microfluidics, microfluidic applications in biomedical engineering, capabilities of microfluidics in biomimetics, organ-on-chip, kidney-on-chip for disease modeling, drug toxicity, and implantable devices. This paper also presents future scope for research in the bio-microfluidics domain and biomimetics domain.
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Affiliation(s)
| | - Koushik Guha
- Department of Electronics and Communication Engineering, National MEMS Design Centre, National Institute of Technology Silchar, Assam 788010, India
| | - Arindam Dutta
- Urologist, RG Stone Urology and Laparoscopic Hospital, Kolkata, West Bengal, India
| | | | | | - Nanda Sai Donepudi
- Medical Interns, Government Siddhartha Medical College, Vijayawada, India
| | - M. Surya Manoj
- Department of Electronics and Communication Engineering, National MEMS Design Centre, National Institute of Technology Silchar, Assam 788010, India
| | - Sk. Shahrukh Sohail
- Department of Electronics and Communication Engineering, National MEMS Design Centre, National Institute of Technology Silchar, Assam 788010, India
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13
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Testa E, Palazzo C, Mastrantonio R, Viscomi MT. Dynamic Interactions between Tumor Cells and Brain Microvascular Endothelial Cells in Glioblastoma. Cancers (Basel) 2022; 14:3128. [PMID: 35804908 PMCID: PMC9265028 DOI: 10.3390/cancers14133128] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/17/2022] [Accepted: 06/22/2022] [Indexed: 02/01/2023] Open
Abstract
GBM is the most aggressive brain tumor among adults. It is characterized by extensive vascularization, and its further growth and recurrence depend on the formation of new blood vessels. In GBM, tumor angiogenesis is a multi-step process involving the proliferation, migration and differentiation of BMECs under the stimulation of specific signals derived from the cancer cells through a wide variety of communication routes. In this review, we discuss the dynamic interaction between BMECs and tumor cells by providing evidence of how tumor cells hijack the BMECs for the formation of new vessels. Tumor cell-BMECs interplay involves multiple routes of communication, including soluble factors, such as chemokines and cytokines, direct cell-cell contact and extracellular vesicles that participate in and fuel this cooperation. We also describe how this interaction is able to modify the BMECs structure, metabolism and physiology in a way that favors tumor growth and invasiveness. Finally, we briefly reviewed the recent advances and the potential future implications of some high-throughput 3D models to better understanding the complexity of BMECs-tumor cell interaction.
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Affiliation(s)
- Erika Testa
- Sezione di Istologia ed Embriologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Roma, Italy; (C.P.); (R.M.)
| | - Claudia Palazzo
- Sezione di Istologia ed Embriologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Roma, Italy; (C.P.); (R.M.)
| | - Roberta Mastrantonio
- Sezione di Istologia ed Embriologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Roma, Italy; (C.P.); (R.M.)
| | - Maria Teresa Viscomi
- Sezione di Istologia ed Embriologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Roma, Italy; (C.P.); (R.M.)
- IRCCS, Fondazione Policlinico Universitario “Agostino Gemelli”, L.go A. Gemelli 8, 00168 Roma, Italy
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14
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Phon BWS, Kamarudin MNA, Bhuvanendran S, Radhakrishnan AK. Transitioning pre-clinical glioblastoma models to clinical settings with biomarkers identified in 3D cell-based models: A systematic scoping review. Biomed Pharmacother 2022; 145:112396. [PMID: 34775238 DOI: 10.1016/j.biopha.2021.112396] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/25/2021] [Accepted: 11/02/2021] [Indexed: 11/02/2022] Open
Abstract
Glioblastoma (GBM) remains incurable despite the overwhelming discovery of 2-dimensional (2D) cell-based potential therapeutics since the majority of them have met unsatisfactory results in animal and clinical settings. Incremental empirical evidence has laid the widespread need of transitioning 2D to 3-dimensional (3D) cultures that better mimic GBM's complex and heterogenic nature to allow better translation of pre-clinical results. This systematic scoping review analyses the transcriptomic data involving 3D models of GBM against 2D models from 22 studies identified from four databases (PubMed, ScienceDirect, Medline, and Embase). From a total of 499 genes reported in these studies, 313 (63%) genes were upregulated across 3D models cultured using different scaffolds. Our analysis showed that 4 of the replicable upregulated genes are associated with GBM stemness, epithelial to mesenchymal transition (EMT), hypoxia, and migration-related genes regardless of the type of scaffolds, displaying close resemblances to primitive undifferentiated tumour phenotypes that are associated with decreased overall survival and increased hazard ratio in GBM patients. The upregulation of drug response and drug efflux genes (e.g. cytochrome P450s and ABC transporters) mirrors the GBM genetic landscape that contributes to in vivo and clinical treatment resistance. These upregulated genes displayed strong protein-protein interactions when analysed using an online bioinformatics software (STRING). These findings reinforce the need for widespread transition to 3D GBM models as a relatively inexpensive humanised pre-clinical tool with suitable genetic biomarkers to bridge clinical gaps in potential therapeutic evaluations.
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Affiliation(s)
- Brandon Wee Siang Phon
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia
| | - Muhamad N A Kamarudin
- Brain Research Institute Monash Sunway, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia.
| | - Saatheeyavaane Bhuvanendran
- Brain Research Institute Monash Sunway, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia
| | - Ammu K Radhakrishnan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia
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15
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Darrigues E, Zhao EH, De Loose A, Lee MP, Borrelli MJ, Eoff RL, Galileo DS, Penthala NR, Crooks PA, Rodriguez A. Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion. Int J Mol Sci 2021; 22:ijms221910720. [PMID: 34639060 PMCID: PMC8509225 DOI: 10.3390/ijms221910720] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/25/2021] [Accepted: 09/26/2021] [Indexed: 12/11/2022] Open
Abstract
Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.
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Affiliation(s)
- Emilie Darrigues
- Department of Neurosurgery, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.D.); (E.H.Z.); (A.D.L.); (M.P.L.)
| | - Edward H. Zhao
- Department of Neurosurgery, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.D.); (E.H.Z.); (A.D.L.); (M.P.L.)
| | - Annick De Loose
- Department of Neurosurgery, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.D.); (E.H.Z.); (A.D.L.); (M.P.L.)
| | - Madison P. Lee
- Department of Neurosurgery, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.D.); (E.H.Z.); (A.D.L.); (M.P.L.)
| | - Michael J. Borrelli
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Robert L. Eoff
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Deni S. Galileo
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA;
| | - Narsimha R. Penthala
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.R.P.); (P.A.C.)
| | - Peter A. Crooks
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.R.P.); (P.A.C.)
| | - Analiz Rodriguez
- Department of Neurosurgery, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.D.); (E.H.Z.); (A.D.L.); (M.P.L.)
- Correspondence:
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16
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Chen J, Lee H, Schmitt P, Choy CJ, Miller DM, Williams BJ, Bearer EL, Frieboes HB. Bioengineered Models to Study Microenvironmental Regulation of Glioblastoma Metabolism. J Neuropathol Exp Neurol 2021; 80:1012–1023. [PMID: 34524448 DOI: 10.1093/jnen/nlab092] [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: 11/12/2022] Open
Abstract
Despite extensive research and aggressive therapies, glioblastoma (GBM) remains a central nervous system malignancy with poor prognosis. The varied histopathology of GBM suggests a landscape of differing microenvironments and clonal expansions, which may influence metabolism, driving tumor progression. Indeed, GBM metabolic plasticity in response to differing nutrient supply within these microenvironments has emerged as a key driver of aggressiveness. Additionally, emergent biophysical and biochemical interactions in the tumor microenvironment (TME) are offering new perspectives on GBM metabolism. Perivascular and hypoxic niches exert crucial roles in tumor maintenance and progression, facilitating metabolic relationships between stromal and tumor cells. Alterations in extracellular matrix and its biophysical characteristics, such as rigidity and topography, regulate GBM metabolism through mechanotransductive mechanisms. This review highlights insights gained from deployment of bioengineering models, including engineered cell culture and mathematical models, to study the microenvironmental regulation of GBM metabolism. Bioengineered approaches building upon histopathology measurements may uncover potential therapeutic strategies that target both TME-dependent mechanotransductive and biomolecular drivers of metabolism to tackle this challenging disease. Longer term, a concerted effort integrating in vitro and in silico models predictive of patient therapy response may offer a powerful advance toward tailoring of treatment to patient-specific GBM characteristics.
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Affiliation(s)
- Joseph Chen
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
| | - Hyunchul Lee
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
| | - Philipp Schmitt
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
| | - Caleb J Choy
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
| | - Donald M Miller
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
| | - Brian J Williams
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
| | - Elaine L Bearer
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
| | - Hermann B Frieboes
- From the Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA (JC, CJC, HBF); Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA (JC, DMM, HBF); Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA (HL, BJW); Department of Medicine, University of Louisville, Louisville, Kentucky, USA (PS, DMM); Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA (DMM, BJW, HBF); Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA (HBF); Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA (ELB)
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17
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Dragoj M, Stojkovska J, Stanković T, Dinić J, Podolski-Renić A, Obradović B, Pešić M. Development and Validation of a Long-Term 3D Glioblastoma Cell Culture in Alginate Microfibers as a Novel Bio-Mimicking Model System for Preclinical Drug Testing. Brain Sci 2021; 11:brainsci11081025. [PMID: 34439644 PMCID: PMC8391761 DOI: 10.3390/brainsci11081025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/18/2022] Open
Abstract
Background: Various three-dimensional (3D) glioblastoma cell culture models have a limited duration of viability. Our aim was to develop a long-term 3D glioblastoma model, which is necessary for reliable drug response studies. Methods: Human U87 glioblastoma cells were cultured in alginate microfibers for 28 days. Cell growth, viability, morphology, and aggregation in 3D culture were monitored by fluorescent and confocal microscopy upon calcein-AM/propidium iodide (CAM/PI) staining every seven days. The glioblastoma 3D model was validated using temozolomide (TMZ) treatments 3 days in a row with a recovery period. Cell viability by MTT and resistance-related gene expression (MGMT and ABCB1) by qPCR were assessed after 28 days. The same TMZ treatment schedule was applied in 2D U87 cell culture for comparison purposes. Results: Within a long-term 3D model system in alginate fibers, U87 cells remained viable for up to 28 days. On day 7, cells formed visible aggregates oriented to the microfiber periphery. TMZ treatment reduced cell growth but increased drug resistance-related gene expression. The latter effect was more pronounced in 3D compared to 2D cell culture. Conclusion: Herein, we described a long-term glioblastoma 3D model system that could be particularly helpful for drug testing and treatment optimization.
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Affiliation(s)
- Miodrag Dragoj
- Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (M.D.); (T.S.); (J.D.); (A.P.-R.)
| | - Jasmina Stojkovska
- Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia; (J.S.); (B.O.)
- Innovation Center of the Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia
| | - Tijana Stanković
- Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (M.D.); (T.S.); (J.D.); (A.P.-R.)
| | - Jelena Dinić
- Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (M.D.); (T.S.); (J.D.); (A.P.-R.)
| | - Ana Podolski-Renić
- Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (M.D.); (T.S.); (J.D.); (A.P.-R.)
| | - Bojana Obradović
- Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia; (J.S.); (B.O.)
| | - Milica Pešić
- Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (M.D.); (T.S.); (J.D.); (A.P.-R.)
- Correspondence:
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The Role of Biomimetic Hypoxia on Cancer Cell Behaviour in 3D Models: A Systematic Review. Cancers (Basel) 2021; 13:cancers13061334. [PMID: 33809554 PMCID: PMC7999912 DOI: 10.3390/cancers13061334] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 03/13/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Cancer remains one of the leading causes of death worldwide. The advancements in 3D tumour models provide in vitro test-beds to study cancer growth, metastasis and response to therapy. We conducted this systematic review on existing experimental studies in order to identify and summarize key biomimetic tumour microenvironmental features which affect aspects of cancer biology. The review noted the significance of in vitro hypoxia and 3D tumour models on epithelial to mesenchymal transition, drug resistance, invasion and migration of cancer cells. We highlight the importance of various experimental parameters used in these studies and their subsequent effects on cancer cell behaviour. Abstract The development of biomimetic, human tissue models is recognized as being an important step for transitioning in vitro research findings to the native in vivo response. Oftentimes, 2D models lack the necessary complexity to truly recapitulate cellular responses. The introduction of physiological features into 3D models informs us of how each component feature alters specific cellular response. We conducted a systematic review of research papers where the focus was the introduction of key biomimetic features into in vitro models of cancer, including 3D culture and hypoxia. We analysed outcomes from these and compiled our findings into distinct groupings to ascertain which biomimetic parameters correlated with specific responses. We found a number of biomimetic features which primed cancer cells to respond in a manner which matched in vivo response.
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Baruffaldi D, Palmara G, Pirri C, Frascella F. 3D Cell Culture: Recent Development in Materials with Tunable Stiffness. ACS APPLIED BIO MATERIALS 2021; 4:2233-2250. [PMID: 35014348 DOI: 10.1021/acsabm.0c01472] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
It is widely accepted that three-dimensional cell culture systems simulate physiological conditions better than traditional 2D systems. Although extracellular matrix components strongly modulate cell behavior, several studies underlined the importance of mechanosensing in the control of different cell functions such as growth, proliferation, differentiation, and migration. Human tissues are characterized by different degrees of stiffness, and various pathologies (e.g., tumor or fibrosis) cause changes in the mechanical properties through the alteration of the extracellular matrix structure. Additionally, these modifications have an impact on disease progression and on therapy response. Hence, the development of platforms whose stiffness could be modulated may improve our knowledge of cell behavior under different mechanical stress stimuli. In this review, we have analyzed the mechanical diversity of healthy and diseased tissues, and we have summarized recently developed materials with a wide range of stiffness.
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Affiliation(s)
- Désirée Baruffaldi
- Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy.,PolitoBIOMed Lab, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy
| | - Gianluca Palmara
- Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy.,PolitoBIOMed Lab, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy
| | - Candido Pirri
- Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy.,PolitoBIOMed Lab, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy.,Center for Sustainable Futures@Polito, Istituto Italiano di Tecnologia, Via Livorno 60, Turin 10144, Italy
| | - Francesca Frascella
- Dipartimento di Scienza Applicata e Tecnologia, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy.,PolitoBIOMed Lab, Politecnico di Torino, C.so Duca degli Abruzzi 24, Turin 10129, Italy
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20
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Stanković T, Ranđelović T, Dragoj M, Stojković Burić S, Fernández L, Ochoa I, Pérez-García VM, Pešić M. In vitro biomimetic models for glioblastoma-a promising tool for drug response studies. Drug Resist Updat 2021; 55:100753. [PMID: 33667959 DOI: 10.1016/j.drup.2021.100753] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023]
Abstract
The poor response of glioblastoma to current treatment protocols is a consequence of its intrinsic drug resistance. Resistance to chemotherapy is primarily associated with considerable cellular heterogeneity, and plasticity of glioblastoma cells, alterations in gene expression, presence of specific tumor microenvironment conditions and blood-brain barrier. In an attempt to successfully overcome chemoresistance and better understand the biological behavior of glioblastoma, numerous tri-dimensional (3D) biomimetic models were developed in the past decade. These novel advanced models are able to better recapitulate the spatial organization of glioblastoma in a real time, therefore providing more realistic and reliable evidence to the response of glioblastoma to therapy. Moreover, these models enable the fine-tuning of different tumor microenvironment conditions and facilitate studies on the effects of the tumor microenvironment on glioblastoma chemoresistance. This review outlines current knowledge on the essence of glioblastoma chemoresistance and describes the progress achieved by 3D biomimetic models. Moreover, comprehensive literature assessment regarding the influence of 3D culturing and microenvironment mimicking on glioblastoma gene expression and biological behavior is also provided. The contribution of the blood-brain barrier as well as the blood-tumor barrier to glioblastoma chemoresistance is also reviewed from the perspective of 3D biomimetic models. Finally, the role of mathematical models in predicting 3D glioblastoma behavior and drug response is elaborated. In the future, technological innovations along with mathematical simulations should create reliable 3D biomimetic systems for glioblastoma research that should facilitate the identification and possibly application in preclinical drug testing and precision medicine.
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Affiliation(s)
- Tijana Stanković
- Department of Neurobiology, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060, Belgrade, Serbia
| | - Teodora Ranđelović
- Tissue Microenvironment Lab (TME), Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Aragon 50018, Spain; Institute for Health Research Aragon (IIS Aragón), Instituto de Salud Carlos III, Zaragoza, Spain
| | - Miodrag Dragoj
- Department of Neurobiology, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060, Belgrade, Serbia
| | - Sonja Stojković Burić
- Department of Neurobiology, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060, Belgrade, Serbia
| | - Luis Fernández
- Tissue Microenvironment Lab (TME), Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Aragon 50018, Spain; Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Aragon 50018, Spain; Institute for Health Research Aragon (IIS Aragón), Instituto de Salud Carlos III, Zaragoza, Spain
| | - Ignacio Ochoa
- Tissue Microenvironment Lab (TME), Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Aragon 50018, Spain; Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Aragon 50018, Spain; Institute for Health Research Aragon (IIS Aragón), Instituto de Salud Carlos III, Zaragoza, Spain
| | - Victor M Pérez-García
- Departamento de Matemáticas, E.T.S.I. Industriales and Instituto de Matemática Aplicada a la Ciencia y la Ingeniería (IMACI), Universidad de Castilla-La Mancha, Ciudad Real, 13071, Spain
| | - Milica Pešić
- Department of Neurobiology, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060, Belgrade, Serbia.
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21
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Guyon J, Chapouly C, Andrique L, Bikfalvi A, Daubon T. The Normal and Brain Tumor Vasculature: Morphological and Functional Characteristics and Therapeutic Targeting. Front Physiol 2021; 12:622615. [PMID: 33746770 PMCID: PMC7973205 DOI: 10.3389/fphys.2021.622615] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/25/2021] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma is among the most common tumor of the central nervous system in adults. Overall survival has not significantly improved over the last decade, even with optimizing standard therapeutic care including extent of resection and radio- and chemotherapy. In this article, we review features of the brain vasculature found in healthy cerebral tissue and in glioblastoma. Brain vessels are of various sizes and composed of several vascular cell types. Non-vascular cells such as astrocytes or microglia also interact with the vasculature and play important roles. We also discuss in vitro engineered artificial blood vessels which may represent useful models for better understanding the tumor-vessel interaction. Finally, we summarize results from clinical trials with anti-angiogenic therapy alone or in combination, and discuss the value of these approaches for targeting glioblastoma.
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Affiliation(s)
- Joris Guyon
- INSERM, LAMC, U1029, University Bordeaux, Pessac, France
| | - Candice Chapouly
- INSERM, Biology of Cardiovascular Diseases, U1034, University Bordeaux, Pessac, France
| | - Laetitia Andrique
- INSERM, LAMC, U1029, University Bordeaux, Pessac, France.,VoxCell 3D Plateform, UMS TBMcore 3427, Bordeaux, France
| | | | - Thomas Daubon
- University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France
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22
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Soubéran A, Tchoghandjian A. Practical Review on Preclinical Human 3D Glioblastoma Models: Advances and Challenges for Clinical Translation. Cancers (Basel) 2020; 12:cancers12092347. [PMID: 32825103 PMCID: PMC7563542 DOI: 10.3390/cancers12092347] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/07/2020] [Accepted: 08/13/2020] [Indexed: 02/06/2023] Open
Abstract
Fifteen years after the establishment of the Stupp protocol as the standard of care to treat glioblastomas, no major clinical advances have been achieved and increasing patient’s overall survival remains a challenge. Nevertheless, crucial molecular and cellular findings revealed the intra-tumoral and inter-tumoral complexities of these incurable brain tumors, and the essential role played by cells of the microenvironment in the lack of treatment efficacy. Taking this knowledge into account, fulfilling gaps between preclinical models and clinical samples is necessary to improve the successful rate of clinical trials. Since the beginning of the characterization of brain tumors initiated by Bailey and Cushing in the 1920s, several glioblastoma models have been developed and improved. In this review, we focused on the most widely used 3D human glioblastoma models, including spheroids, tumorospheres, organotypic slices, explants, tumoroids and glioblastoma-derived from cerebral organoids. We discuss their history, development and especially their usefulness.
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23
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Distinct differences in hypoxic responses between human oral mucosa and skin fibroblasts in a 3D collagen matrix. In Vitro Cell Dev Biol Anim 2020; 56:452-479. [PMID: 32588253 DOI: 10.1007/s11626-020-00458-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 04/16/2020] [Indexed: 02/03/2023]
Abstract
The differences between oral mucosa and skin wound healing involving hypoxic responses of fibroblasts are poorly elucidated. In this study, we aimed to study the different hypoxic responses between oral and skin fibroblasts embedded in a three-dimensional (3D) collagen matrix to address the early stage of wound healing. Primary oral mucosa fibroblasts (OMFs) obtained from the retromolar area and skin fibroblasts (SFs) obtained from the abdomen were cultured in the 3D 'floating model' under either 21%, 5% or 1% O2 for 2 days. Cell viability under hypoxia was higher in the OMFs than in the SFs. Collagen gel contraction was suppressed under hypoxic conditions in both fibroblasts, consistent with the reduction of alpha smooth muscle actin expression, except for SFs under 1% O2. Subsequently, their gene expression profiles between 21 and 1% O2 concentrations were compared via microarray technology, and the expression profiles of the extracellular matrix (ECM)-associated proteins, including matrix metalloproteinases and collagens, were evaluated. The OMFs were more susceptible to 1% O2, and more of their genes were downregulated than the SFs'. Although the production and expression levels of ECM-associated proteins in both fibroblasts diminished under hypoxia, those levels in OMFs were significantly higher than those in SFs. In the case of single origin OMFs and SFs, our findings suggest that OMFs possess a higher baseline production capacity of several ECM-associated proteins than SFs, except type III collagen. The intrinsic hypoxic responses of OMFs may be attributed to a more favourable wound healing in oral mucosa.
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24
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Chaicharoenaudomrung N, Kunhorm P, Promjantuek W, Rujanapun N, Heebkaew N, Soraksa N, Noisa P. Transcriptomic Profiling of 3D Glioblastoma Tumoroids for the Identification of Mechanisms Involved in Anticancer Drug Resistance. In Vivo 2020; 34:199-211. [PMID: 31882480 DOI: 10.21873/invivo.11762] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/07/2019] [Accepted: 10/11/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIM Among various types of brain tumors, glioblastoma is the most malignant and highly aggressive brain tumor that possesses a high resistance against anticancer drugs. To understand the underlined mechanisms of tumor drug resistance, a new and more effective research approach is required. The three dimensional (3D) in vitro cell culture models could be a potential approach to study cancer features and biology, as well as screen for anti-cancer agents due to the close mimicry of the 3D tumor microenvironments. MATERIALS AND METHODS With our developed 3D alginate scaffolds, Ilumina RNA-sequencing was used to transcriptomically analyze and compare the gene expression profiles between glioblastoma cells in traditional 2-dimensional (2D) monolayer and in 3D Ca-alginate scaffolds at day 14. To verify the reliability and accuracy of Illumina RNA-Sequencing data, ATP-binding cassette transporter genes were chosen for quantitative real-time polymerase chain reaction) verification. RESULTS The results showed that 7,411 and 3,915 genes of the 3D glioblastoma were up-regulated and down-regulated, respectively, compared with the 2D-cultured glioblastoma. Furthermore, the Kyoto Encyclopaedia of Genes and Genomes pathway analysis revealed that genes related to the cell cycle and DNA replication were enriched in the group of down-regulated gene. On the other hand, the genes involved in mitogen-activated protein kinase signaling, autophagy, drug metabolism through cytochrome P450, and ATP-binding cassette transporter were found in the up-regulated gene collection. CONCLUSION 3D glioblastoma tumoroids might potentially serve as a powerful platform for exploring glioblastoma biology. They can also be valuable in anti-glioblastoma drug screening, as well as the identification of novel molecular targets in clinical treatment of human glioblastoma.
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Affiliation(s)
- Nipha Chaicharoenaudomrung
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Phongsakorn Kunhorm
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Wilasinee Promjantuek
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Narawadee Rujanapun
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Nudjanad Heebkaew
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Natchadaporn Soraksa
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Parinya Noisa
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima, Thailand
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25
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3D bioprinted hyaluronic acid-based cell-laden scaffold for brain microenvironment simulation. Biodes Manuf 2020. [DOI: 10.1007/s42242-020-00076-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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27
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Chaicharoenaudomrung N, Kunhorm P, Noisa P. Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling. World J Stem Cells 2019; 11:1065-1083. [PMID: 31875869 PMCID: PMC6904866 DOI: 10.4252/wjsc.v11.i12.1065] [Citation(s) in RCA: 250] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 10/09/2019] [Accepted: 11/05/2019] [Indexed: 02/06/2023] Open
Abstract
Three-dimensional (3D) culture systems are becoming increasingly popular due to their ability to mimic tissue-like structures more effectively than the monolayer cultures. In cancer and stem cell research, the natural cell characteristics and architectures are closely mimicked by the 3D cell models. Thus, the 3D cell cultures are promising and suitable systems for various proposes, ranging from disease modeling to drug target identification as well as potential therapeutic substances that may transform our lives. This review provides a comprehensive compendium of recent advancements in culturing cells, in particular cancer and stem cells, using 3D culture techniques. The major approaches highlighted here include cell spheroids, hydrogel embedding, bioreactors, scaffolds, and bioprinting. In addition, the progress of employing 3D cell culture systems as a platform for cancer and stem cell research was addressed, and the prominent studies of 3D cell culture systems were discussed.
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Affiliation(s)
- Nipha Chaicharoenaudomrung
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
| | - Phongsakorn Kunhorm
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
| | - Parinya Noisa
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
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Cellular Spheroids of Mesenchymal Stem Cells and Their Perspectives in Future Healthcare. APPLIED SCIENCES-BASEL 2019. [DOI: 10.3390/app9040627] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Intrinsic cellular properties of several types of cells are dramatically altered as the culture condition shifts from two-dimensional (2D) to three-dimensional (3D) environment. Currently, several lines of evidence have demonstrated the therapeutic potential of mesenchymal stem cells (MSCs) in regenerative medicine. MSCs not only replenish the lost cells, they also promote the regeneration of impaired tissues by modulating the immune responses. Following the development of 3D cell culture, the enhanced therapeutic efficacy of spheroid-forming MSCs have been identified in several animal disease models by promoting differentiation or trophic factor secretion, as compared to planar-cultured MSCs. Due to the complicated and multifunctional applications in the medical field, MSCs are recently named as medicinal signaling cells. In this review, we summarize the predominant differences of cell–environment interactions for the MSC spheroids formed by chitosan-based substrates and other scaffold-free approaches. Furthermore, several important physical and chemical factors affecting cell behaviors in the cell spheroids are discussed. Currently, the understanding of MSCs spheroid interactions is continuously expanding. Overall, this article aims to review the broad advantages and perspectives of MSC spheroids in regenerative medicine and in future healthcare.
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