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1
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Barrios-Esteban S, Reimóndez-Troitiño S, Cabezas-Sainz P, de la Fuente M, Sánchez L, Rahman R, Alexander C, Garcia-Fuentes M, Csaba NS. Protamine-Based Nanotherapeutics for Gene Delivery to Glioblastoma Cells. Mol Pharm 2025. [PMID: 40173305 DOI: 10.1021/acs.molpharmaceut.4c01269] [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: 04/04/2025]
Abstract
Isocitrate dehydrogenase wild-type glioblastoma is the most aggressive primary brain tumor classified as grade 4 of malignancy. Standard treatment, combining surgical resection, radiotherapy, and chemotherapy, often leads to severe side effects, with the emergence of tumor recurrence in all cases. Nucleic acid-based therapy has emerged as a promising strategy for cancer treatment. Non-viral nanosystems have become the vehicles of choice for gene delivery, due to their efficient nucleic acid encapsulation, protection, and intracellular transport. This work explores the potential of a formulation of low molecular weight protamine (LMWP) and dextran sulfate for gene delivery. The nanoparticles (NPs) were evaluated in terms of particle size, surface charge, morphology, and capacity to condense different nucleic acids. NPs formed by ionic complexation resulted in a homogeneous population of spherical particles with a low polydispersity index (PDI), small size, and positive surface charge. Competitive displacement assay demonstrated that the NPs could condense nucleic acids without alterations in their morphology and physicochemical characteristics, even after long-term storage. The efficacy of this formulation as a gene delivery system was evaluated in vitro in different glioblastoma cell lines and three-dimensional (3D) spheroids and in vivo using zebrafish models, showing negligible toxicity, efficient internalization, and consistent expression of fluorescent/luminescent proteins. Overall, these cationic polymeric NPs show promising features for their use as non-viral gene delivery vehicles for glioblastoma treatments.
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Affiliation(s)
- Sheila Barrios-Esteban
- Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Campus Vida, 15706 Santiago de Compostela, Spain
| | - Sonia Reimóndez-Troitiño
- Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Campus Vida, 15706 Santiago de Compostela, Spain
| | - Pablo Cabezas-Sainz
- School of Veterinary, University of Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain
| | - María de la Fuente
- Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Laura Sánchez
- School of Veterinary, University of Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain
| | - Ruman Rahman
- Children's Brain Tumor Research Centre (CBTR) and Biodiscovery Institute (BDI), University of Nottingham, University Park, NG7 2RD Nottingham, U.K
| | - Cameron Alexander
- School of Pharmacy, bBoots Science Building (BSB), University of Nottingham, East Dr, NG7 2TQ Nottingham, U.K
| | - Marcos Garcia-Fuentes
- Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Campus Vida, 15706 Santiago de Compostela, Spain
- Department Pharmacology, Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, Campus Vida, 15706 Santiago de Compostela, Spain
| | - Noemi S Csaba
- Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Campus Vida, 15706 Santiago de Compostela, Spain
- Department Pharmacology, Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, Campus Vida, 15706 Santiago de Compostela, Spain
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2
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Jo H, Lee S, Kim MH, Park S, Lee SY. Recapitulating Glioma Stem Cell Niches Using 3D Spheroid Models for Glioblastoma Research. BIOSENSORS 2024; 14:539. [PMID: 39589998 PMCID: PMC11592235 DOI: 10.3390/bios14110539] [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: 09/30/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024]
Abstract
Glioblastoma multiforme (GBM) is among the most aggressive brain cancers, and it contains glioma stem cells (GSCs) that drive tumor initiation, progression, and recurrence. These cells resist conventional therapies, contributing to high recurrence rates in GBM patients. Developing in vitro models that mimic the tumor microenvironment (TME), particularly the GSC niche, is crucial for understanding GBM growth and therapeutic resistance. Three-dimensional (3D) spheroid models provide a more physiologically relevant approach than traditional two-dimensional (2D) cultures, recapitulating key tumor features like hypoxia, cell heterogeneity, and drug resistance. This review examines scaffold-free and scaffold-based methods for generating 3D GBM spheroids, focusing on their applications in studying the cancer stem cell niche. The discussion encompasses methods such as the hanging drop, low-adhesion plates, and magnetic levitation, alongside advancements in embedding spheroids within extracellular matrix-based hydrogels and employing 3D bioprinting to fabricate more intricate tumor models. These 3D culture systems offer substantial potential for enhancing our understanding of GBM biology and devising more effective targeted therapies.
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Affiliation(s)
- Hyunji Jo
- Department of Metabiohealth, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea; (H.J.); (S.L.)
| | - Seulgi Lee
- Department of Metabiohealth, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea; (H.J.); (S.L.)
| | - Min-Hyeok Kim
- School of Mechanical Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea;
| | - Sungsu Park
- Department of Metabiohealth, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea; (H.J.); (S.L.)
- School of Mechanical Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea;
- Department of Quantum Biophysics, Institute of Quantum Biophysics (IQB), Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
| | - Seo-Yeon Lee
- Department of Pharmacology, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea
- Department of Biomedical Science, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea
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3
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Agosti E, Antonietti S, Ius T, Fontanella MM, Zeppieri M, Panciani PP. Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies. Int J Mol Sci 2024; 25:7979. [PMID: 39063221 PMCID: PMC11276876 DOI: 10.3390/ijms25147979] [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: 05/30/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Gliomas' aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells' distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/β-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/β-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes.
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Affiliation(s)
- Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
| | - Sara Antonietti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
| | - Tamara Ius
- Neurosurgery Unit, Head-Neck and NeuroScience Department, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Marco Maria Fontanella
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Pier Paolo Panciani
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy; (E.A.); (P.P.P.)
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4
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Dixon S, O'connor AT, Brooks-Noreiga C, Clark MA, Levy A, Castejon AM. Role of renin angiotensin system inhibitors and metformin in Glioblastoma Therapy: a review. Cancer Chemother Pharmacol 2024; 94:1-23. [PMID: 38914751 DOI: 10.1007/s00280-024-04686-0] [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: 01/30/2024] [Accepted: 06/13/2024] [Indexed: 06/26/2024]
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome.
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Affiliation(s)
- Sashana Dixon
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA.
| | - Ann Tenneil O'connor
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Chloe Brooks-Noreiga
- Halmos College of Arts and Sciences, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Michelle A Clark
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Arkene Levy
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Ana M Castejon
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA
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5
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Aye KTN, Ferreira JN, Chaweewannakorn C, Souza GR. Advances in the application of iron oxide nanoparticles (IONs and SPIONs) in three-dimensional cell culture systems. SLAS Technol 2024; 29:100132. [PMID: 38582355 DOI: 10.1016/j.slast.2024.100132] [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: 10/08/2023] [Revised: 03/22/2024] [Accepted: 04/04/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND The field of tissue engineering has remarkably progressed through the integration of nanotechnology and the widespread use of magnetic nanoparticles. These nanoparticles have resulted in innovative methods for three-dimensional (3D) cell culture platforms, including the generation of spheroids, organoids, and tissue-mimetic cultures, where they play a pivotal role. Notably, iron oxide nanoparticles and superparamagnetic iron oxide nanoparticles have emerged as indispensable tools for non-contact manipulation of cells within these 3D environments. The variety and modification of the physical and chemical properties of magnetic nanoparticles have profound impacts on cellular mechanisms, metabolic processes, and overall biological function. This review article focuses on the applications of magnetic nanoparticles, elucidating their advantages and potential pitfalls when integrated into 3D cell culture systems. This review aims to shed light on the transformative potential of magnetic nanoparticles in terms of tissue engineering and their capacity to improve the cultivation and manipulation of cells in 3D environments.
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Affiliation(s)
- Khin The Nu Aye
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Joao N Ferreira
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Chayanit Chaweewannakorn
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Occlusion, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
| | - Glauco R Souza
- Greiner Bio-One North America, Inc., 4238 Capital Drive, Monroe, NC 28110, USA
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6
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de Araújo TBS, Nogueira RLR, Siquara da Rocha LDO, Bastos IN, Dias RB, Souza BSDF, Lambert DW, Coletta RD, Silva VAO, Gurgel Rocha CA. Enhancing scaffold-free spheroid models: 3D cell bioprinting method for metastatic HSC3-Oral squamous carcinoma cell line. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2024; 29:100158. [PMID: 38852983 DOI: 10.1016/j.slasd.2024.100158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 04/22/2024] [Accepted: 04/29/2024] [Indexed: 06/11/2024]
Abstract
3D in vitro systems offer advantages over the shortcomings of two-dimensional models by simulating the morphological and functional features of in vivo-like environments, such as cell-cell and cell-extracellular matrix interactions, as well as the co-culture of different cell types. Nevertheless, these systems present technical challenges that limit their potential in cancer research requiring cell line- and culture-dependent standardization. This protocol details the use of a magnetic 3D bioprinting method and other associated techniques (cytotoxicity assay and histological analysis) using oral squamous cell carcinoma cell line, HSC3, which offer advantages compared to existing widely used approaches. This protocol is particularly timely, as it validates magnetic bioprinting as a method for the rapid deployment of 3D cultures as a tool for compound screening and development of heterotypic cultures such as co-culture of oral squamous cell carcinoma cells with cancer-associated fibroblasts (HSC3/CAFs).
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Affiliation(s)
- Taís Bacelar Sacramento de Araújo
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Propaedeutics, School of Dentistry of the Federal University of Bahia, Salvador 40110-150, Bahia, Brazil
| | - Raphael Luís Rocha Nogueira
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Pathology, School of Medicine of the Federal University of Bahia, Salvador 40110-909, Bahia, Brazil
| | - Leonardo de Oliveira Siquara da Rocha
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Pathology, School of Medicine of the Federal University of Bahia, Salvador 40110-909, Bahia, Brazil
| | - Iasmin Nogueira Bastos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Propaedeutics, School of Dentistry of the Federal University of Bahia, Salvador 40110-150, Bahia, Brazil
| | - Rosane Borges Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Propaedeutics, School of Dentistry of the Federal University of Bahia, Salvador 40110-150, Bahia, Brazil
| | - Bruno Solano De Freitas Souza
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Pathology, School of Medicine of the Federal University of Bahia, Salvador 40110-909, Bahia, Brazil; Center for Biotechnology and Cell Therapy, D'Or Institute for Research and Education (IDOR), São Rafael Hospital, Salvador 41253-190, Brazil
| | | | - Ricardo D Coletta
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba 13414-903, São Paulo, Brazil; Graduate Program in Oral Biology, School of Dentistry University of Campinas, Piracicaba 13414-903, São Paulo, Brazil
| | - Viviane Aline Oliveira Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Pathology, School of Medicine of the Federal University of Bahia, Salvador 40110-909, Bahia, Brazil; Center for Biotechnology and Cell Therapy, D'Or Institute for Research and Education (IDOR), São Rafael Hospital, Salvador 41253-190, Brazil; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, São Paulo, Brazil.
| | - Clarissa A Gurgel Rocha
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Bahia, Brazil; Department of Propaedeutics, School of Dentistry of the Federal University of Bahia, Salvador 40110-150, Bahia, Brazil; Department of Pathology, School of Medicine of the Federal University of Bahia, Salvador 40110-909, Bahia, Brazil; Center for Biotechnology and Cell Therapy, D'Or Institute for Research and Education (IDOR), São Rafael Hospital, Salvador 41253-190, Brazil.
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7
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Ren X, Deng D, Xiang S, Feng J. Promoter hypomethylated PDZK1 acts as a tumorigenic gene in glioma by interacting with AKT1. Aging (Albany NY) 2024; 16:7174-7187. [PMID: 38669103 PMCID: PMC11087087 DOI: 10.18632/aging.205750] [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: 11/15/2023] [Accepted: 03/25/2024] [Indexed: 04/28/2024]
Abstract
Glioma is the most frequently diagnosed primary brain tumor and typically has a poor prognosis because of malignant proliferation and invasion. It is urgent to elucidate the mechanisms driving glioma tumorigenesis and develop novel treatments to address this deadly disease. Here, we first revealed that PDZK1 is expressed at high levels in gliomas. Promoter hypomethylation may cause high expression of PDZK1 in glioma. Knockdown of PDZK1 inhibits glioma cell proliferation and invasion in vitro. Mechanistically, further investigations revealed that the loss of PDZK1 expression by siRNA inhibited the activation of the AKT/mTOR signaling pathway, leading to cell cycle arrest and apoptosis. Clinically, high expression of PDZK1 predicts a poorer prognosis for glioma patients than low expression of PDZK1. Overall, our study revealed that PDZK1 acts as a novel oncogene in glioma by binding to AKT1 and maintaining the activation of the AKT/mTOR signaling pathway. Thus, PDZK1 may be a potential therapeutic target for glioma.
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Affiliation(s)
- Xing Ren
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Dan Deng
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Shasha Xiang
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Jianbo Feng
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
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8
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Ballestín A, Armocida D, Ribecco V, Seano G. Peritumoral brain zone in glioblastoma: biological, clinical and mechanical features. Front Immunol 2024; 15:1347877. [PMID: 38487525 PMCID: PMC10937439 DOI: 10.3389/fimmu.2024.1347877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024] Open
Abstract
Glioblastoma is a highly aggressive and invasive tumor that affects the central nervous system (CNS). With a five-year survival rate of only 6.9% and a median survival time of eight months, it has the lowest survival rate among CNS tumors. Its treatment consists of surgical resection, subsequent fractionated radiotherapy and concomitant and adjuvant chemotherapy with temozolomide. Despite the implementation of clinical interventions, recurrence is a common occurrence, with over 80% of cases arising at the edge of the resection cavity a few months after treatment. The high recurrence rate and location of glioblastoma indicate the need for a better understanding of the peritumor brain zone (PBZ). In this review, we first describe the main radiological, cellular, molecular and biomechanical tissue features of PBZ; and subsequently, we discuss its current clinical management, potential local therapeutic approaches and future prospects.
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Affiliation(s)
- Alberto Ballestín
- Tumor Microenvironment Laboratory, UMR3347 CNRS/U1021 INSERM, Institut Curie, Orsay, France
| | - Daniele Armocida
- Human Neurosciences Department, Neurosurgery Division, Sapienza University, Rome, Italy
| | - Valentino Ribecco
- Tumor Microenvironment Laboratory, UMR3347 CNRS/U1021 INSERM, Institut Curie, Orsay, France
| | - Giorgio Seano
- Tumor Microenvironment Laboratory, UMR3347 CNRS/U1021 INSERM, Institut Curie, Orsay, France
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9
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Obrador E, Moreno-Murciano P, Oriol-Caballo M, López-Blanch R, Pineda B, Gutiérrez-Arroyo JL, Loras A, Gonzalez-Bonet LG, Martinez-Cadenas C, Estrela JM, Marqués-Torrejón MÁ. Glioblastoma Therapy: Past, Present and Future. Int J Mol Sci 2024; 25:2529. [PMID: 38473776 PMCID: PMC10931797 DOI: 10.3390/ijms25052529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.
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Affiliation(s)
- Elena Obrador
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Paz Moreno-Murciano
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
| | - María Oriol-Caballo
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Rafael López-Blanch
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Begoña Pineda
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Julia Lara Gutiérrez-Arroyo
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Alba Loras
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Luis G. Gonzalez-Bonet
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon, Spain;
| | - Conrado Martinez-Cadenas
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - José M. Estrela
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain
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10
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Georgescu MM. Translation into Clinical Practice of the G1-G7 Molecular Subgroup Classification of Glioblastoma: Comprehensive Demographic and Molecular Pathway Profiling. Cancers (Basel) 2024; 16:361. [PMID: 38254850 PMCID: PMC10814912 DOI: 10.3390/cancers16020361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/01/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Glioblastoma is the most frequent and malignant primary neoplasm of the central nervous system. In a recent breakthrough study on a prospective Discovery cohort, I proposed the first all-inclusive molecular classification of glioblastoma into seven subgroups, G1-G7, based on MAPK pathway activation. New data from a WHO-grade-4 diffuse glioma prospective Validation cohort offers, in this study, an integrated demographic-molecular analysis of a 213-patient Combined cohort. Despite cohort differences in the median age and molecular subgroup distribution, all the prospectively-acquired cases from the Validation cohort mapped into one of the G1-G7 subgroups defined in the Discovery cohort. A younger age of onset, higher tumor mutation burden and expanded G1/EGFR-mutant and G3/NF1 glioblastoma subgroups characterized the glioblastomas from African American/Black relative to Caucasian/White patients. The three largest molecular subgroups were G1/EGFR, G3/NF1 and G7/Other. The fourth largest subgroup, G6/Multi-RTK, was detailed by describing a novel gene fusion ST7-MET, rare PTPRZ1-MET, LMNA-NTRK1 and GOPC-ROS1 fusions and their overexpression mechanisms in glioblastoma. The correlations between the MAPK pathway G1-G7 subgroups and the PI3-kinase/PTEN, TERT, cell cycle G1 phase and p53 pathways defined characteristic subgroup pathway profiles amenable to personalized targeted therapy. This analysis validated the first all-inclusive molecular classification of glioblastoma, showed significant demographic and molecular differences between subgroups, and provided the first ethnic molecular comparison of glioblastoma.
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11
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Xu D, Li P, Zhang C, Shen Y, Cai J, Wei Q, Cao M, Xu Z, Wu D, Wang H, Bi X, Wang B, Li K. Development of an m6A-Related lncRNAs Signature Predicts Tumor Stemness and Prognosis for Low-Grade Glioma Patients. Stem Cells Int 2024; 2024:2062283. [PMID: 38229597 PMCID: PMC10791469 DOI: 10.1155/2024/2062283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 10/25/2023] [Accepted: 11/22/2023] [Indexed: 01/18/2024] Open
Abstract
Background Growing evidence has revealed that m6A modification of long noncoding RNAs (lncRNAs) dynamically controls tumor stemness and tumorigenesis-related processes. However, the prognostic significance of m6A-related lncRNAs and their associations with stemness in low-grade glioma (LGG) remain to be clarified. Methods A multicenter transcriptome analysis of lncRNA expression in 1,247 LGG samples was performed in this study. The stemness landscape of LGG tumors was presented and associations with clinical features were revealed. The m6A-related lncRNAs were identified between stemness groups and were further prioritized via least absolute shrinkage and selection operator Cox regression analysis. A risk score model based on m6A-related lncRNAs was constructed and validated in external LGG datasets. Results Based on the expression of LINC02984, PFKP-DT, and CRNDE, a risk model and nomogram were constructed; they successfully predicted the survival of patients and were extended to external datasets. Significant correlations were observed between the risk score and tumor stemness. Moreover, patients in different risk groups exhibited distinct tumor immune microenvironments and immune signatures. We finally provided several potential compounds suitable for specific risk groups, which may aid in LGG treatment. Conclusions This novel signature presents noteworthy value in the prediction of prognosis and stemness status for LGG patients and will foster future research on the development of clinical regimens.
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Affiliation(s)
- Dahua Xu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Peihu Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Chunrui Zhang
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100020, China
| | - Yutong Shen
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Jiale Cai
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Qingchen Wei
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Meng Cao
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Zhizhou Xu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Deng Wu
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Hong Wang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Xiaoman Bi
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Bo Wang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
| | - Kongning Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 571199, China
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12
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Kwon H, Yun M, Kwon TH, Bang M, Lee J, Lee YS, Ko HY, Chong K. Fibronectin Type III Domain Containing 3B as a Potential Prognostic and Therapeutic Biomarker for Glioblastoma. Biomedicines 2023; 11:3168. [PMID: 38137388 PMCID: PMC10741045 DOI: 10.3390/biomedicines11123168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/10/2023] [Accepted: 11/13/2023] [Indexed: 12/24/2023] Open
Abstract
Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM.
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Affiliation(s)
- Hyukjun Kwon
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea;
| | - Minji Yun
- Photo-Theranosis and Bioinformatics for Tumor Laboratory, Research Institute for Future Medicine, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea; (M.Y.); (M.B.)
| | - Taek-Hyun Kwon
- Department of Neurosurgery, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea; (T.-H.K.); (Y.S.L.)
| | - Minji Bang
- Photo-Theranosis and Bioinformatics for Tumor Laboratory, Research Institute for Future Medicine, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea; (M.Y.); (M.B.)
| | - Jungsul Lee
- 3billion Inc., 416, Teheran-ro, Gangnam-gu, Seoul 06193, Republic of Korea;
| | - Yeo Song Lee
- Department of Neurosurgery, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea; (T.-H.K.); (Y.S.L.)
| | - Hae Young Ko
- Photo-Theranosis and Bioinformatics for Tumor Laboratory, Research Institute for Future Medicine, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea; (M.Y.); (M.B.)
| | - Kyuha Chong
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea;
- Photo-Theranosis and Bioinformatics for Tumor Laboratory, Research Institute for Future Medicine, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea; (M.Y.); (M.B.)
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13
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Sohrabi A, Lefebvre AEYT, Harrison MJ, Condro MC, Sanazzaro TM, Safarians G, Solomon I, Bastola S, Kordbacheh S, Toh N, Kornblum HI, Digman MA, Seidlits SK. Microenvironmental stiffness induces metabolic reprogramming in glioblastoma. Cell Rep 2023; 42:113175. [PMID: 37756163 PMCID: PMC10842372 DOI: 10.1016/j.celrep.2023.113175] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/28/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state, which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis, which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.
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Affiliation(s)
- Alireza Sohrabi
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Austin E Y T Lefebvre
- Department of Biomedical Engineering, University of California at Irvine, Irvine, CA 92697, USA
| | - Mollie J Harrison
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Michael C Condro
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Talia M Sanazzaro
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Gevick Safarians
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Itay Solomon
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Soniya Bastola
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Shadi Kordbacheh
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Nadia Toh
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Harley I Kornblum
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Michelle A Digman
- Department of Biomedical Engineering, University of California at Irvine, Irvine, CA 92697, USA
| | - Stephanie K Seidlits
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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14
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El-Ayoubi A, Klawitter M, Rüttinger J, Wellhäusser G, Holm PS, Danielyan L, Naumann U. Intranasal Delivery of Oncolytic Adenovirus XVir-N-31 via Optimized Shuttle Cells Significantly Extends Survival of Glioblastoma-Bearing Mice. Cancers (Basel) 2023; 15:4912. [PMID: 37894279 PMCID: PMC10605419 DOI: 10.3390/cancers15204912] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
A glioblastoma (GBM) is an aggressive and lethal primary brain tumor with restricted treatment options and a dismal prognosis. Oncolytic virotherapy (OVT) has developed as a promising approach for GBM treatment. However, reaching invasive GBM cells may be hindered by tumor-surrounding, non-neoplastic cells when the oncolytic virus (OV) is applied intratumorally. Using two xenograft GBM mouse models and immunofluorescence analyses, we investigated the intranasal delivery of the oncolytic adenovirus (OAV) XVir-N-31 via virus-loaded, optimized shuttle cells. Intranasal administration (INA) was selected due to its non-invasive nature and the potential to bypass the blood-brain barrier (BBB). Our findings demonstrate that the INA of XVir-N-31-loaded shuttle cells successfully delivered OAVs to the core tumor and invasive GBM cells, significantly prolonged the survival of the GBM-bearing mice, induced immunogenic cell death and finally reduced the tumor burden, all this highlighting the therapeutic potential of this innovative approach. Overall, this study provides compelling evidence for the effectiveness of the INA of XVir-N-31 via shuttle cells as a promising therapeutic strategy for GBM. The non-invasive nature of the INA of OV-loaded shuttle cells holds great promise for future clinical translation. However, further research is required to assess the efficacy of this approach to ultimately progress in human clinical trials.
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Affiliation(s)
- Ali El-Ayoubi
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Moritz Klawitter
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Jakob Rüttinger
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Giulia Wellhäusser
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Per Sonne Holm
- Department of Urology, Klinikum Rechts der Isar, Technical University of Munich, D-81675 Munich, Germany;
- Department of Oral and Maxillofacial Surgery, Medical University Innsbruck, A-6020 Innsbruck, Austria
- XVir Therapeutics GmbH, D-80331 Munich, Germany
| | - Lusine Danielyan
- Department of Clinical Pharmacology, University Hospital Tübingen, D-72076 Tübingen, Germany;
- Neuroscience Laboratory and Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, Yerevan 0025, Armenia
| | - Ulrike Naumann
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
- Gene and RNA Therapy Center (GRTC), Faculty of Medicine, University of Tübingen, D-72076 Tübingen, Germany
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15
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Slepak TI, Guyot M, Walters W, Eichberg DG, Ivan ME. Dual role of the adhesion G-protein coupled receptor ADRGE5/CD97 in glioblastoma invasion and proliferation. J Biol Chem 2023; 299:105105. [PMID: 37517698 PMCID: PMC10481366 DOI: 10.1016/j.jbc.2023.105105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 07/15/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023] Open
Abstract
CD97, an adhesion G-protein coupled receptor highly expressed in glioblastoma (GBM), consists of two noncovalently bound domains: the N-terminal fragment (NTF) and C-terminal fragment. The C-terminal fragment contains a GPCR domain that couples to Gα12/13, while the NTF interacts with extracellular matrix components and other receptors. We investigated the effects of changing CD97 levels and its function on primary patient-derived GBM stem cells (pdGSCs) in vitro and in vivo. We created two functional mutants: a constitutively active ΔNTF and the noncleavable dominant-negative H436A mutant. The CD97 knockdown in pdGSCs decreased, while overexpression of CD97 increased tumor size. Unlike other constructs, the ΔNTF mutant promoted tumor cell proliferation, but the tumors were comparable in size to those with CD97 overexpression. As expected, the GBM tumors overexpressing CD97 were very invasive, but surprisingly, the knockdown did not inhibit invasiveness and even induced it in noninvasive U87 tumors. Importantly, our results indicate that NTF was present in the tumor core cells but absent in the pdGSCs invading the brain. Furthermore, the expression of noncleavable H436A mutant led to large tumors that invade by sending massive protrusions, but the invasion of individual tumor cells was substantially reduced. These data suggest that NTF association with CD97 GPCR domain inhibits individual cell dissemination but not overall tumor invasion. However, NTF dissociation facilitates pdGSCs brain infiltration and may promote tumor proliferation. Thus, the interplay between two functional domains regulates CD97 activity resulting in either enhanced cell adhesion or stimulation of tumor cell invasion and proliferation.
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Affiliation(s)
- Tatiana I Slepak
- Department of Neurosurgery, University of Miami Hospital, University of Miami, Coral Gables, USA; Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, USA
| | - Manuela Guyot
- Department of Neurosurgery, University of Miami Hospital, University of Miami, Coral Gables, USA; Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, USA
| | - Winston Walters
- Department of Neurosurgery, University of Miami Hospital, University of Miami, Coral Gables, USA; Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, USA
| | - Daniel G Eichberg
- Department of Neurosurgery, University of Miami Hospital, University of Miami, Coral Gables, USA
| | - Michael E Ivan
- Department of Neurosurgery, University of Miami Hospital, University of Miami, Coral Gables, USA; Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, USA.
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16
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Karkon-Shayan S, Aliashrafzadeh H, Dianat-Moghadam H, Rastegar-Pouyani N, Majidi M, Zarei M, Moradi-Vastegani S, Bahramvand Y, Babaniamansour S, Jafarzadeh E. Resveratrol as an antitumor agent for glioblastoma multiforme: Targeting resistance and promoting apoptotic cell deaths. Acta Histochem 2023; 125:152058. [PMID: 37336070 DOI: 10.1016/j.acthis.2023.152058] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/26/2023] [Accepted: 06/01/2023] [Indexed: 06/21/2023]
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive brain and spinal cord tumors. Despite the significant development in application of antitumor drugs, no significant increases have been observed in the survival rates of patients with GBM, as GBM cells acquire resistance to conventional anticancer therapeutic agents. Multiple studies have revealed that PI3K/Akt, MAPK, Nanog, STAT 3, and Wnt signaling pathways are involved in GBM progression and invasion. Besides, biological processes such as anti-apoptosis, autophagy, angiogenesis, and stemness promote GBM malignancy. Resveratrol (RESV) is a non-flavonoid polyphenol with high antitumor activity, the potential of which, regulating signaling pathways involved in cancer malignancy, have been demonstrated by many studies. Herein, we present the potential of RESV in both single and combination therapy- targeting various signaling pathways- which induce apoptotic cell death, re-sensitize cancer cells to radiotherapy, and induce chemo-sensitizing effects to eventually inhibit GBM progression.
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Affiliation(s)
- Sepideh Karkon-Shayan
- Student Research Committee, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Hasan Aliashrafzadeh
- Student Research Committee, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nima Rastegar-Pouyani
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Majidi
- Student Research Committee, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Mahdi Zarei
- Student Research Committee, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sadegh Moradi-Vastegani
- Department of physiology, faculty of medicine, physiology research center, Ahvaz jundishapur university of medical sciences, Ahvaz, Iran
| | - Yaser Bahramvand
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sepideh Babaniamansour
- Department of Pathology, School of Medicine, Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran
| | - Emad Jafarzadeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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17
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Garcia-Diaz C, Pöysti A, Mereu E, Clements MP, Brooks LJ, Galvez-Cancino F, Castillo SP, Tang W, Beattie G, Courtot L, Ruiz S, Roncaroli F, Yuan Y, Marguerat S, Quezada SA, Heyn H, Parrinello S. Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin. Cell Rep 2023; 42:112472. [PMID: 37149862 DOI: 10.1016/j.celrep.2023.112472] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 03/14/2023] [Accepted: 04/19/2023] [Indexed: 05/09/2023] Open
Abstract
Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum.
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Affiliation(s)
- Claudia Garcia-Diaz
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
| | - Anni Pöysti
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
| | - Elisabetta Mereu
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain
| | - Melanie P Clements
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
| | - Lucy J Brooks
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
| | - Felipe Galvez-Cancino
- Cancer Immunology Unit, Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK
| | - Simon P Castillo
- Division of Molecular Pathology & Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
| | - Wenhao Tang
- Department of Mathematics, Imperial College London, London, UK
| | - Gordon Beattie
- CRUK City of London Centre Single Cell Genomics Facility, UCL Cancer Institute, University College London, London, UK; Genomics Translational Technology Platform, UCL Cancer Institute, University College London, London, UK
| | - Lilas Courtot
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
| | - Sara Ruiz
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Federico Roncaroli
- Geoffrey Jefferson Brain Research Centre, Division of Neuroscience, School of Biological Sciences, Faculty of Brain and Mental Health, University of Manchester, Manchester, UK
| | - Yinyin Yuan
- Division of Molecular Pathology & Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
| | - Samuel Marguerat
- Genomics Translational Technology Platform, UCL Cancer Institute, University College London, London, UK
| | - Sergio A Quezada
- Cancer Immunology Unit, Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK
| | - Holger Heyn
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain
| | - Simona Parrinello
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK.
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18
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Kałuzińska-Kołat Ż, Kołat D, Kośla K, Płuciennik E, Bednarek AK. Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations. World J Stem Cells 2023; 15:302-322. [PMID: 37342224 PMCID: PMC10277965 DOI: 10.4252/wjsc.v15.i5.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Literature data on glioblastoma ongoingly underline the link between metabolism and cancer stemness, the latter is one responsible for potentiating the resistance to treatment, inter alia due to increased invasiveness. In recent years, glioblastoma stemness research has bashfully introduced a key aspect of cytoskeletal rearrangements, whereas the impact of the cytoskeleton on invasiveness is well known. Although non-stem glioblastoma cells are less invasive than glioblastoma stem cells (GSCs), these cells also acquire stemness with greater ease if characterized as invasive cells and not tumor core cells. This suggests that glioblastoma stemness should be further investigated for any phenomena related to the cytoskeleton and metabolism, as they may provide new invasion-related insights. Previously, we proved that interplay between metabolism and cytoskeleton existed in glioblastoma. Despite searching for cytoskeleton-related processes in which the investigated genes might have been involved, not only did we stumble across the relation to metabolism but also reported genes that were found to be implicated in stemness. Thus, dedicated research on these genes in GSCs seems justifiable and might reveal novel directions and/or biomarkers that could be utilized in the future. Herein, we review the previously identified cytoskeleton/metabolism-related genes through the prism of glioblastoma stemness.
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Affiliation(s)
- Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland.
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
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19
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Shakiba D, Genin GM, Zustiak SP. Mechanobiology of cancer cell responsiveness to chemotherapy and immunotherapy: Mechanistic insights and biomaterial platforms. Adv Drug Deliv Rev 2023; 196:114771. [PMID: 36889646 PMCID: PMC10133187 DOI: 10.1016/j.addr.2023.114771] [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: 08/30/2022] [Revised: 12/17/2022] [Accepted: 03/03/2023] [Indexed: 03/08/2023]
Abstract
Mechanical forces are central to how cancer treatments such as chemotherapeutics and immunotherapies interact with cells and tissues. At the simplest level, electrostatic forces underlie the binding events that are critical to therapeutic function. However, a growing body of literature points to mechanical factors that also affect whether a drug or an immune cell can reach a target, and to interactions between a cell and its environment affecting therapeutic efficacy. These factors affect cell processes ranging from cytoskeletal and extracellular matrix remodeling to transduction of signals by the nucleus to metastasis of cells. This review presents and critiques the state of the art of our understanding of how mechanobiology impacts drug and immunotherapy resistance and responsiveness, and of the in vitro systems that have been of value in the discovery of these effects.
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Affiliation(s)
- Delaram Shakiba
- NSF Science and Technology Center for Engineering Mechanobiology, Washington University, St. Louis, MO, USA; Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO, USA
| | - Guy M Genin
- NSF Science and Technology Center for Engineering Mechanobiology, Washington University, St. Louis, MO, USA; Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO, USA.
| | - Silviya P Zustiak
- NSF Science and Technology Center for Engineering Mechanobiology, Washington University, St. Louis, MO, USA; Department of Biomedical Engineering, School of Science and Engineering, Saint Louis University, St. Louis, MO, USA.
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20
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Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy. Int J Mol Sci 2023; 24:ijms24065665. [PMID: 36982740 PMCID: PMC10055343 DOI: 10.3390/ijms24065665] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/12/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Primarily, “Reprogramming Therapy”, which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy.
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21
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Peris-Celda M, Carrión-Navarro J, Palacín-Aliana I, Sánchez-Gómez P, Acín RP, Garcia-Romero N, Ayuso-Sacido A. Suppressor of fused associates with dissemination patterns in patients with glioma. Front Oncol 2022; 12:923681. [PMID: 36091108 PMCID: PMC9450955 DOI: 10.3389/fonc.2022.923681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Gliomas are the most common brain tumors, which present poor prognosis, due, in part, to tumor cell migration and infiltration into distant brain areas. However, the underlying mechanisms causing such effects are unknown. Hedgehog (HH)–Gli axis is one of the signaling pathways involved, with a high number of molecular mediators. In this study, we investigated the association between HH-Gli intermediates and clinical parameters. We found that high levels of SuFu are associated with high dissemination patterns in patients with glioma. Therefore, we analyzed SuFu expression data in three glioma cohorts of surgical samples (N =1,759) and modified its expression in Glioblastoma Cancer Stem Cells (GB CSC) in vitro models. Our data reveal that SuFu overexpression increases cancer stemness properties together with a migratory phenotype. This work identifies SuFu as a new molecular player in glioma cell migration and a promising target to develop blocking agents to decrease GB dissemination.
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Affiliation(s)
- María Peris-Celda
- Department of Neurosurgery, Mayo Clinic, Rochester, NY, United States
| | | | - Irina Palacín-Aliana
- Atrys Health, Barcelona, Spain
- Fundación de Investigación HM-Hospitales, Madrid, Spain
- Faculty of Science, Universidad de Alcalá, Madrid, Spain
| | - Pilar Sánchez-Gómez
- Neurooncology Unit, Instituto de Salud Carlos III-Unidad Funcional de Investigación de Enfermedades crónicas (UFIEC), Madrid, Spain
| | - Ricardo Prat Acín
- Departamento de Neurocirugía, Hospital Universitario La Fe, Valencia, Spain
| | - Noemi Garcia-Romero
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
| | - Angel Ayuso-Sacido
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
- Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, Madrid, Spain
- Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain
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22
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Grespi F, Vianello C, Cagnin S, Giacomello M, De Mario A. The Interplay of Microtubules with Mitochondria–ER Contact Sites (MERCs) in Glioblastoma. Biomolecules 2022; 12:biom12040567. [PMID: 35454156 PMCID: PMC9030160 DOI: 10.3390/biom12040567] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 11/16/2022] Open
Abstract
Gliomas are heterogeneous neoplasms, classified into grade I to IV according to their malignancy and the presence of specific histological/molecular hallmarks. The higher grade of glioma is known as glioblastoma (GB). Although progress has been made in surgical and radiation treatments, its clinical outcome is still unfavorable. The invasive properties of GB cells and glioma aggressiveness are linked to the reshaping of the cytoskeleton. Recent works suggest that the different susceptibility of GB cells to antitumor immune response is also associated with the extent and function of mitochondria–ER contact sites (MERCs). The presence of MERCs alterations could also explain the mitochondrial defects observed in GB models, including abnormalities of energy metabolism and disruption of apoptotic and calcium signaling. Based on this evidence, the question arises as to whether a MERCs–cytoskeleton crosstalk exists, and whether GB progression is linked to an altered cytoskeleton–MERCs interaction. To address this possibility, in this review we performed a meta-analysis to compare grade I and grade IV GB patients. From this preliminary analysis, we found that GB samples (grade IV) are characterized by altered expression of cytoskeletal and MERCs related genes. Among them, the cytoskeleton-associated protein 4 (CKAP4 or CLIMP-63) appears particularly interesting as it encodes a MERCs protein controlling the ER anchoring to microtubules (MTs). Although further in-depth analyses remain necessary, this perspective review may provide new hints to better understand GB molecular etiopathogenesis, by suggesting that cytoskeletal and MERCs alterations cooperate to exacerbate the cellular phenotype of high-grade GB and that MERCs players can be exploited as novel biomarkers/targets to enhance the current therapy for GB.
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Affiliation(s)
- Francesca Grespi
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
| | - Caterina Vianello
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
| | - Stefano Cagnin
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
- CRIBI Biotechnology Center, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
- CIR-Myo Myology Center, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
| | - Marta Giacomello
- Department of Biology, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy; (F.G.); (C.V.); (S.C.)
- Department of Biomedical Sciences, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
- Correspondence: (M.G.); (A.D.M.)
| | - Agnese De Mario
- Department of Biomedical Sciences, University of Padua, Via Ugo Bassi 58b, 35100 Padua, Italy
- Correspondence: (M.G.); (A.D.M.)
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23
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Di Nunno V, Franceschi E, Tosoni A, Gatto L, Bartolini S, Brandes AA. Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance. Front Oncol 2022; 12:852950. [PMID: 35311140 PMCID: PMC8924419 DOI: 10.3389/fonc.2022.852950] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/09/2022] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma is an aggressive tumor and is associated with a dismal prognosis. The availability of few active treatments as well as the inexorable recurrence after surgery are important hallmarks of the disease. The biological behavior of glioblastoma tumor cells reveals a very complex pattern of genomic alterations and is partially responsible for the clinical aggressiveness of this tumor. It has been observed that glioblastoma cells can recruit, manipulate and use other cells including neurons, glial cells, immune cells, and endothelial/stromal cells. The final result of this process is a very tangled net of interactions promoting glioblastoma growth and progression. Nonetheless, recent data are suggesting that the microenvironment can also be a niche in which glioblastoma cells can differentiate into glial cells losing their tumoral phenotype. Here we summarize the known interactions between micro-environment and glioblastoma cells highlighting possible therapeutic implications.
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Affiliation(s)
| | - Enrico Franceschi
- Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Alicia Tosoni
- Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Lidia Gatto
- Department of Oncology, AUSL Bologna, Bologna, Italy
| | - Stefania Bartolini
- Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Alba Ariela Brandes
- Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
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24
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Uribe D, Niechi I, Rackov G, Erices JI, San Martín R, Quezada C. Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity. BIOLOGY 2022; 11:313. [PMID: 35205179 PMCID: PMC8869716 DOI: 10.3390/biology11020313] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is the most frequent and aggressive brain tumor, characterized by great resistance to treatments, as well as inter- and intra-tumoral heterogeneity. GBM exhibits infiltration, vascularization and hypoxia-associated necrosis, characteristics that shape a unique microenvironment in which diverse cell types are integrated. A subpopulation of cells denominated GBM stem-like cells (GSCs) exhibits multipotency and self-renewal capacity. GSCs are considered the conductors of tumor progression due to their high tumorigenic capacity, enhanced proliferation, invasion and therapeutic resistance compared to non-GSCs cells. GSCs have been classified into two molecular subtypes: proneural and mesenchymal, the latter showing a more aggressive phenotype. Tumor microenvironment and therapy can induce a proneural-to-mesenchymal transition, as a mechanism of adaptation and resistance to treatments. In addition, GSCs can transition between quiescent and proliferative substates, allowing them to persist in different niches and adapt to different stages of tumor progression. Three niches have been described for GSCs: hypoxic/necrotic, invasive and perivascular, enhancing metabolic changes and cellular interactions shaping GSCs phenotype through metabolic changes and cellular interactions that favor their stemness. The phenotypic flexibility of GSCs to adapt to each niche is modulated by dynamic epigenetic modifications. Methylases, demethylases and histone deacetylase are deregulated in GSCs, allowing them to unlock transcriptional programs that are necessary for cell survival and plasticity. In this review, we described the effects of GSCs plasticity on GBM progression, discussing the role of GSCs niches on modulating their phenotype. Finally, we described epigenetic alterations in GSCs that are important for stemness, cell fate and therapeutic resistance.
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Affiliation(s)
- Daniel Uribe
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Ignacio Niechi
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Gorjana Rackov
- Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), 28049 Madrid, Spain;
| | - José I. Erices
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Rody San Martín
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
| | - Claudia Quezada
- Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 5090000, Chile; (D.U.); (I.N.); (J.I.E.); (R.S.M.)
- Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 5090000, Chile
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Seifert C, Balz E, Herzog S, Korolev A, Gaßmann S, Paland H, Fink MA, Grube M, Marx S, Jedlitschky G, Tzvetkov MV, Rauch BH, Schroeder HWS, Bien-Möller S. PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells. Int J Mol Sci 2021; 22:ijms222011126. [PMID: 34681783 PMCID: PMC8541331 DOI: 10.3390/ijms222011126] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/05/2021] [Accepted: 10/09/2021] [Indexed: 12/15/2022] Open
Abstract
Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy.
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Affiliation(s)
- Carolin Seifert
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
- Department of Neurosurgery, University Medicine Greifswald, 17489 Greifswald, Germany; (S.M.); (H.W.S.S.)
| | - Ellen Balz
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
- Department of Neurosurgery, University Medicine Greifswald, 17489 Greifswald, Germany; (S.M.); (H.W.S.S.)
| | - Susann Herzog
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
| | - Anna Korolev
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
| | - Sebastian Gaßmann
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
| | - Heiko Paland
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
- Department of Neurosurgery, University Medicine Greifswald, 17489 Greifswald, Germany; (S.M.); (H.W.S.S.)
| | - Matthias A. Fink
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
- Department of Neurosurgery, University Medicine Greifswald, 17489 Greifswald, Germany; (S.M.); (H.W.S.S.)
| | - Markus Grube
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
| | - Sascha Marx
- Department of Neurosurgery, University Medicine Greifswald, 17489 Greifswald, Germany; (S.M.); (H.W.S.S.)
| | - Gabriele Jedlitschky
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
| | - Mladen V. Tzvetkov
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
| | - Bernhard H. Rauch
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
- Department of Pharmacology and Toxicology, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany
| | - Henry W. S. Schroeder
- Department of Neurosurgery, University Medicine Greifswald, 17489 Greifswald, Germany; (S.M.); (H.W.S.S.)
| | - Sandra Bien-Möller
- Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany; (C.S.); (E.B.); (S.H.); (A.K.); (S.G.); (H.P.); (M.A.F.); (M.G.); (G.J.); (M.V.T.); (B.H.R.)
- Department of Neurosurgery, University Medicine Greifswald, 17489 Greifswald, Germany; (S.M.); (H.W.S.S.)
- Correspondence: ; Tel.: +49-03834-865646
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26
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Dapash M, Hou D, Castro B, Lee-Chang C, Lesniak MS. The Interplay between Glioblastoma and Its Microenvironment. Cells 2021; 10:2257. [PMID: 34571905 PMCID: PMC8469987 DOI: 10.3390/cells10092257] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 01/05/2023] Open
Abstract
GBM is the most common primary brain tumor in adults, and the aggressive nature of this tumor contributes to its extremely poor prognosis. Over the years, the heterogeneous and adaptive nature of GBM has been highlighted as a major contributor to the poor efficacy of many treatments including various immunotherapies. The major challenge lies in understanding and manipulating the complex interplay among the different components within the tumor microenvironment (TME). This interplay varies not only by the type of cells interacting but also by their spatial distribution with the TME. This review highlights the various immune and non-immune components of the tumor microenvironment and their consequences of the efficacy of immunotherapies. Understanding the independent and interdependent aspects of the various sub-populations encapsulated by the immune and non-immune components will allow for more targeted therapies. Meanwhile, understanding how the TME creates and responds to different environmental pressures such as hypoxia may allow for other multimodal approaches in the treatment of GBM. Ultimately, a better understanding of the GBM TME will aid in the development and advancement of more effective treatments and in improving patient outcomes.
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Affiliation(s)
- Mark Dapash
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.D.); (D.H.); (B.C.)
- Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - David Hou
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.D.); (D.H.); (B.C.)
| | - Brandyn Castro
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.D.); (D.H.); (B.C.)
- Department of Neurosurgery, University of Chicago, Chicago, IL 60637, USA
| | - Catalina Lee-Chang
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.D.); (D.H.); (B.C.)
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Maciej S. Lesniak
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.D.); (D.H.); (B.C.)
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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Wang Y, Shen H, Sun Q, Zhao L, Liu H, Ye L, Xu Y, Cai J, Li Y, Gao L, Tan Y, Liu B, Chen Q. The New PI3K/mTOR Inhibitor GNE-477 Inhibits the Malignant Behavior of Human Glioblastoma Cells. Front Pharmacol 2021; 12:659511. [PMID: 34381355 PMCID: PMC8350478 DOI: 10.3389/fphar.2021.659511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/30/2021] [Indexed: 11/13/2022] Open
Abstract
The most common primary central nervous system tumor in adults is glioblastoma multiforme (GBM). The high invasiveness of GBM cells is an important factor leading to inevitable tumor recurrence and a poor prognosis of patients. GNE-477, a novel PI3K/mTOR inhibitor, has been reported to exert antiproliferative effects on other cancer cells. However, researchers have not clearly determined whether GNE-477 produces antitumor effects on GBM. In the present study, GNE-477 significantly inhibited the proliferation, migration and invasion of U87 and U251 cells. In addition, GNE-477 also induced apoptosis of GBM cells, arresting the cell cycle in G0/G1 phase. More importantly, GNE-477 also reduced the levels of AKT and mTOR phosphorylation in the AKT/mTOR signaling pathway in a concentration-dependent manner. An increase in AKT activity induced by SC79 rescued the GNE-477-mediated inhibition of GBM cell proliferation and apoptosis. The antitumor effects of GNE-477 and the regulatory effects on related molecules were further confirmed in vivo using a nude mouse intracranial xenograft model. In conclusion, our study indicated that GNE-477 exerted significant antitumor effects on GBM cells in vitro and in vivo by downregulating the AKT/mTOR pathway.
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Affiliation(s)
- Yixuan Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Heng Shen
- Department of Neurosurgery, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Qian Sun
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Linyao Zhao
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hao Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Liguo Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Xu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiayang Cai
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuntao Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lun Gao
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yinqiu Tan
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Baohui Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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Brooks LJ, Clements MP, Burden JJ, Kocher D, Richards L, Devesa SC, Zakka L, Woodberry M, Ellis M, Jaunmuktane Z, Brandner S, Morrison G, Pollard SM, Dirks PB, Marguerat S, Parrinello S. The white matter is a pro-differentiative niche for glioblastoma. Nat Commun 2021; 12:2184. [PMID: 33846316 PMCID: PMC8042097 DOI: 10.1038/s41467-021-22225-w] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/23/2021] [Indexed: 02/02/2023] Open
Abstract
Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.
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Affiliation(s)
- Lucy J Brooks
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Melanie P Clements
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Jemima J Burden
- MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Daniela Kocher
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Luca Richards
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Sara Castro Devesa
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Leila Zakka
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Megan Woodberry
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Michael Ellis
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Zane Jaunmuktane
- Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, Queen Square, WC1N 3BG, London, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK
| | - Sebastian Brandner
- Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, Queen Square, WC1N 3BG, London, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK
| | - Gillian Morrison
- MRC Centre for Regenerative Medicine and Edinburgh Cancer Research UK Cancer Centre, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Steven M Pollard
- MRC Centre for Regenerative Medicine and Edinburgh Cancer Research UK Cancer Centre, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Peter B Dirks
- Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Departments of Surgery and Molecular Genetics, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
| | - Samuel Marguerat
- MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Simona Parrinello
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, WC1E 6DD, UK.
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29
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Wang WL, Jiang ZR, Hu C, Chen C, Hu ZQ, Wang AL, Wang L, Liu J, Wang WC, Liu QS. Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52. Acta Pharmacol Sin 2021; 42:633-640. [PMID: 32737469 PMCID: PMC8115168 DOI: 10.1038/s41401-020-0465-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 06/17/2020] [Indexed: 11/09/2022]
Abstract
Inhibition of glycolysis process has been an attractive approach for cancer treatment due to the evidence that tumor cells are more dependent on glycolysis rather than oxidative phosphorylation pathway. Preliminary evidence shows that inhibition of phosphoglycerate kinase 1 (PGK1) kinase activity would reverse the Warburg effect and make tumor cells lose the metabolic advantage for fueling the proliferation through restoration of the pyruvate dehydrogenase (PDH) activity and subsequently promotion of pyruvic acid to enter the Krebs cycle in glioma. However, due to the lack of small molecule inhibitors of PGK1 kinase activity to treat glioma, whether PGK1 could be a therapeutic target of glioma has not been pharmacologically verified yet. In this study we developed a high-throughput screening and discovered that NG52, previously known as a yeast cell cycle-regulating kinase inhibitor, could inhibit the kinase activity of PGK1 (the IC50 = 2.5 ± 0.2 μM). We showed that NG52 dose-dependently inhibited the proliferation of glioma U87 and U251 cell lines with IC50 values of 7.8 ± 1.1 and 5.2 ± 0.2 μM, respectively, meanwhile it potently inhibited the proliferation of primary glioma cells. We further revealed that NG52 (12.5-50 μM) effectively inhibited the phosphorylation of PDHK1 at Thr338 site and the phosphorylation of PDH at Ser293 site in U87 and U251 cells, resulting in more pyruvic acid entering the Krebs cycle with increased production of ATP and ROS. Therefore, NG52 could reverse the Warburg effect by inhibiting PGK1 kinase activity, and switched cellular glucose metabolism from anaerobic mode to aerobic mode. In nude mice bearing patient-derived glioma xenograft, oral administration of NG52 (50, 100, 150 mg· kg-1·d-1, for 13 days) dose-dependently suppressed the growth of glioma xenograft. Together, our results demonstrate that targeting PGK1 kinase activity might be a potential strategy for glioma treatment.
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Affiliation(s)
- Wen-Liang Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230036, China
| | - Zong-Ru Jiang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230036, China
| | - Chen Hu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Cheng Chen
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230036, China
| | - Zhen-Quan Hu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Ao-Li Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Li Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230036, China
| | - Jing Liu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
| | - Wen-Chao Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
- Precision Medicine Research Laboratory of Anhui Province, Hefei, 230088, China.
| | - Qing-Song Liu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
- University of Science and Technology of China, Hefei, 230036, China.
- Precision Medicine Research Laboratory of Anhui Province, Hefei, 230088, China.
- Institutes of Physical Science and Information Technology, Key Laboratory of Structure and Functional Regulation of Hybrid Materials, Ministry of Education, Anhui University, Hefei, 230601, China.
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30
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Gade IS, Richard TS, Chadeneau C, Seite P, Vannier B, Atchade ADT, Seke Etet PF, Talla E, Nwabo Kamdje AH, Muller JM. Anticancer Activity of Combretum fragrans F. Hoffm on Glioblastoma and Prostate Cancer Cell Lines. Asian Pac J Cancer Prev 2021; 22:1087-1093. [PMID: 33906300 PMCID: PMC8325120 DOI: 10.31557/apjcp.2021.22.4.1087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/03/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Cancer incidence has been growing in an alarming rate worldwide and new therapeutics are needed, particularly for intractable and chemoresistant cases. We evaluated the cytotoxic effects of Combretum fragrans F. Hoffm (Combretaceae) on glioblastoma (U87MG and C6) and prostate (PC-3) cancer cell lines. METHODS The cytotoxic effect of the methanolic extract of the stem bark of Combretum fragrans was assessed using XTT (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) test. Expressions of Akt and ERK1/2 were determined using Western blot technique, while Caspase-3/7 kits were used to evaluate caspase-3/7 activity. RESULTS C. fragrans extract inhibited the proliferation of U87 (IC50 = 20.13 µg/mL), C6 (IC50 = 12.17 µg/mL), and PC-3 (IC50 = 11.50 µg/mL) cells. Treatment with the extract resulted in lower levels (p < 0.001) of phospho-ERK1/2 and phospho-Akt in U87 cells, and instead, higher levels of phospho-ERK1/2 (p < 0.001) in C6 and PC-3 cells. An increase in caspase-3/7 activity was observed, mainly after 24 hours of treatment, indicating the activation of apoptotic processes. CONCLUSION Altogether, these results suggest that C. fragrans have potent anticancer properties. This plant should be further investigated for developing new anticancer drugs.
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Affiliation(s)
- Isaac Silvère Gade
- Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
- UFR Sciences Fondamentales et Appliquées, Team “Récepteurs, Régulations, Cellules Tumorales” (2RCT)-EA 3842 CAPTuR, Pôle Biologie Santé-Bât. B36/B37, University of Poitiers, 1 rue Georges Bonnet-TSA, France.
- Department of Chemistry, Faculty of Science, University of Ngaoundere, Ngaoundéré, Cameroon.
| | - Tagne Simo Richard
- Department of Biomedical Sciences, Faculty of Science, University of Ngaoundere, Ngaoundéré, Cameroon.
| | - Corinne Chadeneau
- Department of Chemistry, Faculty of Science, University of Ngaoundere, Ngaoundéré, Cameroon.
| | - Paule Seite
- UFR Sciences Fondamentales et Appliquées, Team “Récepteurs, Régulations, Cellules Tumorales” (2RCT)-EA 3842 CAPTuR, Pôle Biologie Santé-Bât. B36/B37, University of Poitiers, 1 rue Georges Bonnet-TSA, France.
| | - Brigitte Vannier
- UFR Sciences Fondamentales et Appliquées, Team “Récepteurs, Régulations, Cellules Tumorales” (2RCT)-EA 3842 CAPTuR, Pôle Biologie Santé-Bât. B36/B37, University of Poitiers, 1 rue Georges Bonnet-TSA, France.
| | - Alex De Theodore Atchade
- Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
| | - Paul F. Seke Etet
- Department of Physiological Sciences and Biochemistry, FMBS, University of Ngaoundere, Garoua, Cameroon.
| | - Emmanuel Talla
- Department of Chemistry, Faculty of Science, University of Ngaoundere, Ngaoundéré, Cameroon.
| | - Armel H. Nwabo Kamdje
- Department of Biomedical Sciences, Faculty of Science, University of Ngaoundere, Ngaoundéré, Cameroon.
| | - Jean-Marc Muller
- UFR Sciences Fondamentales et Appliquées, Team “Récepteurs, Régulations, Cellules Tumorales” (2RCT)-EA 3842 CAPTuR, Pôle Biologie Santé-Bât. B36/B37, University of Poitiers, 1 rue Georges Bonnet-TSA, France.
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31
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Xiong J, Guo G, Guo L, Wang Z, Chen Z, Nan Y, Cao Y, Li R, Yang X, Dong J, Jin X, Yang W, Huang Q. Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway. ACS OMEGA 2021; 6:4289-4299. [PMID: 33644550 PMCID: PMC7906592 DOI: 10.1021/acsomega.0c05399] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 01/04/2021] [Indexed: 05/05/2023]
Abstract
Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of IKBKE, for GBM. We found that the combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration, and invasion in primary glioma cells and in the human glioma cell line, U87 MG. As expected, TMZ enhanced the expression of p-AMPK and amlexanox led to the reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that compared to other groups treated with each component alone, TMZ combined with amlexanox effectively reversed the TMZ-induced activation of Akt and inhibited the phosphorylation of mTOR. In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. These results suggest that amlexanox sensitized the primary glioma cells and U87 MG cells to TMZ at least partially through the suppression of IKBKE activation and the attenuation of TMZ-induced Akt activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.
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Affiliation(s)
- Jinbiao Xiong
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
| | - Gaochao Guo
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
| | - Lianmei Guo
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
| | - Zengguang Wang
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
| | - Zhijuan Chen
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
| | - Yang Nan
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
| | - Yiyao Cao
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
| | - Ruilong Li
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
| | - Xuejun Yang
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
| | - Jun Dong
- Department
of Neurosurgery, The Second Affiliated Hospital
of Soochow University, Suzhou 215004, China
| | - Xun Jin
- Tianjin
Medical University Cancer Institute and Hospital, Tianjin 300052, China
- National
Clinical Research Center for Cancer, Tianjin 300052, China
- Key
Laboratory of Cancer Prevention and Therapy, Tianjin 300052, China
- Tianjin’s
Clinical Research Center for Cancer, Tianjin 300052, China
| | - Weidong Yang
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- . Tel: (+86)13820763396
| | - Qiang Huang
- Department
of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China
- Key
Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central
Nervous System, Ministry of Education and
Tianjin City, Tianjin 300052, China
- Tianjin
Key Laboratory of Injuries, Variations and
Regeneration of Nervous System, Tianjin 300052, China
- . Tel: (+86)13820689221
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Pruteanu LL, Kopanitsa L, Módos D, Kletnieks E, Samarova E, Bender A, Gomez LD, Bailey DS. Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells. PLoS One 2020; 15:e0239551. [PMID: 32946518 PMCID: PMC7500592 DOI: 10.1371/journal.pone.0239551] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 09/08/2020] [Indexed: 12/20/2022] Open
Abstract
Pathway analysis is an informative method for comparing and contrasting drug-induced gene expression in cellular systems. Here, we define the effects of the marine natural product fucoxanthin, separately and in combination with the prototypic phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002, on gene expression in a well-established human glioblastoma cell system, U87MG. Under conditions which inhibit cell proliferation, LY-294002 and fucoxanthin modulate many pathways in common, including the retinoblastoma, DNA damage, DNA replication and cell cycle pathways. In sharp contrast, we see profound differences in the expression of genes characteristic of pathways such as apoptosis and lipid metabolism, contributing to the development of a differentiated and distinctive drug-induced gene expression signature for each compound. Furthermore, in combination, fucoxanthin synergizes with LY-294002 in inhibiting the growth of U87MG cells, suggesting complementarity in their molecular modes of action and pointing to further treatment combinations. The synergy we observe between the dietary nutraceutical fucoxanthin and the synthetic chemical LY-294002 in producing growth arrest in glioblastoma, illustrates the potential of nutri-pharmaceutical combinations in targeting this challenging disease.
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Affiliation(s)
- Lavinia-Lorena Pruteanu
- IOTA Pharmaceuticals Ltd, St Johns Innovation Centre, Cambridge, United Kingdom
- * E-mail: (LLP); (DSB)
| | - Liliya Kopanitsa
- IOTA Pharmaceuticals Ltd, St Johns Innovation Centre, Cambridge, United Kingdom
| | - Dezső Módos
- Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Cambridge, United Kingdom
| | - Edgars Kletnieks
- Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Cambridge, United Kingdom
| | - Elena Samarova
- IOTA Pharmaceuticals Ltd, St Johns Innovation Centre, Cambridge, United Kingdom
| | - Andreas Bender
- Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Cambridge, United Kingdom
| | - Leonardo Dario Gomez
- Department of Biology, Centre for Novel Agricultural Products, University of York, York, United Kingdom
| | - David Stanley Bailey
- IOTA Pharmaceuticals Ltd, St Johns Innovation Centre, Cambridge, United Kingdom
- * E-mail: (LLP); (DSB)
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2D and 3D in vitro assays to quantify the invasive behavior of glioblastoma stem cells in response to SDF-1α. Biotechniques 2020; 69:339-346. [PMID: 32867513 DOI: 10.2144/btn-2020-0046] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Invasion is a hallmark of cancer and therefore in vitro invasion assays are important tools in cancer research. We aimed to describe in vitro 2D transwell assays and 3D spheroid assays to quantitatively determine the invasive behavior of glioblastoma stem cells in response to the chemoattractant SDF-1α. Matrigel was used as a matrix in both assays. We demonstrated quantitatively that SDF-1α increased invasive behavior of glioblastoma stem cells in both assays. We conclude that the 2D transwell invasion assay is easy to perform, fast and less complex whereas the more time-consuming 3D spheroid invasion assay is physiologically closer to the in vivo situation.
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34
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Targeting Glioblastoma: Advances in Drug Delivery and Novel Therapeutic Approaches. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000124] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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35
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Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity. Cell Oncol (Dordr) 2020; 43:1175-1190. [PMID: 32761562 DOI: 10.1007/s13402-020-00550-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 07/11/2020] [Accepted: 07/14/2020] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Recent studies have reported important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). Here, we tested the antitumor activity of a Dopamine receptor D1 (DRD1) agonist, either alone or in combination with temozolomide (TMZ) on GBM cells. METHODS Immunofluorescence, immunohistochemistry and Western blotting were used to detect dopamine receptor expression in primary human GBM tissues. In addition, clinical data of GBM patients downloaded from The Cancer Genome Atlas (TCGA) were analyzed. Image-based tracking analysis of LC3 using a mCherry-eGFP-LC3 plasmid was utilized to monitor autophagic flux. Transmission electron microscopy (TEM) was used to visualize aggregation of autophagosomes/autolysosomes. Finally, DRD1 agonist (SKF83959)-induced inhibition of GBM growth was assessed in vitro and in vivo. RESULTS Positive DRD1 expression was observed in human GBM tissues and found to be related with a good clinical outcome. DRD1 activation specifically inhibited GBM cell growth and significantly disrupted autophagic flux, which led to tumor cell death. Moreover, we found that DRD1 agonist treatment inhibited auto-lysosomal degradation in GBM cells and that this process was calcium overload dependent and related to inhibition of mammalian target of rapamycin (mTOR). Finally, we found that DRD1 agonist and TMZ co-treatment yielded a synergistic therapeutic effect both in vivo and in vitro. CONCLUSIONS From our data we conclude that DRD1 activation inhibits GBM cell growth and may serve as an alternative avenue for the design of future GBM therapies.
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Georgescu MM, Islam MZ, Li Y, Circu ML, Traylor J, Notarianni CM, Kline CN, Burns DK. Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma. Acta Neuropathol Commun 2020; 8:111. [PMID: 32680567 PMCID: PMC7367358 DOI: 10.1186/s40478-020-00992-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 12/18/2022] Open
Abstract
Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/β receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.
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Zhou S, Zhang M, Zhou C, Wang W, Yang H, Ye W. The role of epithelial-mesenchymal transition in regulating radioresistance. Crit Rev Oncol Hematol 2020; 150:102961. [PMID: 32361589 DOI: 10.1016/j.critrevonc.2020.102961] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer patients with different stages can benefit from radiotherapy, but there are still limited due to inherent or acquired radioresistance. The epithelial-mesenchymal transition (EMT) is a complex biological process that is implicated in malignant characteristics of cancer, such as radioresistance. Although the possible mechanisms of EMT-dependent radioresistance are being extensively studied, there is a lack of a clear picture of the overall signaling of EMT-mediated radioresistance. In this review, we highlight the role and possible molecular mechanisms of EMT in cancer radioresistance, in particular to EMT-associated signaling pathway, EMT-inducing transcription factors (EMT-TFs), EMT-related non-coding RNAs. The knowledge of EMT-associated mechanisms of radioresistance will offer more potent therapy targets to improve the radiotherapy responses.
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Affiliation(s)
- Suna Zhou
- Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China; Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China.
| | - Mingxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Medical University, Xi'an 710077, Shaanxi, China
| | - Chao Zhou
- Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China; Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China
| | - Wei Wang
- Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China; Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China
| | - Haihua Yang
- Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China; Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China
| | - Wenguang Ye
- Department of Gastroenterology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, China.
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Vollmann-Zwerenz A, Leidgens V, Feliciello G, Klein CA, Hau P. Tumor Cell Invasion in Glioblastoma. Int J Mol Sci 2020; 21:E1932. [PMID: 32178267 PMCID: PMC7139341 DOI: 10.3390/ijms21061932] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/02/2020] [Accepted: 03/09/2020] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches.
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Affiliation(s)
- Arabel Vollmann-Zwerenz
- Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, 93053 Regensburg, Germany; (A.V.-Z.); (V.L.)
| | - Verena Leidgens
- Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, 93053 Regensburg, Germany; (A.V.-Z.); (V.L.)
| | - Giancarlo Feliciello
- Fraunhofer-Institute for Toxicology and Experimental Medicine, Division of Personalized Tumor Therapy, 93053 Regensburg, Germany; (G.F.); (C.A.K.)
| | - Christoph A. Klein
- Fraunhofer-Institute for Toxicology and Experimental Medicine, Division of Personalized Tumor Therapy, 93053 Regensburg, Germany; (G.F.); (C.A.K.)
- Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany
| | - Peter Hau
- Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, 93053 Regensburg, Germany; (A.V.-Z.); (V.L.)
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Georgescu MM, Olar A. Genetic and histologic spatiotemporal evolution of recurrent, multifocal, multicentric and metastatic glioblastoma. Acta Neuropathol Commun 2020; 8:10. [PMID: 32014051 PMCID: PMC6998196 DOI: 10.1186/s40478-020-0889-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 01/27/2020] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by extensive brain invasion and rarely, systemic metastases. The pathogenesis of metastatic glioblastoma is largely unknown. We present the first integrated clinical/histologic/genetic analysis of 5 distinct brain and lung foci from a unique case of recurrent, multifocal, multicentric and metastatic glioblastoma. The initial right frontotemporal gliosarcoma received standard surgical/chemoradiation therapy and recurred 1.5 years later, co-occurring with three additional masses localized to the ipsilateral temporal lobe, cerebellum and lung. Synchronous metastatic lung carcinoma was suspected in this long-term smoker patient with family history of cancer. However, glioblastoma was confirmed in all tumors, although with different morphologic patterns, including ependymomatous and epithelioid. Genomic profiling revealed a germline FANCD2 variant of unknown significance, and a 4-gene somatic mutation signature shared by all tumors, consisting of TERT promoter and PTEN, RB1 and TP53 tumor suppressor mutations. Additional GRIN2A and ATM heterozygous mutations were selected in the cerebellar and lung foci, but were variably present in the supratentorial foci, indicating reduced post-therapeutic genetic evolution in brain foci despite morphologic variability. Significant genetic drift characterized the lung metastasis, likely explaining the known resistance of circulating glioblastoma cells to systemic seeding. MET overexpression was detected in the initial gliosarcoma and lung metastasis, possibly contributing to invasiveness. This comprehensive analysis sheds light on the temporospatial evolution of glioblastoma and underscores the importance of genetic testing for diagnosis and personalized therapy.
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40
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Mazurek M, Litak J, Kamieniak P, Kulesza B, Jonak K, Baj J, Grochowski C. Metformin as Potential Therapy for High-Grade Glioma. Cancers (Basel) 2020; 12:E210. [PMID: 31952173 PMCID: PMC7016983 DOI: 10.3390/cancers12010210] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open
Abstract
Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy.
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Affiliation(s)
- Marek Mazurek
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Jakub Litak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
- Department of Immunology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Piotr Kamieniak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Bartłomiej Kulesza
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Katarzyna Jonak
- Department of Foregin Languages, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Cezary Grochowski
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
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Signaling Determinants of Glioma Cell Invasion. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1202:129-149. [PMID: 32034712 DOI: 10.1007/978-3-030-30651-9_7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Tumor cell invasiveness is a critical challenge in the clinical management of glioma patients. In addition, there is accumulating evidence that current therapeutic modalities, including anti-angiogenic therapy and radiotherapy, can enhance glioma invasiveness. Glioma cell invasion is stimulated by both autocrine and paracrine factors that act on a large array of cell surface-bound receptors. Key signaling elements that mediate receptor-initiated signaling in the regulation of glioblastoma invasion are Rho family GTPases, including Rac, RhoA and Cdc42. These GTPases regulate cell morphology and actin dynamics and stimulate cell squeezing through the narrow extracellular spaces that are typical of the brain parenchyma. Transient attachment of cells to the extracellular matrix is also necessary for glioblastoma cell invasion. Interactions with extracellular matrix components are mediated by integrins that initiate diverse intracellular signalling pathways. Key signaling elements stimulated by integrins include PI3K, Akt, mTOR and MAP kinases. In order to detach from the tumor mass, glioma cells secrete proteolytic enzymes that cleave cell surface adhesion molecules, including CD44 and L1. Key proteases produced by glioma cells include uPA, ADAMs and MMPs. Increased understanding of the molecular mechanisms that control glioma cell invasion has led to the identification of molecular targets for therapeutic intervention in this devastating disease.
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Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches. JOURNAL OF ONCOLOGY 2019; 2019:4878547. [PMID: 32082376 PMCID: PMC7012245 DOI: 10.1155/2019/4878547] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 10/07/2019] [Accepted: 10/25/2019] [Indexed: 12/31/2022]
Abstract
Glioblastoma is the most common primary adult brain tumour, and despite optimal treatment, the median survival is 12–15 months. Patients with matched recurrent glioblastomas were investigated to try to find actionable mutations. Tumours were profiled using a validated DNA-based gene panel. Copy number variations (CNVs) and single nucleotide variants (SNVs) were examined, and potentially pathogenic variants and clinically actionable mutations were identified. The results revealed that glioblastomas were IDH-wildtype (IDHWT; n = 38) and IDH-mutant (IDHMUT; n = 3). SNVs in TSC2, MSH6, TP53, CREBBP, and IDH1 were variants of unknown significance (VUS) that were predicted to be pathogenic in both subtypes. IDHWT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, WNT, SHH, NOTCH, Rb, and G-protein pathways. Many tumours had BRCA1/2 (18%) variants, including confirmed somatic mutations in haemangioblastoma. IDHWT recurrent tumours had fewer pathways impacted (RTK/Ras/PI(3)K, p53, WNT, and G-protein) and CNV gains (BRCA2, GNAS, and EGFR) and losses (TERT and SMARCA4). IDHMUT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, and WNT pathways. VUS in KLK1 was possibly pathogenic in IDHMUT. Recurrent tumours also had fewer pathways (p53, WNT, and G-protein) impacted by genetic alterations. Public datasets (TCGA and GDC) confirmed the clinical significance of findings in both subtypes. Overall in this cohort, potentially actionable variation was most often identified in EGFR, PTEN, BRCA1/2, and ATM. This study underlines the need for detailed molecular profiling to identify individual GBM patients who may be eligible for novel treatment approaches. This information is also crucial for patient recruitment to clinical trials.
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Zhang X, Sun L, Yu Y, Zhao Y. Flexible Ferrofluids: Design and Applications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1903497. [PMID: 31583782 DOI: 10.1002/adma.201903497] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 07/13/2019] [Indexed: 06/10/2023]
Abstract
Ferrofluids, also known as ferromagnetic particle suspensions, are materials with an excellent magnetic response, which have attracted increasing interest in both industrial production and scientific research areas. Because of their outstanding features, such as rapid magnetic reaction, flexible flowability, as well as tunable optical and thermal properties, ferrofluids have found applications in various fields, including material science, physics, chemistry, biology, medicine, and engineering. Here, a comprehensive, in-depth insight into the diverse applications of ferrofluids from material fabrication, droplet manipulation, and biomedicine to energy and machinery is provided. Design of ferrofluid-related devices, recent developments, as well as present challenges and future prospects are also outlined.
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Affiliation(s)
- Xiaoxuan Zhang
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Lingyu Sun
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Yunru Yu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Yuanjin Zhao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
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Ray P, Nair G, Ghosh A, Banerjee S, Golovko MY, Banerjee SK, Reindl KM, Mallik S, Quadir M. Microenvironment-sensing, nanocarrier-mediated delivery of combination chemotherapy for pancreatic cancer. J Cell Commun Signal 2019; 13:407-420. [PMID: 30915617 PMCID: PMC6732147 DOI: 10.1007/s12079-019-00514-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 03/05/2019] [Indexed: 12/13/2022] Open
Abstract
Limited effectiveness of Raf and MEK inhibitors has impelled the interest to use the inhibitors of Extra-cellular Receptor Kinase (ERK) pathway in combination with Gemcitabine (GEM) in pancreatic cancer. However, off-target abundance of ERK receptors, challenging physico-chemical properties, and dose-limiting toxicity of the inhibitor has presented critical challenges towards fabricating this combination amenable for clinical translation. Herein we report a pharmaceutical nanoformulation of GEM and an ERK inhibitor (SCH 772984) co-stabilized within a pH-sensing nanocarrier (NC, with a hydrodynamic diameter of 161 ± 5.0 nm). The NCs were modularly derived from a triblock, self-assembling copolymer, and were chemically conjugated with GEM and encapsulated with SCH772984 at a loading content of 20.2% and 18.3%, respectively. Through pH-mediated unfolding of the individual blocks of the copolymer, the NCs were able to control the release of encapsulated drugs, traffic through cellular membranes, engage target receptors, suppress proliferation of pancreatic cancer cells, and accumulate at disease sites. Collectively our studies showed the feasibility of co-delivery of a combination chemotherapy consisting of GEM and an ERK inhibitor from a NC platform, which can sense and respond to tumor microenvironment of pancreatic cancer setting.
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Affiliation(s)
- Priyanka Ray
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND, 58108, USA
| | - Gauthami Nair
- Cellular and Molecular Biology Program, Department of Biology, North Dakota State University, Fargo, ND, 58108, USA
| | - Arnab Ghosh
- Cancer Research Unit, VA Medical Center, Kansas City, MO, 64128, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Snigdha Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO, 64128, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Mikhail Y Golovko
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, 58202, USA
| | - Sushanta K Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO, 64128, USA.
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
| | - Katie M Reindl
- Cellular and Molecular Biology Program, Department of Biology, North Dakota State University, Fargo, ND, 58108, USA
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58108, USA
| | - Mohiuddin Quadir
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND, 58108, USA.
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Logun MT, Wynens KE, Simchick G, Zhao W, Mao L, Zhao Q, Mukherjee S, Brat DJ, Karumbaiah L. Surfen-mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion. FASEB J 2019; 33:11973-11992. [PMID: 31398290 DOI: 10.1096/fj.201802610rr] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Invasive spread of glioblastoma (GBM) is linked to changes in chondroitin sulfate (CS) proteoglycan (CSPG)-associated sulfated glycosaminoglycans (GAGs) that are selectively up-regulated in the tumor microenvironment (TME). We hypothesized that inhibiting CS-GAG signaling in the TME would stem GBM invasion. Rat F98 GBM cells demonstrated enhanced preferential cell invasion into oversulfated 3-dimensional composite of CS-A and CS-E [4- and 4,6-sulfated CS-GAG (COMP)] matrices compared with monosulfated (4-sulfated) and unsulfated hyaluronic acid matrices in microfluidics-based choice assays, which is likely influenced by differential GAG receptor binding specificities. Both F98 and human patient-derived glioma stem cells (GSCs) demonstrated a high degree of colocalization of the GSC marker CD133 and CSPGs. The small molecule sulfated GAG antagonist bis-2-methyl-4-amino-quinolyl-6-carbamide (surfen) reduced invasion and focal adhesions in F98 cells encapsulated in COMP matrices and blocked CD133 and antichondroitin sulfate antibody (CS-56) detection of respective antigens in F98 cells and human GSCs. Surfen-treated F98 cells down-regulated CSPG-binding receptor transcripts and protein, as well as total and activated ERK and protein kinase B. Lastly, rats induced with frontal lobe tumors and treated with a single intratumoral dose of surfen demonstrated reduced tumor burden and spread compared with untreated controls. These results present a first demonstration of surfen as an inhibitor of sulfated GAG signaling to stem GBM invasion.-Logun, M. T., Wynens, K. E., Simchick, G., Zhao, W., Mao, L., Zhao, Q., Mukherjee, S., Brat, D. J., Karumbaiah, L. Surfen-mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion.
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Affiliation(s)
- Meghan T Logun
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,Division of Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, Athens, Georgia, USA.,Edgar L. Rhodes Center for Animal and Dairy Science, College of Agriculture and Environmental Sciences, University of Georgia, Athens, Georgia, USA
| | - Kallie E Wynens
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA
| | - Gregory Simchick
- Department of Physics and Astronomy, University of Georgia, Athens, Georgia, USA
| | - Wujun Zhao
- Department of Chemistry, University of Georgia, Athens, Georgia, USA
| | - Leidong Mao
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, Georgia, USA
| | - Qun Zhao
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,Department of Physics and Astronomy, University of Georgia, Athens, Georgia, USA
| | - Subhas Mukherjee
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Daniel J Brat
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lohitash Karumbaiah
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,Division of Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, Athens, Georgia, USA.,Edgar L. Rhodes Center for Animal and Dairy Science, College of Agriculture and Environmental Sciences, University of Georgia, Athens, Georgia, USA
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Czolk R, Schwarz N, Koch H, Schötterl S, Wuttke TV, Holm PS, Huber SM, Naumann U. Irradiation enhances the therapeutic effect of the oncolytic adenovirus XVir-N-31 in brain tumor initiating cells. Int J Mol Med 2019; 44:1484-1494. [PMID: 31432139 PMCID: PMC6713431 DOI: 10.3892/ijmm.2019.4296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 07/19/2019] [Indexed: 12/20/2022] Open
Abstract
Virotherapy using oncolytic viruses is an upcoming therapy strategy for cancer treatment. A variety of preclinical and clinical trials have indicated that adenoviruses may be used as potent agents in the treatment of a variety of cancers, and also for the treatment of brain tumors. In these studies, it has also been shown that oncovirotherapy is safe in terms of toxicity and side effects. In addition, previous studies have presented evidence for a significant role of oncovirotherapy in the activation of anti‑tumor immune responses. With regard to oncolytic adenoviruses, we have demonstrated previously that the multifunctional protein Y‑box binding protein‑1 (YB‑1) is a potent factor that was used to develop an YB‑1‑dependent oncolytic adenovirus (XVir‑N‑31). XVir‑N‑31 provides the opportunity for tumor‑selective replication and exhibited marked oncolytic properties in a mouse glioma tumor model using therapy‑resistant brain tumor initiating cells (BTICs). In a number of, but not all, patients with glioma, YB‑1 is primarily located in the nucleus; this promotes XVir‑N‑31‑replication and subsequently tumor cell lysis. However, in certain BTICs, only a small amount of YB‑1 has been identified to be nuclear, and therefore virus replication is suboptimal. YB‑1 in BTICs was demonstrated to be translocated into the nucleus following irradiation, which was accompanied by an enhancement in XVir‑N‑31 production. R28 glioma spheres implanted in living organotypic human brain slices exhibited a significantly delayed growth rate when pre‑irradiated prior to XVir‑N‑31‑infection as compared with single treatment methods. Consistent with the in vitro data, R28 glioma‑bearing mice exhibited a prolonged mean and median survival following single tumor irradiation prior to intratumoral XVir‑N‑31 injection, compared with the single treatment methods. In conclusion, the present study demonstrated that in an experimental glioma model, tumor irradiation strengthened the effect of an XVir‑N‑31‑based oncovirotherapy.
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Affiliation(s)
- Rebecca Czolk
- Department of Vascular Neurology, Laboratory for Molecular Neuro‑Oncology, Hertie Institute for Clinical Brain Research, Tübingen NeuroCampus, University of Tübingen, D‑72076 Tübingen, Germany
| | - Niklas Schwarz
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen NeuroCampus, University of Tübingen, D‑72076 Tübingen, Germany
| | - Henner Koch
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen NeuroCampus, University of Tübingen, D‑72076 Tübingen, Germany
| | - Sonja Schötterl
- Department of Vascular Neurology, Laboratory for Molecular Neuro‑Oncology, Hertie Institute for Clinical Brain Research, Tübingen NeuroCampus, University of Tübingen, D‑72076 Tübingen, Germany
| | - Thomas V Wuttke
- Department of Neurosurgery, University Hospital Tübingen, D‑72076 Tübingen, Germany
| | - Per S Holm
- Department of Urology, Hospital 'Rechts der Isar', Technical University of Munich, D‑81675 Munich, Germany
| | - Stephan M Huber
- Department of Radiation Oncology, University Hospital Tübingen, D‑72076 Tübingen, Germany
| | - Ulrike Naumann
- Department of Vascular Neurology, Laboratory for Molecular Neuro‑Oncology, Hertie Institute for Clinical Brain Research, Tübingen NeuroCampus, University of Tübingen, D‑72076 Tübingen, Germany
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47
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Ray P, Ferraro M, Haag R, Quadir M. Dendritic Polyglycerol-Derived Nano-Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer. Macromol Biosci 2019; 19:e1900073. [PMID: 31183964 DOI: 10.1002/mabi.201900073] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/07/2019] [Indexed: 12/14/2022]
Abstract
Dendritic polyglycerol-co-polycaprolactone (PG-co-PCL)-derived block copolymers are synthesized and explored as nanoscale drug delivery platforms for a chemotherapeutic agent, gemcitabine (GEM), which is the cornerstone of therapy for pancreatic ductal adenocarcinoma (PDAC). Current treatment strategies with GEM result in suboptimal therapeutic outcome owing to microenvironmental resistance and rapid metabolic degradation of GEM. To address these challenges, physicochemical and cell-biological properties of both covalently conjugated and non-covalently stabilized variants of GEM-containing PG-co-PCL architectures have been evaluated. Self-assembly behavior, drug loading and release capacity, cytotoxicity, and cellular uptake properties of these constructs in monolayer and in spheroid cultures of PDAC cells are investigated. To realize the covalently conjugated carrier systems, GEM, in conjunction with a tertiary amine, is attached to the polycarbonate block grafted from the PG-co-PCL core. It is observed that pH-dependent ionization properties of these amine side-chains direct the formation of self-assembly of block copolymers in the form of nanoparticles. For non-covalent encapsulation, a facile "solvent-shifting" technique is adopted. Fabrication techniques are found to control colloidal and cellular properties of GEM-loaded nanoconstructs. The feasibility and potential of these newly developed architectures for designing carrier systems for GEM to achieve augmented prognosis for pancreatic cancer are reported.
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Affiliation(s)
- Priyanka Ray
- Department of Coatings and Polymeric Materials, 1735 Research Park Drive, Fargo, ND, 58108-6050, USA
| | - Magda Ferraro
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195, Berlin, Germany
| | - Rainer Haag
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195, Berlin, Germany
| | - Mohiuddin Quadir
- Department of Coatings and Polymeric Materials, 1735 Research Park Drive, Fargo, ND, 58108-6050, USA
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48
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Georgescu MM, Li Y, Islam MZ, Notarianni C, Sun H, Olar A, Fuller GN. Mutations of the MAPK/TSC/mTOR pathway characterize periventricular glioblastoma with epithelioid SEGA-like morphology-morphological and therapeutic implications. Oncotarget 2019; 10:4038-4052. [PMID: 31258848 PMCID: PMC6592288 DOI: 10.18632/oncotarget.27005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 05/20/2019] [Indexed: 12/15/2022] Open
Abstract
Epithelioid glioblastoma is a recognized glioblastoma variant, recently added to the World Health Organization brain tumor classification, with similar prognosis as the classic variant and B-Raf V600E mutations in 50% of the cases. We identified a new subset of epithelioid glioblastoma with periventricular location and subependymal giant cell astrocytoma (SEGA)-like morphology. Genomic profiling of these tumors revealed driver mutations in NF1, subclonal mutations in TSC1, and a novel driver mutation in MTOR, suggesting upregulation of the MAPK/TSC1/mTOR pathway. Strong mTOR activation was confirmed by immunohistochemistry for the mTOR kinase target 4E-BP1. TSC1 and MTOR mutations have been previously described in low-grade glioma, such as SEGA, and focal cortical dysplasia, respectively, that display large cells with abundant cytoplasm, most likely resulting from the biogenetic signaling of mTOR. Unlike these, the mutations in SEGA-like glioblastoma occurred in the context of other genetic aberrations present in high-grade neoplasms, including in the CDKN2A/B, PIK3R1, PIK3CA and EGFR genes. For one patient with two temporally distinct specimens, the subclonal TSC1 pathogenic mutation was detected only in the specimen showing SEGA-like morphology, indicating requirement for mTOR activation as trigger for specific epithelioid/SEGA-like morphology. As FDA-approved kinase inhibitors are available and target many steps of the MAPK/mTOR pathway, recognition of this new subset of periventricular high-grade gliomas with clear phenotypic-genotypic correlates is essential for prompt biomarker testing and appropriate targeted therapeutic management of these patients.
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Affiliation(s)
- Maria-Magdalena Georgescu
- Department of Pathology and Pathobiology and Feist-Weiller Cancer Center, Louisiana State University, Shreveport, LA 71103, USA
| | - Yan Li
- Department of Pathology and Pathobiology and Feist-Weiller Cancer Center, Louisiana State University, Shreveport, LA 71103, USA
| | - Mohammad Zahidul Islam
- Department of Pathology and Pathobiology and Feist-Weiller Cancer Center, Louisiana State University, Shreveport, LA 71103, USA
| | - Christina Notarianni
- Department of Neurosurgery, Louisiana State University, Shreveport, LA 71103, USA
| | - Hai Sun
- Department of Neurosurgery, Louisiana State University, Shreveport, LA 71103, USA
| | - Adriana Olar
- Department of Pathology and Laboratory Medicine and Neurosurgery, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC 29425, USA
| | - Gregory N Fuller
- Department of Pathology, The University of Texas MD Anderson Cancer Center, TX 77030, USA
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49
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Melatonin Modulates the Microenvironment of Glioblastoma Multiforme by Targeting Sirtuin 1. Nutrients 2019; 11:nu11061343. [PMID: 31207928 PMCID: PMC6627125 DOI: 10.3390/nu11061343] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 06/06/2019] [Accepted: 06/10/2019] [Indexed: 01/21/2023] Open
Abstract
Natural products have historically been regarded as an important resource of therapeutic agents. Resveratrol and melatonin have been shown to increase SIRT1 activity and stimulate deacetylation. Glioblastoma multiforme (GBM) is the deadliest of malignant types of tumor in the central nervous system (CNS) and their biological features make treatment difficult. In the glioma microenvironment, infiltrating immune cells has been shown to possess beneficial effects for tumor progression. We analyzed SIRT1, CCL2, VCAM-1 and ICAM-1 in human glioma cell lines by immunoblotting. The correlation between those markers and clinico-pathological grade of glioma patients were assessed by the Gene Expression Omnibus (GEO) datasets analysis. We also used monocyte-binding assay to study the effects of melatonin on monocyte adhesion to GBM. Importantly, overexpression of SIRT1 by genetic modification or treatment of melatonin significantly downregulated the adhesion molecular VCAM-1 and ICAM-1 expression in GBM. CCL2-mediated monocyte adhesion and expression of VCAM-1 and ICAM-1 were regulated through SIRT1 signaling. SIRT1 is an important modulator of monocytes interaction with GBM that gives the possibility of improved therapies for GBM. Hence, this study provides a novel treatment strategy for the understanding of microenvironment changes in tumor progression.
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50
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Lo Dico A, Valtorta S, Ottobrini L, Moresco RM. Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells. Front Oncol 2019; 9:463. [PMID: 31214505 PMCID: PMC6554426 DOI: 10.3389/fonc.2019.00463] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 05/15/2019] [Indexed: 01/29/2023] Open
Abstract
Hypoxia is a key driver of tumor adaptation promoting tumor progression and resistance to therapy. Hypoxia related pathways might represent attractive targets for the treatment of Glioblastoma Multiforme (GBM), that up to date is characterized by a poor prognosis. Primary aim of this study was to investigate the role of hypoxia and hypoxia-related modifications in the effect of temozolomide (TMZ) given alone or in association with the antidiabetic agent Metformin (MET) or the PI3K/mTOR blocker, BEZ235. The study was conducted in the TMZ responsive U251 and resistant T98 GBM cells. Our results showed that during hypoxia, TMZ plus MET reduced viability of U251 cells affecting also CD133 and CD90 expressing cells. This effect was associated with a reduction of HIF-1α activity, VEGF release and AKT activation. In T98 TMZ-resistant cells, TMZ plus MET exerted similar effects on HIF-1α. However, in this cell line, TMZ plus MET failed to reduce CD133 positive cells and AKT phosphorylation. Nevertheless, the administration of the dual PI3K/mTOR inhibitor BEZ235 potentiated the effect of TMZ plus MET on cell viability, inducing a pro-apoptotic phenotype during hypoxic condition also in T98 cells, suggesting the block of the PI3K/AKT/mTOR pathway as a complementary target to further overcome GBM resistance during hypoxia. In conclusion, we proposed TMZ plus MET as suitable treatment to revert TMZ-resistance also during hypoxia, an effect potentiated by the inhibition of PI3K/mTOR axis.
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Affiliation(s)
- Alessia Lo Dico
- Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.,Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, Italy
| | - Silvia Valtorta
- Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, Italy.,Tecnomed Foundation, Medicine and Surgery Department, University of Milano- Bicocca, Monza, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luisa Ottobrini
- Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.,Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, Italy
| | - Rosa Maria Moresco
- Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, Italy.,Tecnomed Foundation, Medicine and Surgery Department, University of Milano- Bicocca, Monza, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
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