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Sharma R, Yadav J, Bhat SA, Musayev A, Myrzagulova S, Sharma D, Padha N, Saini M, Tuli HS, Singh T. Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research. Mol Neurobiol 2025; 62:6423-6466. [PMID: 39804528 DOI: 10.1007/s12035-024-04680-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 12/20/2024] [Indexed: 03/29/2025]
Abstract
This review explores the current understanding and recent advancements in neuroblastoma, one of the most common extracranial solid pediatric cancers, accounting for ~ 15% of childhood cancer-related mortality. The hallmarks of NBL, including angiogenesis, metastasis, apoptosis resistance, cell cycle dysregulation, drug resistance, and responses to hypoxia and ROS, underscore its complex biology. The tumor microenvironment's significance in disease progression is acknowledged in this study, along with the pivotal role of cancer stem cells in sustaining tumor growth and heterogeneity. A number of molecular signatures are being studied in order to better understand the disease, with many of them serving as targets for the development of new therapeutics. This includes inhibitor therapies for NBL patients, which notably concentrate on ALK signaling, MDM2, PI3K/Akt/mTOR, Wnt, and RAS-MAPK pathways, along with regulators of epigenetic mechanisms. Additionally, this study offers an extensive understanding of the molecular therapies used, such as monoclonal antibodies and CAR-T therapy, focused on both preclinical and clinical studies. Radiation therapy's evolving role and the promise of stem cell transplantation-mediated interventions underscore the dynamic landscape of NBL treatment. This study has also emphasized the recent progress in the field of diagnosis, encompassing the adoption of artificial intelligence and liquid biopsy as a non-intrusive approach for early detection and ongoing monitoring of NBL. Furthermore, the integration of innovative treatment approaches such as CRISPR-Cas9, and cancer stem cell therapy has also been emphasized in this review.
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Affiliation(s)
- Rishabh Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Jaya Yadav
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Sajad Ahmad Bhat
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
- Department of Biochemistry, NIMS University, Rajasthan, Jaipur, 303121, India
| | - Abdugani Musayev
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
| | | | - Deepika Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
| | - Nipun Padha
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Department of Zoology, Cluster University of Jammu, Jammu, 180001, India
| | - Manju Saini
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, 133207, India
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India.
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, (INMAS-DRDO), New Delhi, Delhi, 110054, India.
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Petrosiute A, Zakšauskas A, Lučiūnaitė A, Petrauskas V, Baranauskienė L, Kvietkauskaitė A, Ščerbavičienė A, Tamošiūnaitė M, Musvicaitė J, Jankūnaitė A, Žvinys G, Stančaitis L, Čapkauskaitė E, Mickevičiūtė A, Juozapaitienė V, Dudutienė V, Zubrienė A, Grincevičienė Š, Bukelskienė V, Schiöth HB, Matulienė J, Matulis D. Carbonic anhydrase IX inhibition as a path to treat neuroblastoma. Br J Pharmacol 2025; 182:1610-1629. [PMID: 39776083 DOI: 10.1111/bph.17429] [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: 06/03/2024] [Revised: 11/12/2024] [Accepted: 11/23/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND AND PURPOSE Tumour hypoxia frequently presents a major challenge in the treatment of neuroblastoma (NBL). The neuroblastoma cells produce carbonic anhydrase IX (CA IX), an enzyme crucial for the survival of cancer cells in low-oxygen environments. EXPERIMENTAL APPROACH We designed and synthesised a novel high-affinity inhibitor of CA IX. The highest to-date. The affinities were determined for all human catalytically active CA isozymes showing significant selectivity for CA IX over other isozymes. The inhibitor effect on neuroblastoma cancer cell growth was determined in vitro and in vivo via a mice xenograft model. KEY RESULTS The novel designed inhibitor effectively mitigated the acidification induced by CA IX and reduced spheroid growth under hypoxic conditions in the SK-N-AS cell line. It also diminished the secretion of pro-tumour chemokines IL-8 (CXCL2) and CCL2. When we combined this novel CA IX inhibitor with a compound that inhibits the chemokine receptor CCR2 protein activity, we observed a reduction in mouse tumour growth. The combined treatment also prompted tumours to exhibit adaptive resistance by producing higher levels of vascular endothelial growth factor receptors (VEGFR) and other compensatory signals. CONCLUSIONS AND IMPLICATIONS This research underscores the pivotal role of CA IX in cancer and the potential of a novel CA IX inhibitor-based combination intervention therapy for neuroblastoma treatment.
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Affiliation(s)
- Agne Petrosiute
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Audrius Zakšauskas
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Asta Lučiūnaitė
- Department of Immunology, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Vytautas Petrauskas
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Lina Baranauskienė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Agnė Kvietkauskaitė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Alvilė Ščerbavičienė
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Marta Tamošiūnaitė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Justina Musvicaitė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Alberta Jankūnaitė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Gediminas Žvinys
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Laimonas Stančaitis
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Edita Čapkauskaitė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Aurelija Mickevičiūtė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Vaida Juozapaitienė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Virginija Dudutienė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Asta Zubrienė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Švitrigailė Grincevičienė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Virginija Bukelskienė
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Helgi B Schiöth
- Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Jurgita Matulienė
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Daumantas Matulis
- Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
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Otero JG, Belmonte-Beitia J, Jiménez-Sánchez J. Exploring neuroblastoma's cellular microenvironment: A novel approach using cellular automata to model Celyvir treatment. Comput Biol Med 2025; 188:109782. [PMID: 39946782 DOI: 10.1016/j.compbiomed.2025.109782] [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: 10/15/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 03/05/2025]
Abstract
Neuroblastoma is a significant health concern in children, as it is one of the most common types of cancer among this age group and is associated with poor survival rates. Currently, there are no effective therapies that significantly improve outcomes for these patients. This study explores the efficacy of Celyvir - an advanced therapy comprising mesenchymal stem cells (MSCs) carrying the oncolytic virus ICOVIR 5 - against neuroblastoma, by means of an individual-based model. A probabilistic cellular automaton was developed to implement the dynamic interactions between neuroblastoma cells, T lymphocytes, and the therapeutic agent Celyvir. The model examines various sizes, shapes, and positions of the tumour within a lattice, along with different infection probabilities associated with the action of Celyvir and various treatment schedules. This analysis identifies the most influential infection probabilities according to the cellular automaton model, and demonstrates that different treatment regimens can effectively eradicate the tumour, in contrast to standard clinical approaches. Additionally, Kaplan-Meier curves have been generated to assess different treatment schedules under specific tumour scenarios, highlighting the importance of precise treatment scheduling to optimise therapeutic outcomes. This study provides insights into the potential of Celyvir in neuroblastoma treatment, emphasising the need to understand tumour dynamics and strategically implement treatment schemes to improve clinical outcomes.
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Affiliation(s)
- José García Otero
- Mathematical Oncology Laboratory (MOLAB), University Castilla-La Mancha, Avda. Camilo José Cela s/n, Ciudad Real, 13071, Castilla-La Mancha, Spain.
| | - Juan Belmonte-Beitia
- Mathematical Oncology Laboratory (MOLAB), University Castilla-La Mancha, Avda. Camilo José Cela s/n, Ciudad Real, 13071, Castilla-La Mancha, Spain.
| | - Juan Jiménez-Sánchez
- Mathematical Oncology Laboratory (MOLAB), University Castilla-La Mancha, Avda. Camilo José Cela s/n, Ciudad Real, 13071, Castilla-La Mancha, Spain; Dipartimento di Scienze Matematiche Giuseppe Luigi Lagrange, Politecnico di Torino, Corso Duca degli Abruzzi, 24, 10129, Turin, Italy.
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Jung EM, Heck JE, Spector LG. The relative contributions of genetic and non-genetic factors to the risk of neuroblastoma. Pediatr Investig 2025; 9:82-93. [PMID: 40241886 PMCID: PMC11998183 DOI: 10.1002/ped4.12455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 09/02/2024] [Indexed: 04/18/2025] Open
Abstract
Previous literature has well-established genetic factors as being associated with neuroblastoma (NB). About 1%-2% of NB cases are familial, with 85% of these cases predisposed to mutations in the PHOX2B and ALK genes. The genetic basis of sporadic NB has been studied through genome-wide association studies and next-generation sequencing approaches. Particularly, germline variants, as well as copy number variations, confer increased risks of NB, often with effect estimates ≥1.5, underscoring the strong genetic contributions to NB. However, the strength of the association varied in non-genetic factors. Some risk factors, such as birth defects, maternal illicit drug use, and early infections, had relatively stronger associations (effect estimates ≥1.5 or ≤0.67), while some other factors remain inconclusive. This suggests that certain non-genetic factors may play a more prominent role in NB risk, while further research is needed to clarify the impact of others. We synthesized and critically evaluated existing literature on the risk factors of NB to provide an overview, analyze the current state of knowledge, and outline a research path to address the relative contributions of genetic and non-genetic factors in NB. Future epidemiologic studies should incorporate novel methods for measuring genetic and non-genetic factors to comprehensively assess the full extent of factors contributing to NB. Furthermore, the utilization of dried blood spots holds promise to overcome technical and recruitment challenges for future studies. These strategies will contribute to a more holistic understanding of NB etiology and potentially lead to improved prevention strategies.
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Affiliation(s)
- Eun Mi Jung
- Department of PediatricsDivision of Epidemiology and Clinical Research, University of MinnesotaMinneapolisMinnesotaUSA
| | - Julia E. Heck
- College of Health and Public ServiceUniversity of North TexasDentonTexasUSA
| | - Logan G. Spector
- Department of PediatricsDivision of Epidemiology and Clinical Research, University of MinnesotaMinneapolisMinnesotaUSA
- Masonic Cancer CenterUniversity of MinnesotaMinneapolisMinnesotaUSA
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5
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Ghasempour A, Mohseni R, Sharif PM, Hamidieh AA. Natural killer cell-based therapies in neuroblastoma. Cell Immunol 2025; 407:104898. [PMID: 39631142 DOI: 10.1016/j.cellimm.2024.104898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/21/2024] [Accepted: 11/23/2024] [Indexed: 12/07/2024]
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood forming around 15 % of all pediatric tumors. Despite advances in the treatment of NB, high-risk patients still face a grave prognosis. Adoptive cell therapies based on NK cells are becoming an assistive treatment for such cases. Moreover, there is also evidence that NKT-based therapies have promising results in the management of NB. Lower complications in comparison with adoptive T cell therapies, various cell sources, and miscellaneous tumor recognition mechanisms are some of the advantages of NK- and NKT-based therapies. This review is dedicated to searching for recent advances in this field.
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Affiliation(s)
- Abtin Ghasempour
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rashin Mohseni
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Pouya Mahdavi Sharif
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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6
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Rahimi S, Shirin F, Moassesfar M, Zafari H, Bahmaie N, Baghebani K, Bidmeshki Y, Sajjadi Manesh SM, Rasoulzadeh Darabad K, Bahmaie M, Nouri E, Kilic A, Ansarin M, Özışık P, Simsek E, Ozensoy Guler O. Role of Hypoxia Induced by Medicinal Plants; A Revolutionary Era of Cellular and Molecular Herbal Medicine in Neuroblastoma Treatment. FRONT BIOSCI-LANDMRK 2024; 29:422. [PMID: 39735975 DOI: 10.31083/j.fbl2912422] [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: 07/13/2024] [Accepted: 07/19/2024] [Indexed: 12/31/2024]
Abstract
As one of the most common solid pediatric cancers, Neuroblastoma (NBL) accounts for 15% of all of the cancer-related mortalities in infants with increasing incidence all around the world. Despite current therapeutic approaches for NBL (radiotherapies, surgeries, and chemotherapies), these approaches could not be beneficial for all of patients with NBL due to their low effectiveness, and some severe side effects. These challenges lead basic medical scientists and clinical specialists toward an optimal medical interventions for clinical management of NBL. Regardingly, taking molecular and cellular immunopathophysiology involved in the hypoxic microenvironment of NBL into account, it can practically be a contributing approach in the development of "molecular medicine" for treatment of NBL. Interestingly, pivotal roles of "herbal medicine" in the hypoxic microenvironment of NBL have been extensively interrogated for treating a NBL, functionally being served as an anti-cancer agent via inducing a wide range of molecular and cellular signaling, like apoptosis, cell cycle arrest, and inhibiting angiogenesis. Hence, in this review study, the authors aim to summarize the anti-tumor effects of some medicinal plants and their phytoconstituents through molecular immunopathophysiological mechanisms involved in the hypoxic microenvironment of NBL. In addition, they try to open promising windows to immune gene-based therapies for NBL "precision medicine" through clinical advantages of herbal and molecular medicine. An interdisciplinary collaboration among translation and molecular medicine specialists, immunobiologists, herbal medicine specialists, and pediatric neuro-oncologists is highly recommended.
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Affiliation(s)
- Samin Rahimi
- Department of Genetics, Faculty of Natural Sciences, Tabriz University, 5166616471 Tabriz, Iran
| | - Fatemeh Shirin
- Department of Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, 1651153311 Tehran, Iran
| | - Mahdi Moassesfar
- Department of Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, 1651153311 Tehran, Iran
| | - Hossein Zafari
- Department of Chemical Engineering, Faculty of Chemical Engineering, Shahreza Branch, Islamic Azad University, 8648146411 Shahreza, Iran
| | - Nazila Bahmaie
- Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey
| | - Kimia Baghebani
- Department of Biology, College of Basic Sciences, Kermanshah Branch, Islamic Azad University, 6718997551 Kermanshah, Iran
- Now with Department of Biotechnology, College of Environmental and Bioresource Sciences, Jeonbuk National University, 54896 Jeonbuk, Republic of Korea
| | - Yasna Bidmeshki
- Department of Biology, College of Basic Sciences, Kermanshah Branch, Islamic Azad University, 6718997551 Kermanshah, Iran
| | - Seyede Masoumeh Sajjadi Manesh
- Department of Biomedical Engineering, College of Basic Sciences, Qom Branch, Islamic Azad University, 3716146611 Qom, Iran
| | | | - Massoud Bahmaie
- Department of Herbal Medicine, University of Poona, 411007 Poona, India
| | - Elham Nouri
- Clinical Diagnosis Laboratory, Shahid Beheshti University-affiliated Hospital, Zanjan University of Medical Sciences (ZUMS), 4513956111 Zanjan, Iran
- Department of Medical Laboratory Science, Faculty of Paramedicine, Zanjan University of Medical Sciences (ZUMS), 4513956111 Zanjan, Iran
| | - Ahmet Kilic
- Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey
| | - Melika Ansarin
- Department of Obstetrics and Gynecology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), 1449614535 Tehran, Iran
| | - Pınar Özışık
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Ankara Bilkent City Hospital, 06800 Ankara, Turkey
- Department of Brain and Nerve Surgery, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey
| | - Ender Simsek
- Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey
| | - Ozen Ozensoy Guler
- Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey
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Namusamba M, Wu Y, Yang J, Zhang Q, Wang C, Wang T, Wang B. BAP31 Promotes Angiogenesis via Galectin-3 Upregulation in Neuroblastoma. Int J Mol Sci 2024; 25:2946. [PMID: 38474195 PMCID: PMC10931962 DOI: 10.3390/ijms25052946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/05/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB.
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Affiliation(s)
- Mwichie Namusamba
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China
| | - Yufei Wu
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China
| | - Jiaying Yang
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China
| | - Qi Zhang
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China
| | - Changli Wang
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China
| | - Tianyi Wang
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China
| | - Bing Wang
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China
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Zhang W, Li X, Zeng J, Wen X, Zhang C, Zhang Y, He J, Yang L. Enhancing the sensitization of neuroblastoma to radiotherapy by the construction of a dual-channel parallel free radicals nanoamplifier. Mater Today Bio 2023; 23:100828. [PMID: 37822451 PMCID: PMC10562674 DOI: 10.1016/j.mtbio.2023.100828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/13/2023] [Accepted: 10/01/2023] [Indexed: 10/13/2023] Open
Abstract
Radiation therapy (RT) has emerged as one of the most promising anti-tumor strategies for neuroblastoma. Nevertheless, the special tumor microenvironment (TME), including hypoxic and GSH-overexpressed TME, often greatly restricts the RT outcome. In this study, we demonstrated a dual-channel parallel radicals nanoamplifier (ATO@PAE-PEG-AS1411/Fe3+). The nanoamplifier was shaped into a bilayer shell-core structure, in which atovaquone-loaded poly (β-amino esters)-poly (ethylene glycol) (ATO@PAE-PEG) served as the core while Fe3+-absorbed AS1411 aptamer (AS1411/Fe3+) served as the shell. Taking advantage of the targeting ability of AS1411, ATO@PAE-PEG-AS1411/Fe3+ specifically accumulated in tumor cells, and then released ATO as well as Fe3+ in response to the acidic TME. The released ATO dramatically inhibited the mitochondrial respiration of tumor cells, thus sparing vast amounts of oxygen for the generation of free radicals during RT process, which was the first free radicals-amplifying pathway Meanwhile, the released Fe3+ could consume the tumor-overexpressed GSH through the redox reaction, thus effectively preserving the generated free radicals in RT process, which was the second free radicals-amplifying pathway. Taken together, our study demonstrates a dual-channel parallel free radicals-amplifying RT strategy, and it is expected this work will promote the clinical application prospects of RT treatment against neuroblastoma.
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Affiliation(s)
- Wenxin Zhang
- Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
| | - Xiaodie Li
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
| | - Jialin Zeng
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
| | - Xin Wen
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Chao Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
| | - Yinan Zhang
- School of Chemical Science and Engineering, Tongji University, Shanghai, 200092, China
| | - Jian He
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Lihua Yang
- Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China
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Krawczyk E, Kitlińska J. Preclinical Models of Neuroblastoma-Current Status and Perspectives. Cancers (Basel) 2023; 15:3314. [PMID: 37444423 PMCID: PMC10340830 DOI: 10.3390/cancers15133314] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Preclinical in vitro and in vivo models remain indispensable tools in cancer research. These classic models, including two- and three-dimensional cell culture techniques and animal models, are crucial for basic and translational studies. However, each model has its own limitations and typically does not fully recapitulate the course of the human disease. Therefore, there is an urgent need for the development of novel, advanced systems that can allow for efficient evaluation of the mechanisms underlying cancer development and progression, more accurately reflect the disease pathophysiology and complexity, and effectively inform therapeutic decisions for patients. Preclinical models are especially important for rare cancers, such as neuroblastoma, where the availability of patient-derived specimens that could be used for potential therapy evaluation and screening is limited. Neuroblastoma modeling is further complicated by the disease heterogeneity. In this review, we present the current status of preclinical models for neuroblastoma research, discuss their development and characteristics emphasizing strengths and limitations, and describe the necessity of the development of novel, more advanced and clinically relevant approaches.
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Affiliation(s)
- Ewa Krawczyk
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Joanna Kitlińska
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
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10
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Iwanicki I, Wu LL, Flores-Guzman F, Sundland R, Viza-Gomes P, Nordgren R, Centner CS, Kandel JJ, Applebaum MA, Bader KB, Hernandez SL. Histotripsy induces apoptosis and reduces hypoxia in a neuroblastoma xenograft model. Int J Hyperthermia 2023; 40:2222941. [PMID: 37344380 DOI: 10.1080/02656736.2023.2222941] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/09/2023] [Accepted: 06/05/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Neuroblastoma (NB) is the most common extracranial solid tumor of childhood, and high-risk disease is resistant to intensive treatment. Histotripsy is a focused ultrasound therapy under development for tissue ablation via bubble activity. The goal of this study was to assess outcomes of histotripsy ablation in a xenograft model of high-risk NB. METHODS Female NCr nude mice received NGP-luciferase cells intrarenally. Under ultrasound image guidance, histotripsy pulses were applied over a distance of 4-6 mm within the tumors. Bioluminescence indicative of tumor viability was quantified before, immediately after, and 24 h after histotripsy exposure. Tumors were immunostained to assess apoptosis (TUNEL), endothelium (endomucin), pericytes (αSMA), hypoxia (pimonidazole), vascular endothelial growth factor A (VEGFA), and platelet-derived growth factor-B (PDGF-B). The apoptotic cytokine TNFα and its downstream effector cleaved caspase-3 (c-casp-3) were assessed with SDS-PAGE. RESULTS Histotripsy induced a 50% reduction in bioluminescence compared to untreated controls, with an absence of nuclei in the treatment core surrounded by a dense rim of TUNEL-positive cells. Tumor regions not targeted by histotripsy also showed an increase in TUNEL staining density. Increased apoptosis in histotripsy samples was consistent with increases in TNFα and c-casp-3 relative to controls. Treated tumors exhibited a decrease in hypoxia, VEGF, PDGF-B, and pericyte coverage of vasculature compared to control samples. Further, increases in vasodilation were found in histotripsy-treated specimens. CONCLUSIONS In addition to ablative effects, histotripsy was found to drive tumor apoptosis through intrinsic pathways, altering blood vessel architecture, and reducing hypoxia.
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Affiliation(s)
- Isabella Iwanicki
- Department of Surgery, Section of Pediatric Surgery, The University of Chicago, Chicago, IL, USA
| | - Lydia L Wu
- Department of Surgery, Section of Pediatric Surgery, The University of Chicago, Chicago, IL, USA
| | - Fernando Flores-Guzman
- Department of Surgery, Section of Pediatric Surgery, The University of Chicago, Chicago, IL, USA
| | - Rachael Sundland
- Department of Surgery, Section of Pediatric Surgery, The University of Chicago, Chicago, IL, USA
| | - Paula Viza-Gomes
- Department of Surgery, Section of Pediatric Surgery, The University of Chicago, Chicago, IL, USA
| | - Rachel Nordgren
- Department of Public Health Sciences, The University of Chicago, Chicago, IL
| | | | - Jessica J Kandel
- Department of Surgery, Section of Pediatric Surgery, The University of Chicago, Chicago, IL, USA
| | - Mark A Applebaum
- Department of Pediatrics, Section of Hematology/Oncology, The University of Chicago, Chicago, IL
| | - Kenneth B Bader
- Department of Radiology, The University of Chicago, Chicago, IL
| | - Sonia L Hernandez
- Department of Surgery, Section of Pediatric Surgery, The University of Chicago, Chicago, IL, USA
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11
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Hains AE, Uppal S, Cao JZ, Salwen HR, Applebaum MA, Cohn SL, Godley LA. MYCN and HIF-1 directly regulate TET1 expression to control 5-hmC gains and enhance neuroblastoma cell migration in hypoxia. Epigenetics 2022; 17:2056-2074. [PMID: 35942521 PMCID: PMC9665154 DOI: 10.1080/15592294.2022.2106078] [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: 03/19/2022] [Accepted: 07/14/2022] [Indexed: 11/03/2022] Open
Abstract
Ten-Eleven-Translocation 5-methylcytosine dioxygenases 1-3 (TET1-3) convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), using oxygen as a co-substrate. Contrary to expectations, hypoxia induces 5-hmC gains in MYCN-amplified neuroblastoma (NB) cells via upregulation of TET1. Here, we show that MYCN directly controls TET1 expression in normoxia, and in hypoxia, HIF-1 augments TET1 expression and TET1 protein stability. Through gene-editing, we identify two MYCN and HIF-1 binding sites within TET1 that regulate gene expression. Bioinformatic analyses of 5-hmC distribution and RNA-sequencing data from hypoxic cells implicate hypoxia-regulated genes important for cell migration, including CXCR4. We show that hypoxic cells lacking the two MYCN/HIF-1 binding sites within TET1 migrate slower than controls. Treatment of MYCN-amplified NB cells with a CXCR4 antagonist results in slower migration under hypoxic conditions, suggesting that inclusion of a CXCR4 antagonist into NB treatment regimens could be beneficial for children with MYCN-amplified NBs.
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Affiliation(s)
- Anastasia E. Hains
- Section of Hematology/Oncology, Department of Medicine, and the University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA
| | - Sakshi Uppal
- Section of Hematology/Oncology, Department of Medicine, and the University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA
| | - John Z. Cao
- Section of Hematology/Oncology, Department of Medicine, and the University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA
| | - Helen R. Salwen
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | - Mark A. Applebaum
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | - Susan L. Cohn
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | - Lucy A. Godley
- Section of Hematology/Oncology, Department of Medicine, and the University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA
- Department of Human Genetics, The University of Chicago, Chicago, IL, USA
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12
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Fiz F, Bottoni G, Bini F, Cerroni F, Marinozzi F, Conte M, Treglia G, Morana G, Sorrentino S, Garaventa A, Siri G, Piccardo A. Prognostic value of texture analysis of the primary tumour in high-risk neuroblastoma: An 18 F-DOPA PET study. Pediatr Blood Cancer 2022; 69:e29910. [PMID: 35920594 DOI: 10.1002/pbc.29910] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/22/2022] [Accepted: 07/14/2022] [Indexed: 01/01/2023]
Abstract
PURPOSE To evaluate the prognostic value of texture analysis of the primary tumour with 18 fluorine-dihydroxyphenylalanine positron emission tomography/X-ray computed tomography (18 F-DOPA PET/CT) in patients affected by high-risk neuroblastoma (HR-NBL). METHODS We retrospectively analysed 18 patients with HR-NBL, which had been prospectively enrolled in the course of a previous trial investigating the diagnostic role of 18 F-DOPA PET/CT at the time of the first onset. Texture analysis of the primary tumour was carried out on the PET images using LifeX. Conventional indices, histogram parameters, grey level co-occurrence (GLCM), run-length (GLRLM), neighbouring difference (NGLDM) and zone-length (GLZLM) matrices parameter were extracted; their values were compared with the overall metastatic load, expressed by means of whole-body metabolic burden (WBMB) score and the progression-free/overall survival (PFS and OS). RESULTS There was a direct correlation between WBMB and radiomics parameter describing uptake intensity (SUVmean : p = .004) and voxel heterogeneity (entropy: p = .026; GLCM_Contrast: p = .001). Conversely, texture indices of homogeneity showed an inverse correlation with WBMB (energy: p = .026; GLCM_Homogeneity: p = .006). On the multivariate model, WBMB (p < .01) and the first standardised uptake value (SUV) quartile (p < .001) predicted PFS; OS was predicted by WBMB and the N-myc proto-oncogene protein (MYCN) amplification (p < .05) for both. CONCLUSIONS Textural parameters describing heterogeneity and metabolic intensity of the primary HR-NBL are closely associated with its overall metastatic burden. In turn, the whole-body tumour load appears to be one of the most relevant predictors of progression-free and overall survival.
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Affiliation(s)
- Francesco Fiz
- Department of Nuclear Medicine, E.O. 'Ospedali Galliera', Genoa, Italy
| | - Gianluca Bottoni
- Department of Nuclear Medicine, E.O. 'Ospedali Galliera', Genoa, Italy
| | - Fabiano Bini
- Department of Mechanical and Aerospace Engineering, 'Sapienza' University of Rome, Rome, Italy
| | - Francesca Cerroni
- Department of Mechanical and Aerospace Engineering, 'Sapienza' University of Rome, Rome, Italy
| | - Franco Marinozzi
- Department of Mechanical and Aerospace Engineering, 'Sapienza' University of Rome, Rome, Italy
| | - Massimo Conte
- Oncology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Giorgio Treglia
- Clinic of Nuclear Medicine, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.,Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland.,Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Giovanni Morana
- Pediatric Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Department of Neurosciences, University of Turin, Turin, Italy
| | | | | | - Giacomo Siri
- Scientific Directorate, E.O. 'Ospedali Galliera', Genoa, Italy
| | - Arnoldo Piccardo
- Department of Nuclear Medicine, E.O. 'Ospedali Galliera', Genoa, Italy
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13
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Zhuo Z, Lin L, Miao L, Li M, He J. Advances in liquid biopsy in neuroblastoma. FUNDAMENTAL RESEARCH 2022; 2:903-917. [PMID: 38933377 PMCID: PMC11197818 DOI: 10.1016/j.fmre.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/18/2022] [Accepted: 08/09/2022] [Indexed: 10/15/2022] Open
Abstract
Even with intensive treatment of high-risk neuroblastoma (NB) patients, half of high-risk NB patients still relapse. New therapies targeting the biological characteristics of NB have important clinical value for the personalized treatment of NB. However, the current biological markers for NB are mainly analyzed by tissue biopsy. In recent years, circulating biomarkers of NB based on liquid biopsy have attracted more and more attention. This review summarizes the analytes and methods for liquid biopsy of NB. We focus on the application of liquid biopsy in the diagnosis, prognosis assessment, and monitoring of NB. Finally, we discuss the prospects and challenges of liquid biopsy in NB.
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Affiliation(s)
- Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
- Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Meng Li
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
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14
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Gomez RL, Ibragimova S, Ramachandran R, Philpott A, Ali FR. Tumoral heterogeneity in neuroblastoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188805. [PMID: 36162542 DOI: 10.1016/j.bbcan.2022.188805] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/28/2022] [Accepted: 09/17/2022] [Indexed: 10/31/2022]
Abstract
Neuroblastoma is a solid, neuroendocrine tumor with divergent clinical behavior ranging from asymptomatic to fatal. The diverse clinical presentations of neuroblastoma are directly linked to the high intra- and inter-tumoral heterogeneity it presents. This heterogeneity is strongly associated with therapeutic resistance and continuous relapses, often leading to fatal outcomes. The development of successful risk assessment and tailored treatment strategies lies in evaluating the extent of heterogeneity via the accurate genetic and epigenetic profiling of distinct cell subpopulations present in the tumor. Recent studies have focused on understanding the molecular mechanisms that drive tumoral heterogeneity in pursuing better therapeutic and diagnostic approaches. This review describes the cellular, genetic, and epigenetic aspects of neuroblastoma heterogeneity. In addition, we summarize the recent findings on three crucial factors that can lead to heterogeneity in solid tumors: the inherent diversity of the progenitor cells, the presence of cancer stem cells, and the influence of the tumor microenvironment.
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Affiliation(s)
- Roshna Lawrence Gomez
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Shakhzada Ibragimova
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Revathy Ramachandran
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Anna Philpott
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Center, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Fahad R Ali
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates.
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15
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Lin L, Miao L, Lin H, Cheng J, Li M, Zhuo Z, He J. Targeting RAS in neuroblastoma: Is it possible? Pharmacol Ther 2022; 236:108054. [PMID: 34915055 DOI: 10.1016/j.pharmthera.2021.108054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 02/07/2023]
Abstract
Neuroblastoma is a common solid tumor in children and a leading cause of cancer death in children. Neuroblastoma exhibits genetic, morphological, and clinical heterogeneity that limits the efficacy of current monotherapies. With further research on neuroblastoma, the pathogenesis of neuroblastoma is found to be complex, and more and more treatment therapies are needed. The importance of personalized therapy is growing. Currently, various molecular features, including RAS mutations, are being used as targets for the development of new therapies for patients with neuroblastoma. A recent study found that RAS mutations are frequently present in recurrent neuroblastoma. RAS mutations have been shown to activate the MAPK pathway and play an important role in neuroblastoma. Treating RAS mutated neuroblastoma is a difficult challenge, but many preclinical studies have yielded effective results. At the same time, many of the therapies used to treat RAS mutated tumors also have good reference values for treating RAS mutated neuroblastoma. The success of KRAS-G12C inhibitors has greatly stimulated confidence in the direct suppression of RAS. This review describes the biological role of RAS and the frequency of RAS mutations in neuroblastoma. This paper focuses on the strategies, preclinical, and clinical progress of targeting carcinogenic RAS in neuroblastoma, and proposes possible prospects and challenges in the future.
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Affiliation(s)
- Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Huiran Lin
- Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Jiwen Cheng
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China
| | - Meng Li
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China; Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China.
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16
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Ning L, Shim J, Tomov ML, Liu R, Mehta R, Mingee A, Hwang B, Jin L, Mantalaris A, Xu C, Mahmoudi M, Goldsmith KC, Serpooshan V. A 3D Bioprinted in vitro Model of Neuroblastoma Recapitulates Dynamic Tumor-Endothelial Cell Interactions Contributing to Solid Tumor Aggressive Behavior. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200244. [PMID: 35644929 PMCID: PMC9376856 DOI: 10.1002/advs.202200244] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 05/02/2022] [Indexed: 05/04/2023]
Abstract
Neuroblastoma (NB) is the most common extracranial tumor in children resulting in substantial morbidity and mortality. A deeper understanding of the NB tumor microenvironment (TME) remains an area of active research but there is a lack of reliable and biomimetic experimental models. This study utilizes a 3D bioprinting approach, in combination with NB spheroids, to create an in vitro vascular model of NB for exploring the tumor function within an endothelialized microenvironment. A gelatin methacryloyl (gelMA) bioink is used to create multi-channel cubic tumor analogues with high printing fidelity and mechanical tunability. Human-derived NB spheroids and human umbilical vein endothelial cells (HUVECs) are incorporated into the biomanufactured gelMA and cocultured under static versus dynamic conditions, demonstrating high levels of survival and growth. Quantification of NB-EC integration and tumor cell migration suggested an increased aggressive behavior of NB when cultured in bioprinted endothelialized models, when cocultured with HUVECs, and also as a result of dynamic culture. This model also allowed for the assessment of metabolic, cytokine, and gene expression profiles of NB spheroids under varying TME conditions. These results establish a high throughput research enabling platform to study the TME-mediated cellular-molecular mechanisms of tumor growth, aggression, and response to therapy.
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Affiliation(s)
- Liqun Ning
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
| | - Jenny Shim
- Department of PediatricsEmory University School of MedicineAtlantaGA30322USA
- Aflac Cancer and Blood Disorders CenterChildren's Healthcare of AtlantaAtlantaGA30342USA
- Children's Healthcare of AtlantaAtlantaGA30322USA
| | - Martin L. Tomov
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
| | - Rui Liu
- Department of PediatricsEmory University School of MedicineAtlantaGA30322USA
| | - Riya Mehta
- Department of BiologyEmory UniversityAtlantaGA30322USA
| | - Andrew Mingee
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
| | - Boeun Hwang
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
| | - Linqi Jin
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
| | - Athanasios Mantalaris
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
| | - Chunhui Xu
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
- Department of PediatricsEmory University School of MedicineAtlantaGA30322USA
| | - Morteza Mahmoudi
- Department of Radiology and Precision Health ProgramMichigan State UniversityEast LansingMI48824USA
| | - Kelly C. Goldsmith
- Department of PediatricsEmory University School of MedicineAtlantaGA30322USA
- Aflac Cancer and Blood Disorders CenterChildren's Healthcare of AtlantaAtlantaGA30342USA
- Children's Healthcare of AtlantaAtlantaGA30322USA
| | - Vahid Serpooshan
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGA30332USA
- Department of PediatricsEmory University School of MedicineAtlantaGA30322USA
- Children's Healthcare of AtlantaAtlantaGA30322USA
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17
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Guo M, Li D, Feng Y, Li M, Yang B. Adipose-derived stem cell-derived extracellular vesicles inhibit neuroblastoma growth by regulating GABBR1 activity through LINC00622-mediated transcription factor AR. J Leukoc Biol 2022; 111:19-32. [PMID: 34448502 DOI: 10.1002/jlb.1mia0321-164r] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma (NB) is a huge threat to children's health. Adipose-derived stem cells-derived extracellular vesicles (ADSC-Evs) can regulate tumor progression. This study aimed to identify the role of ADSC-Evs in NB. Following ADSC-Ev isolation and identification, PKH26-labeled ADSC-Evs were cocultured with NB cells to observe the internalization of ADSC-Evs. ADSC-Ev effects on NB cell proliferation, invasion, and migration were assessed. The regulatory molecules related to NB development were predicted. The expressions of and relations among LINC00622, transcriptional factor androgen receptor (AR), and gamma-aminobutyric acid B-type receptor 1 (GABRR1) were detected and verified. LINC00622 was inhibited in ADSCs to evaluate ADSC-Ev effects on NB cells. Xenograft tumor experiment in nude mice was further performed to evaluate the effects of ADSC-Evs-carried LINC00622 on NB in vivo. ADSC-Evs inhibited NB cell proliferation, invasion, and migration. ADSC-Evs increased GABBR1 expression in NB cells. ADSC-Evs-carried LINC00622 mediated AR to promote GABBR1 expression. Silencing LINC00622 in ADSCs weakened the inhibition of ADSC-Evs on NB cell malignant behaviors. ADSC-Evs reduced tumor growth in nude mice, which was restored after inhibiting LINC00622 expression in ADSCs. We highlighted that ADSC-Evs carried LINC00622 into NB cells to inhibit transcription factor AR and promote GABBR1 expression, thus inhibiting NB cell growth.
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Affiliation(s)
- Mengguo Guo
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, China
| | - Dongpeng Li
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, China
| | - Yawen Feng
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, China
| | - Mu Li
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, China
| | - Bo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, China
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18
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Brum PO, Viola GD, Saibro-Girardi C, Tiefensee-Ribeiro C, Brum MO, Gasparotto J, Krolow R, Moreira JCF, Gelain DP. Hypoxia-Inducible Factor-1α (HIF-1α) Inhibition Impairs Retinoic Acid-Induced Differentiation in SH-SY5Y Neuroblastoma Cells, Leading to Reduced Neurite Length and Diminished Gene Expression Related to Cell Differentiation. Neurochem Res 2021; 47:409-421. [PMID: 34557995 PMCID: PMC8827409 DOI: 10.1007/s11064-021-03454-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 11/30/2022]
Abstract
Neuroblastoma is the most common extracranial solid tumour in childhood, originated from cells of the neural crest during the development of the Sympathetic Nervous System. Retinoids are vitamin-A derived differentiating agents utilised to avoid disease resurgence in high-risk neuroblastoma treatment. Several studies indicate that hypoxia—a common feature of the tumoural environment—is a key player in cell differentiation and proliferation. Hypoxia leads to the accumulation of the hypoxia-inducible factor-1α (HIF-1α). This work aims to investigate the effects of the selective inhibition of HIF-1α on the differentiation induced by retinoic acid in human neuroblastoma cells from the SH-SY5Y lineage to clarify its role in cell differentiation. Our results indicate that HIF-1α inhibition impairs RA-induced differentiation by reducing neuron-like phenotype and diminished immunolabeling and expression of differentiation markers.
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Affiliation(s)
- Pedro Ozorio Brum
- Departamento de Bioquímica, Centro de Estudos em Estresse Oxidativo, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. .,Max F. Perutz Labs, University of Vienna, Dr Bohr-Gasse 9, Room 4.510, 1030, Vienna, Austria.
| | - Guilherme Danielski Viola
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Carolina Saibro-Girardi
- Departamento de Bioquímica, Centro de Estudos em Estresse Oxidativo, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Camila Tiefensee-Ribeiro
- Departamento de Bioquímica, Centro de Estudos em Estresse Oxidativo, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | | | - Juciano Gasparotto
- Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, MG, Brazil
| | - Rachel Krolow
- Laboratório de Programação Neurobiológica do Comportamento Alimentar, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - José Cláudio Fonseca Moreira
- Departamento de Bioquímica, Centro de Estudos em Estresse Oxidativo, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Daniel Pens Gelain
- Departamento de Bioquímica, Centro de Estudos em Estresse Oxidativo, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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19
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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20
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Hypoxia in Lung Cancer Management: A Translational Approach. Cancers (Basel) 2021; 13:cancers13143421. [PMID: 34298636 PMCID: PMC8307602 DOI: 10.3390/cancers13143421] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/30/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hypoxia is a common feature of lung cancers. Nonetheless, no guidelines have been established to integrate hypoxia-associated biomarkers in patient management. Here, we discuss the current knowledge and provide translational novel considerations regarding its clinical detection and targeting to improve the outcome of patients with non-small-cell lung carcinoma of all stages. Abstract Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management.
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21
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Uva P, Bosco MC, Eva A, Conte M, Garaventa A, Amoroso L, Cangelosi D. Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma. Cancers (Basel) 2021; 13:cancers13112809. [PMID: 34199959 PMCID: PMC8200206 DOI: 10.3390/cancers13112809] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/17/2021] [Accepted: 06/01/2021] [Indexed: 11/16/2022] Open
Abstract
Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis.
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Affiliation(s)
- Paolo Uva
- Clinical Bioinformatics Unit, Scientific Direction, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy;
- Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy; (M.C.B.); (A.E.)
| | - Alessandra Eva
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy; (M.C.B.); (A.E.)
| | - Massimo Conte
- UOC Oncologia, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy; (M.C.); (A.G.); (L.A.)
| | - Alberto Garaventa
- UOC Oncologia, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy; (M.C.); (A.G.); (L.A.)
| | - Loredana Amoroso
- UOC Oncologia, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy; (M.C.); (A.G.); (L.A.)
| | - Davide Cangelosi
- Clinical Bioinformatics Unit, Scientific Direction, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy;
- Correspondence:
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22
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Guo S, Meng L, Liu H, Yuan L, Zhao N, Ni J, Zhang Y, Ben J, Li YP, Ma J. Trio cooperates with Myh9 to regulate neural crest-derived craniofacial development. Am J Cancer Res 2021; 11:4316-4334. [PMID: 33754063 PMCID: PMC7977452 DOI: 10.7150/thno.51745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 02/07/2021] [Indexed: 02/06/2023] Open
Abstract
Trio is a unique member of the Rho-GEF family that has three catalytic domains and is vital for various cellular processes in both physiological and developmental settings. TRIO mutations in humans are involved in craniofacial abnormalities, in which patients present with mandibular retrusion. However, little is known about the molecular mechanisms of Trio in neural crest cell (NCC)-derived craniofacial development, and there is still a lack of direct evidence to assign a functional role to Trio in NCC-induced craniofacial abnormalities. Methods: In vivo, we used zebrafish and NCC-specific knockout mouse models to investigate the phenotype and dynamics of NCC development in Trio morphants. In vitro, iTRAQ, GST pull-down assays, and proximity ligation assay (PLA) were used to explore the role of Trio and its potential downstream mediators in NCC migration and differentiation. Results: In zebrafish and mouse models, disruption of Trio elicited a migration deficit and impaired the differentiation of NCC derivatives, leading to craniofacial growth deficiency and mandibular retrusion. Moreover, Trio positively regulated Myh9 expression and directly interacted with Myh9 to coregulate downstream cellular signaling in NCCs. We further demonstrated that disruption of Trio or Myh9 inhibited Rac1 and Cdc42 activity, specifically affecting the nuclear export of β-catenin and NCC polarization. Remarkably, craniofacial abnormalities caused by trio deficiency in zebrafish could be partially rescued by the injection of mRNA encoding myh9, ca-Rac1, or ca-Cdc42. Conclusions: Here, we identified that Trio, interacting mostly with Myh9, acts as a key regulator of NCC migration and differentiation during craniofacial development. Our results indicate that trio morphant zebrafish and Wnt1-cre;Triofl/fl mice offer potential model systems to facilitate the study of the pathogenic mechanisms of Trio mutations causing craniofacial abnormalities.
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Ornell KJ, Mistretta KS, Ralston CQ, Coburn JM. Development of a stacked, porous silk scaffold neuroblastoma model for investigating spatial differences in cell and drug responsiveness. Biomater Sci 2021; 9:1272-1290. [PMID: 33336667 DOI: 10.1039/d0bm01153c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Development of in vitro, preclinical cancer models that contain cell-driven microenvironments remains a challenge. Engineering of millimeter-scale, in vitro tumor models with spatially distinct regions that can be independently assessed to study tumor microenvironments has been limited. Here, we report the use of porous silk scaffolds to generate a high cell density neuroblastoma (NB) model that can spatially recapitulate changes resulting from cell and diffusion driven changes. Using COMSOL modeling, a scaffold holder design that facilitates stacking of thin, 200 μm silk scaffolds into a thick, bulk millimeter-scale tumor model (2, 4, 6, and 8 stacked scaffolds) and supports cell-driven oxygen gradients was developed. Cell-driven oxygen gradients were confirmed through pimonidazole staining. Post-culture, the stacked scaffolds were separated for analysis on a layer-by-layer basis. The analysis of each scaffold layer demonstrated decreasing DNA and increasing expression of hypoxia related genes (VEGF, CAIX, and GLUT1) from the exterior scaffolds to the interior scaffolds. Furthermore, the expression of hypoxia related genes at the interior of the stacks was comparable to that of a single scaffold cultured under 1% O2 and at the exterior of the stacks was comparable to that of a single scaffold cultured under 21% O2. The four-stack scaffold model underwent further evaluation to determine if a hypoxia activated drug, tirapazamine, induced reduced cell viability within the internal stacks (region of reduced oxygen) as compared with the external stacks. Decreased DNA content was observed in the internal stacks as compared to the external stacks when treated with tirapazamine, which suggests the internal scaffold stacks had higher levels of hypoxia than the external scaffolds. This stacked silk scaffold system presents a method for creating a single culture model capable of generating controllable cell-driven microenvironments through different stacks that can be individually assessed and used for drug screening.
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Affiliation(s)
- Kimberly J Ornell
- Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA.
| | - Katelyn S Mistretta
- Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA.
| | - Coulter Q Ralston
- Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA.
| | - Jeannine M Coburn
- Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA.
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24
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Shuvalov O, Daks A, Fedorova O, Petukhov A, Barlev N. Linking Metabolic Reprogramming, Plasticity and Tumor Progression. Cancers (Basel) 2021; 13:cancers13040762. [PMID: 33673109 PMCID: PMC7917602 DOI: 10.3390/cancers13040762] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 02/03/2021] [Accepted: 02/07/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary In the present review, we discuss the role of metabolic reprogramming which occurs in malignant cells. The process of metabolic reprogramming is also known as one of the “hallmarks of cancer”. Due to several reasons, including the origin of cancer, tumor microenvironment, and the tumor progression stage, metabolic reprogramming can be heterogeneous and dynamic. In this review, we provide evidence that the usage of metabolic drugs is a promising approach to treat cancer. However, because these drugs can damage not only malignant cells but also normal rapidly dividing cells, it is important to understand the exact metabolic changes which are elicited by particular drivers in concrete tissue and are specific for each stage of cancer development, including metastases. Finally, the review highlights new promising targets for the development of new metabolic drugs. Abstract The specific molecular features of cancer cells that distinguish them from the normal ones are denoted as “hallmarks of cancer”. One of the critical hallmarks of cancer is an altered metabolism which provides tumor cells with energy and structural resources necessary for rapid proliferation. The key feature of a cancer-reprogrammed metabolism is its plasticity, allowing cancer cells to better adapt to various conditions and to oppose different therapies. Furthermore, the alterations of metabolic pathways in malignant cells are heterogeneous and are defined by several factors including the tissue of origin, driving mutations, and microenvironment. In the present review, we discuss the key features of metabolic reprogramming and plasticity associated with different stages of tumor, from primary tumors to metastases. We also provide evidence of the successful usage of metabolic drugs in anticancer therapy. Finally, we highlight new promising targets for the development of new metabolic drugs.
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Affiliation(s)
- Oleg Shuvalov
- Institute of Cytology RAS, 194064 St-Petersburg, Russia; (O.S.); (A.D.); (O.F.); (A.P.)
| | - Alexandra Daks
- Institute of Cytology RAS, 194064 St-Petersburg, Russia; (O.S.); (A.D.); (O.F.); (A.P.)
| | - Olga Fedorova
- Institute of Cytology RAS, 194064 St-Petersburg, Russia; (O.S.); (A.D.); (O.F.); (A.P.)
| | - Alexey Petukhov
- Institute of Cytology RAS, 194064 St-Petersburg, Russia; (O.S.); (A.D.); (O.F.); (A.P.)
- Almazov National Medical Research Center, 197341 St-Petersburg, Russia
| | - Nickolai Barlev
- Institute of Cytology RAS, 194064 St-Petersburg, Russia; (O.S.); (A.D.); (O.F.); (A.P.)
- MIPT, 141701 Dolgoprudny, Moscow Region, Russia
- Orekhovich IBMC, 119435 Moscow, Russia
- Correspondence: ; Tel.: +7-812-297-4519
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25
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Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F, Foster J, Zhou J, Zhang R. Molecular targeting therapies for neuroblastoma: Progress and challenges. Med Res Rev 2020; 41:961-1021. [PMID: 33155698 PMCID: PMC7906923 DOI: 10.1002/med.21750] [Citation(s) in RCA: 220] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/25/2020] [Accepted: 10/28/2020] [Indexed: 01/09/2023]
Abstract
There is an urgent need to identify novel therapies for childhood cancers. Neuroblastoma is the most common pediatric solid tumor, and accounts for ~15% of childhood cancer‐related mortality. Neuroblastomas exhibit genetic, morphological and clinical heterogeneity, which limits the efficacy of existing treatment modalities. Gaining detailed knowledge of the molecular signatures and genetic variations involved in the pathogenesis of neuroblastoma is necessary to develop safer and more effective treatments for this devastating disease. Recent studies with advanced high‐throughput “omics” techniques have revealed numerous genetic/genomic alterations and dysfunctional pathways that drive the onset, growth, progression, and resistance of neuroblastoma to therapy. A variety of molecular signatures are being evaluated to better understand the disease, with many of them being used as targets to develop new treatments for neuroblastoma patients. In this review, we have summarized the contemporary understanding of the molecular pathways and genetic aberrations, such as those in MYCN, BIRC5, PHOX2B, and LIN28B, involved in the pathogenesis of neuroblastoma, and provide a comprehensive overview of the molecular targeted therapies under preclinical and clinical investigations, particularly those targeting ALK signaling, MDM2, PI3K/Akt/mTOR and RAS‐MAPK pathways, as well as epigenetic regulators. We also give insights on the use of combination therapies involving novel agents that target various pathways. Further, we discuss the future directions that would help identify novel targets and therapeutics and improve the currently available therapies, enhancing the treatment outcomes and survival of patients with neuroblastoma.
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Affiliation(s)
- Atif Zafar
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA.,Drug Discovery Institute, University of Houston, Houston, Texas, USA
| | - Gang Liu
- Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas, USA
| | - Xinjie Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Wa Xian
- Department of Biology and Biochemistry, Stem Cell Center, University of Houston, Houston, Texas, USA
| | - Frank McKeon
- Department of Biology and Biochemistry, Stem Cell Center, University of Houston, Houston, Texas, USA
| | - Jennifer Foster
- Department of Pediatrics, Texas Children's Hospital, Section of Hematology-Oncology Baylor College of Medicine, Houston, Texas, USA
| | - Jia Zhou
- Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas, USA
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA.,Drug Discovery Institute, University of Houston, Houston, Texas, USA
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Cangelosi D, Morini M, Zanardi N, Sementa AR, Muselli M, Conte M, Garaventa A, Pfeffer U, Bosco MC, Varesio L, Eva A. Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming. Cancers (Basel) 2020; 12:E2343. [PMID: 32825087 PMCID: PMC7563184 DOI: 10.3390/cancers12092343] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/09/2020] [Accepted: 08/17/2020] [Indexed: 12/23/2022] Open
Abstract
The biological and clinical heterogeneity of neuroblastoma (NB) demands novel biomarkers and therapeutic targets in order to drive the most appropriate treatment for each patient. Hypoxia is a condition of low-oxygen tension occurring in poorly vascularized tumor tissues. In this study, we aimed to assess the role of hypoxia in the pathogenesis of NB and at developing a new clinically relevant hypoxia-based predictor of outcome. We analyzed the gene expression profiles of 1882 untreated NB primary tumors collected at diagnosis and belonging to four existing data sets. Analyses took advantage of machine learning methods. We identified NB-hop, a seven-gene hypoxia biomarker, as a predictor of NB patient prognosis, which is able to discriminate between two populations of patients with unfavorable or favorable outcome on a molecular basis. NB-hop retained its prognostic value in a multivariate model adjusted for established risk factors and was able to additionally stratify clinically relevant groups of patients. Tumors with an unfavorable NB-hop expression showed a significant association with telomerase activation and a hypoxic, immunosuppressive, poorly differentiated, and apoptosis-resistant tumor microenvironment. NB-hop defines a new population of NB patients with hypoxic tumors and unfavorable prognosis and it represents a critical factor for the stratification and treatment of NB patients.
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Affiliation(s)
- Davide Cangelosi
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.M.); (N.Z.); (L.V.); (A.E.)
| | - Martina Morini
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.M.); (N.Z.); (L.V.); (A.E.)
| | - Nicolò Zanardi
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.M.); (N.Z.); (L.V.); (A.E.)
| | - Angela Rita Sementa
- Laboratory of Pathology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy;
| | - Marco Muselli
- Institute of Electronics, Computer and Telecommunication Engineering, Italian National Research Council, 16149 Genova, Italy;
| | - Massimo Conte
- Pediatric Oncology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.C.); (A.G.)
| | - Alberto Garaventa
- Pediatric Oncology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.C.); (A.G.)
| | - Ulrich Pfeffer
- Integrated Oncology Therapies Department, Molecular Pathology, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.M.); (N.Z.); (L.V.); (A.E.)
| | - Luigi Varesio
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.M.); (N.Z.); (L.V.); (A.E.)
| | - Alessandra Eva
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; (M.M.); (N.Z.); (L.V.); (A.E.)
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