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Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025; 10:106. [PMID: 40180907 PMCID: PMC11968978 DOI: 10.1038/s41392-025-02142-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/13/2024] [Accepted: 12/29/2024] [Indexed: 04/05/2025] Open
Abstract
The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Wu L, Katsube T, Li X, Wang B, Xie Y. Unveiling the impact of CD133 on cell cycle regulation in radio- and chemo-resistance of cancer stem cells. Front Public Health 2025; 13:1509675. [PMID: 39980929 PMCID: PMC11839412 DOI: 10.3389/fpubh.2025.1509675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/13/2025] [Indexed: 02/22/2025] Open
Abstract
The adaptation of malignancy to therapy presents a significant challenge in cancer treatment. The cell cycle plays a crucial role in regulating the evolution of radio- and chemo-resistance in tumor cells. Cancer stem cells (CSCs) are the primary source of therapy resistance, with CD133 being one of the most recognized and valuable cell surface markers of CSCs. Evidence increasingly suggests that CD133 is associated with cancer resistance. The current understanding of the molecular biological function of CD133 is limited, leading to ongoing debates about its role in cancer biology. In this review, we explore recent research and emerging trends related to CD133 through extensive literature and content analysis. It was summarized that new insights into the relationships of CD133 and cell cycle signaling pathways in resistant CSCs. The aim of this review is to provide a foundational understanding of how these signaling pathways and their interactions impact cancer prognosis and inform treatment strategies.
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Affiliation(s)
- Luyao Wu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Graduate School of the Chinese Academy of Sciences, Beijing, China
| | - Takanori Katsube
- Institute for Radiological Science, National Institutes for Quantum Science and Technology, Chiba, Japan
| | - Xiaofei Li
- Gansu Nuclear and Radiation Safety Center, Lanzhou, China
| | - Bing Wang
- Institute for Radiological Science, National Institutes for Quantum Science and Technology, Chiba, Japan
| | - Yi Xie
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
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Lica JJ, Jakóbkiewicz-Banecka J, Hellmann A. In Vitro models of leukemia development: the role of very small leukemic stem-like cells in the cellular transformation cascade. Front Cell Dev Biol 2025; 12:1463807. [PMID: 39830209 PMCID: PMC11740207 DOI: 10.3389/fcell.2024.1463807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 11/28/2024] [Indexed: 01/22/2025] Open
Abstract
Recent experimental findings indicate that cancer stem cells originate from transformed very small embryonic-like stem cells. This finding represents an essential advancement in uncovering the processes that drive the onset and progression of cancer. In continuously growing cell lines, for the first time, our team's follow-up research on leukemia, lung cancer, and healthy embryonic kidney cells revealed stages that resembles very small precursor stem cells. This review explores the origin of leukemic stem-like cells from very small leukemic stem-like cells establish from transformed very small embryonic-like stem cells. We explore theoretical model of acute myeloid leukemia initiation and progresses through various stages, as well basing the HL60 cell line, present its hierarchical stage development in vitro, highlighting the role of these very small precursor primitive stages. We also discuss the potential implications of further research into these unique cellular stages for advancing leukemia and cancer treatment and prevention.
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Affiliation(s)
- Jan Jakub Lica
- Department Medical Biology and Genetics, Faculty of Biology, University of Gdansk, Gdansk, Poland
- Department Health Science; Powiśle University, Gdańsk, Poland
| | | | - Andrzej Hellmann
- Department of Hematology and Transplantology, Faculty of Medicine, Medical University of Gdansk, Gdańsk, Poland
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Amacker A, Peng CC, Jiang N, Sirivolu S, Higa N, Stachelek K, Reiser B, Kuhn P, Cobrinik D, Neviani P, Berry JL, Jovanovic-Talisman T, Xu L. Phenotypic Biomarkers of Aqueous Extracellular Vesicles from Retinoblastoma Eyes. Int J Mol Sci 2024; 25:11660. [PMID: 39519212 PMCID: PMC11545953 DOI: 10.3390/ijms252111660] [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: 10/06/2024] [Revised: 10/25/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024] Open
Abstract
Recent advancements in aqueous humor (AH) cell-free DNA (cfDNA) genomics have opened new avenues for ex vivo molecular profiling of retinoblastoma (RB), the most common pediatric intraocular malignancy, where biopsy is typically prohibited. While these insights offer a genetic blueprint of the tumor, they lack multi-omic molecular phenotyping, which is essential for understanding the functional state. Extracellular vesicles (EVs), naturally present in AH, are promising by offering time-resolved phenotypic information. We employed multiplex bead-based flow cytometry and Single Extracellular Vesicle Nanoscopy (SEVEN) to analyze EV phenotypes in AH from a cohort of five RB, with three uveal melanoma (UM) and two age-matched glaucoma (GLC) samples serving as controls. The studies identified CD133-enriched EVs uniquely in RB AH, absent in both GLC and UM AH. This was corroborated by further analysis of five RB cell lines, including two commercial (Y79, Weri) and three in-house developed lines, confirming CD133 enrichment and supporting its role as an RB-specific EV marker. Single-vesicle analysis demonstrated a strong association of CD133 with CD81 and CD63, with minimal CD9 presence. These results, validated through complementary techniques, position CD133 as a critical marker in RB-derived EVs, paving the way for enhanced multi-omic RB characterization and potential advancements in clinical diagnostics.
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Affiliation(s)
- Anne Amacker
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Chen-Ching Peng
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Nan Jiang
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (N.J.); (T.J.-T.)
| | - Shreya Sirivolu
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Nikki Higa
- Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer, University of Southern California, Los Angeles, CA 90089, USA; (N.H.); (P.K.)
| | - Kevin Stachelek
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Bibiana Reiser
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Peter Kuhn
- Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer, University of Southern California, Los Angeles, CA 90089, USA; (N.H.); (P.K.)
| | - David Cobrinik
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Paolo Neviani
- The Extracellular Vesicle Core, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA;
| | - Jesse L. Berry
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Tijana Jovanovic-Talisman
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (N.J.); (T.J.-T.)
| | - Liya Xu
- The Vision Center, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (A.A.); (C.-C.P.); (S.S.); (K.S.); (B.R.); (D.C.); (J.L.B.)
- USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Kamei N, Day K, Guo W, Haus DL, Nguyen HX, Scarfone VM, Booher K, Jia XY, Cummings BJ, Anderson AJ. Injured inflammatory environment overrides the TET2 shaped epigenetic landscape of pluripotent stem cell derived human neural stem cells. Sci Rep 2024; 14:25186. [PMID: 39448736 PMCID: PMC11502794 DOI: 10.1038/s41598-024-75689-3] [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: 04/19/2024] [Accepted: 10/08/2024] [Indexed: 10/26/2024] Open
Abstract
Spinal cord injury creates an inflammatory microenvironment that regulates the capacity of transplanted human Neural Stem Cells (hNSC) to migrate, differentiate, and repair injury. Despite similarities in gene expression and markers detected by immunostaining, hNSC populations exhibit heterogeneous therapeutic potential. This heterogeneity derives in part from the epigenetic landscape in the hNSC genome, specifically methylation (5mC) and hydroxymethylation (5hmC) state, which may affect the response of transplanted hNSC in the injury microenvironment and thereby modulate repair capacity. We demonstrate a significant up-regulation of methylcytosine dioxygenase 2 gene (TET2) expression in undifferentiated hNSC derived from human embryonic stem cells (hES-NSC), and report that this is associated with hES-NSC competence for differentiation marker expression. TET2 protein catalyzes active demethylation and TET2 upregulation could be a signature of pluripotent exit, while shaping the epigenetic landscape in hES-NSC. We determine that the inflammatory environment overrides epigenetic programming in vitro and in vivo by directly modulating TET2 expression levels in hES-NSC to change cell fate. We also report the effect of cell fate and microenvironment on differential methylation 5mC/5hmC balance. Understanding how the activity of epigenetic modifiers changes within the transplantation niche in vivo is crucial for assessment of hES-NSC behavior for potential clinical applications.
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Affiliation(s)
- Noriko Kamei
- Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, 92697-1705, USA.
- Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, 92697-4475, USA.
| | - Kenneth Day
- Zymo Research Corp, 17062 Murphy Ave, Irvine, CA, 92614, USA
- Vidium Animal Health, 7201 E Henkel Way Suite210, Scottsdale, AZ, 85255, USA
| | - Wei Guo
- Zymo Research Corp, 17062 Murphy Ave, Irvine, CA, 92614, USA
| | - Daniel L Haus
- Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, 92697-1705, USA
| | - Hal X Nguyen
- Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, 92697-1705, USA
| | - Vanessa M Scarfone
- Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, 92697-1705, USA
| | - Keith Booher
- Zymo Research Corp, 17062 Murphy Ave, Irvine, CA, 92614, USA
| | - Xi-Yu Jia
- Zymo Research Corp, 17062 Murphy Ave, Irvine, CA, 92614, USA
| | - Brian J Cummings
- Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, 92697-1705, USA.
| | - Aileen J Anderson
- Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, 92697-1705, USA.
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Das P, Pal D, Roy S, Chaudhuri S, Kesh SS, Basak P, Nandi SK. Unveiling advanced strategies for therapeutic stem cell interventions in severe burn injuries: a comprehensive review. Int J Surg 2024; 110:6382-6401. [PMID: 38869979 PMCID: PMC11487052 DOI: 10.1097/js9.0000000000001812] [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: 02/03/2024] [Accepted: 05/29/2024] [Indexed: 06/15/2024]
Abstract
This comprehensive review explores the complex terrain of stem cell therapies as a potential therapeutic frontier in the healing of complicated burn wounds. Serious tissue damage, impaired healing processes, and possible long-term consequences make burn wounds a complex problem. An in-depth review is required since, despite medical progress, existing methods for treating severe burn wounds have significant limitations. Burn wounds are difficult to heal because they cause extensive tissue damage. The challenges of burn injury-induced tissue regeneration and functional recovery are also the subject of this review. Although there is a lot of promise in current stem cell treatments, there are also some limitations with scalability, finding the best way to transport the cells, and finding consistent results across different types of patients. To shed light on how to improve stem cell interventions to heal severe burn wounds, this review covers various stem cell applications in burn wounds and examines these obstacles. To overcome these obstacles, one solution is to enhance methods of stem cell distribution, modify therapies according to the severity of the burn, and conduct more studies on how stem cell therapy affects individual patients. Novel solutions may also be possible through the combination of cutting-edge technologies like nanotechnology and biotechnology. This review seeks to increase stem cell interventions by analyzing present challenges and suggesting strategic improvements. The goal is to provide a more effective and tailored way to repair serious burn wounds.
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Affiliation(s)
- Pratik Das
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
- School of Bioscience and Engineering, Jadavpur University
| | - Debajyoti Pal
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
| | - Sudipta Roy
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
| | - Shubhamitra Chaudhuri
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, India
| | - Shyam S. Kesh
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, India
| | - Piyali Basak
- School of Bioscience and Engineering, Jadavpur University
| | - Samit K. Nandi
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences
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Senesi G, Guerricchio L, Ghelardoni M, Bertola N, Rebellato S, Grinovero N, Bartolucci M, Costa A, Raimondi A, Grange C, Bolis S, Massa V, Paladini D, Coviello D, Pandolfi A, Bussolati B, Petretto A, Fazio G, Ravera S, Barile L, Balbi C, Bollini S. Extracellular vesicles from II trimester human amniotic fluid as paracrine conveyors counteracting oxidative stress. Redox Biol 2024; 75:103241. [PMID: 38901103 PMCID: PMC11253147 DOI: 10.1016/j.redox.2024.103241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 06/07/2024] [Accepted: 06/15/2024] [Indexed: 06/22/2024] Open
Abstract
BACKGROUND We previously demonstrated that the human amniotic fluid (hAF) from II trimester of gestation is a feasible source of stromal progenitors (human amniotic fluid stem cells, hAFSC), with significant paracrine potential for regenerative medicine. Extracellular vesicles (EVs) separated and concentrated from hAFSC secretome can deliver pro-survival, proliferative, anti-fibrotic and cardioprotective effects in preclinical models of skeletal and cardiac muscle injury. While hAFSC-EVs isolation can be significantly influenced by in vitro cell culture, here we profiled EVs directly concentrated from hAF as an alternative option and investigated their paracrine potential against oxidative stress. METHODS II trimester hAF samples were obtained as leftover material from prenatal diagnostic amniocentesis following written informed consent. EVs were separated by size exclusion chromatography and concentrated by ultracentrifugation. hAF-EVs were assessed by nanoparticle tracking analysis, transmission electron microscopy, Western Blot, and flow cytometry; their metabolic activity was evaluated by oximetric and luminometric analyses and their cargo profiled by proteomics and RNA sequencing. hAF-EV paracrine potential was tested in preclinical in vitro models of oxidative stress and dysfunction on murine C2C12 cells and on 3D human cardiac microtissue. RESULTS Our protocol resulted in a yield of 6.31 ± 0.98 × 109 EVs particles per hAF milliliter showing round cup-shaped morphology and 209.63 ± 6.10 nm average size, with relevant expression of CD81, CD63 and CD9 tetraspanin markers. hAF-EVs were enriched in CD133/1, CD326, CD24, CD29, and SSEA4 and able to produce ATP by oxygen consumption. While oxidative stress significantly reduced C2C12 survival, hAF-EV priming resulted in significant rescue of cell viability, with notable recovery of ATP synthesis and concomitant reduction of cell damage and lipid peroxidation activity. 3D human cardiac microtissues treated with hAF-EVs and experiencing H2O2 stress and TGFβ stimulation showed improved survival with a remarkable decrease in the onset of fibrosis. CONCLUSIONS Our results suggest that leftover samples of II trimester human amniotic fluid can represent a feasible source of EVs to counteract oxidative damage on target cells, thus offering a novel candidate therapeutic option to counteract skeletal and cardiac muscle injury.
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Affiliation(s)
- Giorgia Senesi
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino and Laboratories for Traslational Research Ente Ospedaliero Cantonale, CH-6500, Bellinzona, Switzerland; Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-6900, Lugano, Switzerland
| | - Laura Guerricchio
- Department of Experimental Medicine (DIMES), University of Genova, 16132, Genova, Italy
| | | | - Nadia Bertola
- IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Stefano Rebellato
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900, Monza, Italy; School of Medicine and Surgery, University of Milano-Bicocca, 20900, Monza, Italy
| | - Nicole Grinovero
- Core Facilities - Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, 16147, Genova, Italy
| | - Martina Bartolucci
- Core Facilities - Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, 16147, Genova, Italy
| | - Ambra Costa
- IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Andrea Raimondi
- Institute for Research in Biomedicine, Università della Svizzera Italiana, CH-6500, Bellinzona, Switzerland
| | - Cristina Grange
- VEXTRA Facility and Department of Medical Sciences, University of Turin, 10126, Turin, Italy
| | - Sara Bolis
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino and Laboratories for Traslational Research Ente Ospedaliero Cantonale, CH-6500, Bellinzona, Switzerland
| | - Valentina Massa
- Department of Health Sciences, University of Milan, 20146, Milan, Italy
| | - Dario Paladini
- Fetal Medicine and Surgery Unit, IRCCS Istituto Giannina Gaslini, 16147, Genova, Italy
| | - Domenico Coviello
- Human Genetics Laboratory, IRCCS Istituto Giannina Gaslini, 16147, Genova, Italy
| | - Assunta Pandolfi
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara and Center for Advanced Studies and Technology - CAST, 66100, Chieti, Italy
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126, Turin, Italy
| | - Andrea Petretto
- Core Facilities - Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, 16147, Genova, Italy
| | - Grazia Fazio
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900, Monza, Italy; School of Medicine and Surgery, University of Milano-Bicocca, 20900, Monza, Italy
| | - Silvia Ravera
- Department of Experimental Medicine (DIMES), University of Genova, 16132, Genova, Italy
| | - Lucio Barile
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino and Laboratories for Traslational Research Ente Ospedaliero Cantonale, CH-6500, Bellinzona, Switzerland; Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-6900, Lugano, Switzerland.
| | - Carolina Balbi
- Center for Molecular Cardiology, University of Zurich, 8952, Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland.
| | - Sveva Bollini
- Department of Experimental Medicine (DIMES), University of Genova, 16132, Genova, Italy; IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy.
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Puertas-Neyra K, Coco-Martin RM, Hernandez-Rodriguez LA, Gobelli D, Garcia-Ferrer Y, Palma-Vecino R, Tellería JJ, Simarro M, de la Fuente MA, Fernandez-Bueno I. Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes. Stem Cell Res Ther 2024; 15:192. [PMID: 38956727 PMCID: PMC11218195 DOI: 10.1186/s13287-024-03804-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/16/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global financial burden due to the lack of understanding of a significant part of its pathophysiology, molecular diagnosis, and the near absence of non-palliative treatment options. Patient-derived induced pluripotent stem cells (iPSC) for IRD seem to be an excellent option for addressing these questions, serving as exceptional tools for in-depth studies of IRD pathophysiology and testing new therapeutic approaches. METHODS From a cohort of 8 patients with PROM1-related IRD, we identified 3 patients carrying the same variant (c.1354dupT) but expressing three different IRD phenotypes: Cone and rod dystrophy (CORD), Retinitis pigmentosa (RP), and Stargardt disease type 4 (STGD4). These three target patients, along with one healthy relative from each, underwent comprehensive ophthalmic examinations and their genetic panel study was expanded through clinical exome sequencing (CES). Subsequently, non-integrative patient-derived iPSC were generated and fully characterized. Correction of the c.1354dupT mutation was performed using CRISPR/Cas9, and the genetic restoration of the PROM1 gene was confirmed through flow cytometry and western blotting in the patient-derived iPSC lines. RESULTS CES revealed that 2 target patients with the c.1354dupT mutation presented monoallelic variants in genes associated with the complement system or photoreceptor differentiation and peroxisome biogenesis disorders, respectively. The pluripotency and functionality of the patient-derived iPSC lines were confirmed, and the correction of the target mutation fully restored the capability of encoding Prominin-1 (CD133) in the genetically repaired patient-derived iPSC lines. CONCLUSIONS The c.1354dupT mutation in the PROM1 gene is associated to three distinct AR phenotypes of IRD. This pleotropic effect might be related to the influence of monoallelic variants in other genes associated with retinal dystrophies. However, further evidence needs to be provided. Future experiments should include gene-edited patient-derived iPSC due to its potential as disease modelling tools to elucidate this matter in question.
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Affiliation(s)
- Kevin Puertas-Neyra
- Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain
| | - Rosa M Coco-Martin
- Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain.
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS-REI), Inflamación E Inmunopatologia de Organos y Sistemas, Instituto de Salud Carlos III, Valladolid, Spain.
- Centro en Red de Medicina Regenerativa, y Terapia Celular de Castilla y León, Valladolid, Spain.
| | | | - Dino Gobelli
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain
- Departamento de Biología Celular, Genética, Histología y Farmacología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain
| | - Yenisey Garcia-Ferrer
- Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain
| | - Raicel Palma-Vecino
- Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain
| | - Juan José Tellería
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain
| | - Maria Simarro
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain
- Departamento de Biología Celular, Genética, Histología y Farmacología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain
| | - Miguel A de la Fuente
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain
- Departamento de Biología Celular, Genética, Histología y Farmacología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain
| | - Ivan Fernandez-Bueno
- Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Valladolid, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS-REI), Inflamación E Inmunopatologia de Organos y Sistemas, Instituto de Salud Carlos III, Valladolid, Spain
- Centro en Red de Medicina Regenerativa, y Terapia Celular de Castilla y León, Valladolid, Spain
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9
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Gisina A, Yarygin K, Lupatov A. The Impact of Glycosylation on the Functional Activity of CD133 and the Accuracy of Its Immunodetection. BIOLOGY 2024; 13:449. [PMID: 38927329 PMCID: PMC11200695 DOI: 10.3390/biology13060449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 06/01/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024]
Abstract
The membrane glycoprotein CD133 (prominin-1) is widely regarded as the main molecular marker of cancer stem cells, which are the most malignant cell subpopulation within the tumor, responsible for tumor growth and metastasis. For this reason, CD133 is considered a promising prognostic biomarker and molecular target for antitumor therapy. Under normal conditions, CD133 is present on the cell membrane in glycosylated form. However, in malignancies, altered glycosylation apparently leads to changes in the functional activity of CD133 and the availability of some of its epitopes for antibodies. This review focuses on CD133's glycosylation in human cells and its impact on the function of this glycoprotein. The association of CD133 with proliferation, differentiation, apoptosis, autophagy, epithelial-mesenchymal transition, the organization of plasma membrane protrusions and extracellular trafficking is discussed. In this review, particular attention is paid to the influence of CD133's glycosylation on its immunodetection. A list of commercially available and custom antibodies with their characteristics is provided. The available data indicate that the development of CD133-based biomedical technologies should include an assessment of CD133's glycosylation in each tumor type.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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10
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Zhang Z, Zhang Y. Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies. J Exp Clin Cancer Res 2024; 43:99. [PMID: 38561775 PMCID: PMC10986082 DOI: 10.1186/s13046-024-03021-y] [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: 12/04/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Cancer stem cells (CSCs) were first discovered in the 1990s, revealing the mysteries of cancer origin, migration, recurrence and drug-resistance from a new perspective. The expression of pluripotent genes and complex signal regulatory networks are significant features of CSC, also act as core factors to affect the characteristics of CSC. Transcription is a necessary link to regulate the phenotype and potential of CSC, involving chromatin environment, nucleosome occupancy, histone modification, transcription factor (TF) availability and cis-regulatory elements, which suffer from ambient pressure. Especially, the expression and activity of pluripotent TFs are deeply affected by both internal and external factors, which is the foundation of CSC transcriptional regulation in the current research framework. Growing evidence indicates that regulating epigenetic modifications to alter cancer stemness is effective, and some special promoters and enhancers can serve as targets to influence the properties of CSC. Clarifying the factors that regulate CSC transcription will assist us directly target key stem genes and TFs, or hinder CSC transcription through environmental and other related factors, in order to achieve the goal of inhibiting CSC and tumors. This paper comprehensively reviews the traditional aspects of transcriptional regulation, and explores the progress and insights of the impact on CSC transcription and status through tumor microenvironment (TME), hypoxia, metabolism and new meaningful regulatory factors in conjunction with the latest research. Finally, we present opinions on omnidirectional targeting CSCs transcription to eliminate CSCs and address tumor resistance.
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Affiliation(s)
- Zhengyue Zhang
- Department of Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201900, People's Republic of China
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, People's Republic of China
| | - Yanjie Zhang
- Department of Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201900, People's Republic of China.
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, People's Republic of China.
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11
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Lemmens TP, Bröker V, Rijpkema M, Hughes CCW, Schurgers LJ, Cosemans JMEM. Fundamental considerations for designing endothelialized in vitro models of thrombosis. Thromb Res 2024; 236:179-190. [PMID: 38460307 DOI: 10.1016/j.thromres.2024.03.004] [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: 11/18/2023] [Revised: 02/19/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Endothelialized in vitro models for cardiovascular disease have contributed greatly to our current understanding of the complex molecular mechanisms underlying thrombosis. To further elucidate these mechanisms, it is important to consider which fundamental aspects to incorporate into an in vitro model. In this review, we will focus on the design of in vitro endothelialized models of thrombosis. Expanding our understanding of the relation and interplay between the different pathways involved will rely in part on complex models that incorporate endothelial cells, blood, the extracellular matrix, and flow. Importantly, the use of tissue-specific endothelial cells will help in understanding the heterogeneity in thrombotic responses between different vascular beds. The dynamic and complex responses of endothelial cells to different shear rates underlines the importance of incorporating appropriate shear in in vitro models. Alterations in vascular extracellular matrix composition, availability of bioactive molecules, and gradients in concentration and composition of these molecules can all regulate the function of both endothelial cells and perivascular cells. Factors modulating these elements in in vitro models should therefore be considered carefully depending on the research question at hand. As the complexity of in vitro models increases, so can the variability. A bottom-up approach to designing such models will remain an important tool for researchers studying thrombosis. As new techniques are continuously being developed and new pathways are brought to light, research question-dependent considerations will have to be made regarding what aspects of thrombosis to include in in vitro models.
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Affiliation(s)
- Titus P Lemmens
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Vanessa Bröker
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Minke Rijpkema
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Christopher C W Hughes
- Department of Molecular Biology and Biochemistry, and Department of Biomedical Engineering, University of California, Irvine, USA
| | - Leon J Schurgers
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Judith M E M Cosemans
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
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12
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Krivec N, Ghosh MS, Spits C. Gains of 20q11.21 in human pluripotent stem cells: Insights from cancer research. Stem Cell Reports 2024; 19:11-27. [PMID: 38157850 PMCID: PMC10828824 DOI: 10.1016/j.stemcr.2023.11.013] [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: 09/08/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 01/03/2024] Open
Abstract
The genetic abnormalities observed in hPSC cultures worldwide have been suggested to pose an important hurdle in their safe use in regenerative medicine due to the possibility of oncogenic transformation by mutant cells in the patient posttransplantation. One of the best-characterized genetic lesions in hPSCs is the gain of 20q11.21, found in 20% of hPSC lines worldwide, and strikingly, also amplified in 20% of human cancers. In this review, we have curated the existing knowledge on the incidence of this mutation in hPSCs and cancer, explored the significance of chromosome 20q11.21 amplification in cancer progression, and reviewed the oncogenic role of the genes in the smallest common region of gain, to shed light on the significance of this mutation in hPSC-based cell therapy. Lastly, we discuss the state-of-the-art strategies devised to detect aneuploidies in hPSC cultures, avoid genetic changes in vitro cultures of hPSCs, and strategies to eliminate genetically abnormal cells from culture.
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Affiliation(s)
- Nuša Krivec
- Research Group Reproduction and Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Manjusha S Ghosh
- Research Group Reproduction and Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Claudia Spits
- Research Group Reproduction and Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Laarbeeklaan 103, 1090 Brussels, Belgium.
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13
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Moreno-Londoño AP, Robles-Flores M. Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment. Stem Cell Rev Rep 2024; 20:25-51. [PMID: 37922108 PMCID: PMC10799829 DOI: 10.1007/s12015-023-10647-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2023] [Indexed: 11/05/2023]
Abstract
CD133 protein has been one of the most used surface markers to select and identify cancer cells with stem-like features. However, its expression is not restricted to tumoral cells; it is also expressed in differentiated cells and stem/progenitor cells in various normal tissues. CD133 participates in several cellular processes, in part orchestrating signal transduction of essential pathways that frequently are dysregulated in cancer, such as PI3K/Akt signaling and the Wnt/β-catenin pathway. CD133 expression correlates with enhanced cell self-renewal, migration, invasion, and survival under stress conditions in cancer. Aside from the intrinsic cell mechanisms that regulate CD133 expression in each cellular type, extrinsic factors from the surrounding niche can also impact CD33 levels. The enhanced CD133 expression in cells can confer adaptive advantages by amplifying the activation of a specific signaling pathway in a context-dependent manner. In this review, we do not only describe the CD133 physiological functions known so far, but importantly, we analyze how the microenvironment changes impact the regulation of CD133 functions emphasizing its value as a marker of cell adaptability beyond a cancer-stem cell marker.
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Affiliation(s)
- Angela Patricia Moreno-Londoño
- Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), 04510, Mexico City, Mexico
| | - Martha Robles-Flores
- Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), 04510, Mexico City, Mexico.
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14
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Pleet ML, Welsh JA, Stack EH, Cook S, Johnson DA, Killingsworth B, Traynor T, Clauze A, Hughes R, Monaco MC, Ngouth N, Ohayon J, Enose-Akahata Y, Nath A, Cortese I, Reich DS, Jones JC, Jacobson S. Viral Immune signatures from cerebrospinal fluid extracellular vesicles and particles in HAM and other chronic neurological diseases. Front Immunol 2023; 14:1235791. [PMID: 37622115 PMCID: PMC10446883 DOI: 10.3389/fimmu.2023.1235791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
Background and objectives Extracellular vesicles and particles (EVPs) are released from virtually all cell types, and may package many inflammatory factors and, in the case of infection, viral components. As such, EVPs can play not only a direct role in the development and progression of disease but can also be used as biomarkers. Here, we characterized immune signatures of EVPs from the cerebrospinal fluid (CSF) of individuals with HTLV-1-associated myelopathy (HAM), other chronic neurologic diseases, and healthy volunteers (HVs) to determine potential indicators of viral involvement and mechanisms of disease. Methods We analyzed the EVPs from the CSF of HVs, individuals with HAM, HTLV-1-infected asymptomatic carriers (ACs), and from patients with a variety of chronic neurologic diseases of both known viral and non-viral etiologies to investigate the surface repertoires of CSF EVPs during disease. Results Significant increases in CD8+ and CD2+ EVPs were found in HAM patient CSF samples compared to other clinical groups (p = 0.0002 and p = 0.0003 compared to HVs, respectively, and p = 0.001 and p = 0.0228 compared to MS, respectively), consistent with the immunopathologically-mediated disease associated with CD8+ T-cells in the central nervous system (CNS) of HAM patients. Furthermore, CD8+ (p < 0.0001), CD2+ (p < 0.0001), CD44+ (p = 0.0176), and CD40+ (p = 0.0413) EVP signals were significantly increased in the CSF from individuals with viral infections compared to those without. Discussion These data suggest that CD8+ and CD2+ CSF EVPs may be important as: 1) potential biomarkers and indicators of disease pathways for viral-mediated neurological diseases, particularly HAM, and 2) as possible meditators of the disease process in infected individuals.
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Affiliation(s)
- Michelle L. Pleet
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Joshua A. Welsh
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Emily H. Stack
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Sean Cook
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Dove-Anna Johnson
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Bryce Killingsworth
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Tim Traynor
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Annaliese Clauze
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Randall Hughes
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Maria Chiara Monaco
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Nyater Ngouth
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Joan Ohayon
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Yoshimi Enose-Akahata
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Avindra Nath
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Irene Cortese
- Experimental Immunotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Daniel S. Reich
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Jennifer C. Jones
- Translational Nanobiology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Steven Jacobson
- Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
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15
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Kalvala AK, Nimma R, Bagde A, Surapaneni SK, Patel N, Arthur P, Sun L, Singh R, Kommineni N, Nathani A, Li Y, Singh M. The role of Cannabidiol and tetrahydrocannabivarin to overcome doxorubicin resistance in MDA-MB-231 xenografts in athymic nude mice. Biochimie 2023; 208:19-30. [PMID: 36535544 PMCID: PMC11866400 DOI: 10.1016/j.biochi.2022.12.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The significant resistance to currently available chemotherapeutics makes treatment for TNBC a key clinical concern. Herein, we studied the anti-cancer potentials of synthetic cannabidiol (CBD) and Tetrahydrocannabivarin (THCV) when used alone or in combination with doxorubicin (DOX) against MDA-MB-231 resistant cells. Pre-treatment with CBD and THCV significantly increased the cytotoxicity of DOX in MDA-MB-231 2D and 3D cultures that were DOX-resistant. Transcriptomics and Proteomics studies revealed that CBD and THCV, by downregulating PD-L1, TGF-β, sp1, NLRP3, P38-MAPK, and upregulating AMPK induced apoptosis leading to improved DOX's chemosensitivity against DOX resistant MDA-MB-231 tumors in BALB/c nude mice. CBD/THCV in combination with DOX significantly inhibited H3k4 methylation and H2K5 acetylation as demonstrated by western blotting and RT-PCR. Based on these findings, CBD and THCV appear to counteract histone modifications and their subsequent effects on DOX, resulting in chemo-sensitization against MDA-MB-231 resistant cancers.
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Affiliation(s)
- Anil Kumar Kalvala
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Ramesh Nimma
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Arvind Bagde
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Sunil Kumar Surapaneni
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Nilkumar Patel
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Peggy Arthur
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Li Sun
- Department of Biomedical Sciences, Florida State University College of Medicine, 1115 West Call Street, Tallahassee, FL, 32306-4300, USA
| | - Rakesh Singh
- Department of Translational Science Laboratory, College of Medicine, Florida State University, 1115 West Call St., Tallahassee, FL, 32306-4300, USA
| | - Nagavendra Kommineni
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Aakash Nathani
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Yan Li
- Department of Biomedical Sciences, Florida State University College of Medicine, 1115 West Call Street, Tallahassee, FL, 32306-4300, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA.
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16
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de Figueiredo AMB, dos Santos JC, Kischkel B, Ardiansyah E, Oosting M, Guimarães Matos G, Barreto Neves Oliveira I, van de Veerdonk F, Netea MG, Soares CMDA, Ribeiro-Dias F, Joosten LAB. Genome-Wide Association Study Reveals CLEC7A and PROM1 as Potential Regulators of Paracoccidioides brasiliensis-Induction of Cytokine Production in Peripheral Blood Mononuclear Cells. J Fungi (Basel) 2023; 9:jof9040428. [PMID: 37108883 PMCID: PMC10144159 DOI: 10.3390/jof9040428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 03/25/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Paracoccidioidomycosis (PCM) is a systemic mycosis caused by fungi of the genus Paracoccidioides and the different clinical forms of the disease are associated with the host immune responses. Quantitative trait loci mapping analysis was performed to assess genetic variants associated with mononuclear-cells-derived cytokines induced by P. brasiliensis on 158 individuals. We identified the rs11053595 SNP, which is present in the CLEC7A gene (encodes the Dectin-1 receptor) and the rs62290169 SNP located in the PROM1 gene (encodes CD133) associated with the production of IL-1β and IL-22, respectively. Functionally, the blockade of the dectin-1 receptor abolished the IL-1β production in P. brasiliensis-stimulated PBMCs. Moreover, the rs62290169-GG genotype was associated with higher frequency of CD38+ Th1 cells in PBMCs cultured with P. brasiliensis yeasts. Therefore, our research indicates that the CLEC7A and PROM1 genes are important for the cytokine response induced by P. brasiliensis and may influence the Paracoccidioidomycosis disease outcome.
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17
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Song WP, Jin LY, Zhu MD, Wang H, Xia DS. Clinical trials using dental stem cells: 2022 update. World J Stem Cells 2023; 15:31-51. [PMID: 37007456 PMCID: PMC10052340 DOI: 10.4252/wjsc.v15.i3.31] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/20/2023] [Accepted: 03/08/2023] [Indexed: 03/23/2023] Open
Abstract
For nearly 20 years, dental stem cells (DSCs) have been successfully isolated from mature/immature teeth and surrounding tissue, including dental pulp of permanent teeth and exfoliated deciduous teeth, periodontal ligaments, dental follicles, and gingival and apical papilla. They have several properties (such as self-renewal, multidirectional differentiation, and immunomodulation) and exhibit enormous potential for clinical applications. To date, many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis, periapical lesions, periodontitis, cleft lip and palate, acute ischemic stroke, and so on, and DSC-based therapies obtained satisfactory effects in most clinical trials. In these studies, no adverse events were reported, which suggested the safety of DSC-based therapy. In this review, we outline the characteristics of DSCs and summarize clinical trials and their safety as DSC-based therapies. Meanwhile, we also present the current limitations and perspectives of DSC-based therapy (such as harvesting DSCs from inflamed tissue, applying DSC-conditioned medium/DSC-derived extracellular vesicles, and expanding-free strategies) to provide a theoretical basis for their clinical applications.
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Affiliation(s)
- Wen-Peng Song
- Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Lu-Yuan Jin
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
| | - Meng-Di Zhu
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
| | - Hao Wang
- Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Deng-Sheng Xia
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China.
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18
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Kinnel B, Singh SK, Oprea-Ilies G, Singh R. Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer. Cancers (Basel) 2023; 15:1320. [PMID: 36831661 PMCID: PMC9954028 DOI: 10.3390/cancers15041320] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/15/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Breast cancer is the most common cause of cancer-related death in women worldwide. Multidrug resistance (MDR) has been a large hurdle in reducing BC death rates. The drug resistance mechanisms include increased drug efflux, enhanced DNA repair, senescence escape, epigenetic alterations, tumor heterogeneity, tumor microenvironment (TME), and the epithelial-to-mesenchymal transition (EMT), which make it challenging to overcome. This review aims to explain the mechanisms of resistance in BC further, identify viable drug targets, and elucidate how those targets relate to the progression of BC and drug resistance.
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Affiliation(s)
- Briana Kinnel
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Santosh Kumar Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Gabriela Oprea-Ilies
- Department of Pathology & Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
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19
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Zhong A, Short C, Xu J, Fernandez GE, Malkoff N, Noriega N, Yeo T, Wang L, Mavila N, Asahina K, Wang KS. Prominin-1 promotes restitution of the murine extrahepatic biliary luminal epithelium following cholestatic liver injury. Hepatol Commun 2023; 7:e0018. [PMID: 36662671 PMCID: PMC10019165 DOI: 10.1097/hc9.0000000000000018] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/22/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND AND AIMS Restitution of the extrahepatic biliary luminal epithelium in cholangiopathies is poorly understood. Prominin-1 (Prom1) is a key component of epithelial ciliary body of stem/progenitor cells. Given that intrahepatic Prom1-expressing progenitor cells undergo cholangiocyte differentiation, we hypothesized that Prom1 may promote restitution of the extrahepatic bile duct (EHBD) epithelium following injury. APPROACH AND RESULTS Utilizing various murine biliary injury models, we identified Prom1-expressing cells in the peribiliary glands of the EHBD. These Prom1-expressing cells are progenitor cells which give rise to cholangiocytes as part of the normal maintenance of the EHBD epithelium. Following injury, these cells proliferate significantly more rapidly to re-populate the biliary luminal epithelium. Null mutation of Prom1 leads to significantly >10-fold dilated peribiliary glands following rhesus rotavirus-mediated biliary injury. Cultured organoids derived from Prom1 knockout mice are comprised of biliary progenitor cells with altered apical-basal cellular polarity, significantly fewer and shorter cilia, and decreased organoid proliferation dynamics consistent with impaired cell motility. CONCLUSIONS We, therefore, conclude that Prom1 is involved in biliary epithelial restitution following biliary injury in part through its role in supporting cell polarity.
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Affiliation(s)
- Allen Zhong
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | - Celia Short
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | - Jiabo Xu
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | - G. Esteban Fernandez
- Cellular Imaging Core, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | - Nicolas Malkoff
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | - Nicolas Noriega
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | - Theresa Yeo
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | - Larry Wang
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Nirmala Mavila
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Kinji Asahina
- Central Research Laboratory, Shiga University of Medical Science, Ōtsu, Shiga Prefecture, Japan
| | - Kasper S. Wang
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children’s Hospital of Los Angeles, Los Angeles, California, USA
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20
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Rawangkan A, Wongsirisin P, Pook-In G, Siriphap A, Yosboonruang A, Kiddee A, Chuerduangphui J, Reukngam N, Duangjai A, Saokaew S, Praphasawat R. Dinactin: A New Antitumor Antibiotic with Cell Cycle Progression and Cancer Stemness Inhibiting Activities in Lung Cancer. Antibiotics (Basel) 2022; 11:antibiotics11121845. [PMID: 36551502 PMCID: PMC9774622 DOI: 10.3390/antibiotics11121845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Lung cancer, especially non-small cell lung cancer (NSCLC), is one of the most complex diseases, despite the existence of effective treatments such as chemotherapy and immunotherapy. Since cancer stem cells (CSCs) are responsible for chemo- and radio-resistance, metastasis, and cancer recurrence, finding new therapeutic targets for CSCs is critical. Dinactin is a natural secondary metabolite produced by microorganisms. Recently, dinactin has been revealed as a promising antitumor antibiotic via various mechanisms. However, the evidence relating to cell cycle progression regulation is constrained, and effects on cancer stemness have not been elucidated. Therefore, the aim of this study is to evaluate the new function of dinactin in anti-NSCLC proliferation, focusing on cell cycle progression and cancer stemness properties in Lu99 and A549 cells. Flow cytometry and immunoblotting analyses revealed that 0.1-1 µM of dinactin suppresses cell growth through induction of the G0/G1 phase associated with down-regulation of cyclins A, B, and D3, and cdk2 protein expression. The tumor-sphere forming capacity was used to assess the effect of dinactin on the cancer stemness potential in NSCLC cells. At a concentration of 1 nM, dinactin reduced both the number and size of the tumor-spheres. The quantitative RT-PCR analyses indicated that dinactin suppressed sphere formation by significantly reducing expression of CSC markers (i.e., ALDH1A1, Nanog, Oct4, and Sox2) in Lu99 cells. Consequently, dinactin could be a promising strategy for NSCLC therapy targeting CSCs.
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Affiliation(s)
- Anchalee Rawangkan
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
- UNIt of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Pattama Wongsirisin
- Department of Medical Services, National Cancer Institute, Bangkok 10400, Thailand
| | - Grissana Pook-In
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Achiraya Siriphap
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Atchariya Yosboonruang
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Anong Kiddee
- Division of Microbiology and Parasitology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | | | - Nanthawan Reukngam
- Laboratory of Organic Synthesis, Chulabhorn Research Institute, Bangkok 10210, Thailand
| | - Acharaporn Duangjai
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Surasak Saokaew
- UNIt of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Division of Social and Administrative Pharmacy, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Ratsada Praphasawat
- Department of Pathology, School of Medicine, University of Phayao, Phayao 56000, Thailand
- Correspondence: ; Tel.: +66-54466666 (ext. 3824) or +66-86-926-2448
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21
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Chen Q, Lu L, Ma W. Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors. Cancers (Basel) 2022; 14:5983. [PMID: 36497465 PMCID: PMC9739567 DOI: 10.3390/cancers14235983] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/18/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored.
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Affiliation(s)
- Qiuqiang Chen
- Key Laboratory for Translational Medicine, The First Affiliated Hospital, Huzhou University School of Medicine, Huzhou 313000, China
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, School of Medicine, Yale School of Public Health, New Haven, CT 06520, USA
- Yale Cancer Center and Center for Biomedical Data Science, Yale University, 60 College Street, New Haven, CT 06520, USA
| | - Wenxue Ma
- Sanford Stem Cell Clinical Center, Moores Cancer Center, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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22
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Ogawa E, Oguma Y, Kushida Y, Wakao S, Okawa K, Dezawa M. Naïve pluripotent-like characteristics of non-tumorigenic Muse cells isolated from human amniotic membrane. Sci Rep 2022; 12:17222. [PMID: 36241699 PMCID: PMC9568515 DOI: 10.1038/s41598-022-22282-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 10/12/2022] [Indexed: 01/06/2023] Open
Abstract
Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic pluripotent-like stem cells that exhibit triploblastic differentiation and self-renewability at the single-cell level, and are collectable as pluripotent surface marker SSEA-3(+) from the bone marrow (BM), peripheral blood, and organ connective tissues. SSEA-3(+) cells from human amniotic membrane mesenchymal stem cells (hAMSCs) were compared with hBM-Muse cells. Similar to hBM-Muse cells, hAMSC-SSEA-3(+) cells expressed pluripotency genes (OCT3/4, NANOG, and SOX2), differentiated into triploblastic cells from a single cell, self-renewed, and exhibited non-tumorigenicity. Notably, however, they exhibited unique characteristics not seen in hBM-Muse cells, including higher expression of genes related to germline- and extraembryonic cell-lineages compared with those in hBM-Muse cells in single-cell RNA-sequencing; and enhanced expression of markers relevant to germline- (PRDM14, TFAP2C, and NANOS3) and extraembryonic cell- (CDX2, GCM1, and ID2) lineages when induced by cytokine subsets, suggesting a broader differentiation potential similar to naïve pluripotent stem cells. t-SNE dimensionality reduction and Gene ontology analysis visualized hAMSC-SSEA-3(+) cells comprised a large undifferentiated subpopulation between epithelial- and mesenchymal-cell states and a small mesenchymal subpopulation expressing genes relevant to the placental formation. The AM is easily accessible by noninvasive approaches. These unique cells are a potentially interesting target naïve pluripotent stem cell-like resource without tumorigenicity.
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Affiliation(s)
- Eiji Ogawa
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Yo Oguma
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Yoshihiro Kushida
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Shohei Wakao
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Kana Okawa
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Mari Dezawa
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
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23
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Zhang S, Zhu N, Li HF, Gu J, Zhang CJ, Liao DF, Qin L. The lipid rafts in cancer stem cell: a target to eradicate cancer. Stem Cell Res Ther 2022; 13:432. [PMID: 36042526 PMCID: PMC9429646 DOI: 10.1186/s13287-022-03111-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/03/2022] [Indexed: 11/10/2022] Open
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem cell properties that sustain cancers, which may be responsible for cancer metastasis or recurrence. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in the plasma membrane that mediate various intracellular signaling. The occurrence and progression of cancer are closely related to lipid rafts. Emerging evidence indicates that lipid raft levels are significantly enriched in CSCs compared to cancer cells and that most CSC markers such as CD24, CD44, and CD133 are located in lipid rafts. Furthermore, lipid rafts play an essential role in CSCs, specifically in CSC self-renewal, epithelial-mesenchymal transition, drug resistance, and CSC niche. Therefore, lipid rafts are critical regulatory platforms for CSCs and promising therapeutic targets for cancer therapy.
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Affiliation(s)
- Shuo Zhang
- Laboratory of Stem Cell Regulation With Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, 410208, Changsha, Hunan, People's Republic of China
| | - Neng Zhu
- Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Hong Fang Li
- Laboratory of Stem Cell Regulation With Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, 410208, Changsha, Hunan, People's Republic of China
| | - Jia Gu
- Laboratory of Stem Cell Regulation With Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, 410208, Changsha, Hunan, People's Republic of China
| | - Chan Juan Zhang
- Laboratory of Stem Cell Regulation With Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, 410208, Changsha, Hunan, People's Republic of China
| | - Duan Fang Liao
- Laboratory of Stem Cell Regulation With Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, 410208, Changsha, Hunan, People's Republic of China
| | - Li Qin
- Laboratory of Stem Cell Regulation With Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, 410208, Changsha, Hunan, People's Republic of China. .,Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Hunan University of Chinese Medicine, Changsha, China. .,Hunan Province Engineering Research Center of Bioactive Substance Discovery of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China.
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24
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Quader S, Tanabe S, Cabral H. Abnormal Glycosylation in Cancer Cells and Cancer Stem Cells as a Therapeutic Target. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1393:141-156. [PMID: 36587306 DOI: 10.1007/978-3-031-12974-2_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Tumor resistance and recurrence have been associated with the presence of cancer stem cells (CSCs) in tumors. The functions and survival of the CSCs have been associated with several intracellular and extracellular features. Particularly, the abnormal glycosylation of these signaling pathways and markers of CSCs have been correlated with maintaining survival, self-renewal and extravasation properties. Here, we highlight the importance of glycosylation in promoting the stemness character of CSCs and the current strategies for targeting abnormal glycosylation toward generating effective therapies against the CSC population.
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Affiliation(s)
- Sabina Quader
- Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
| | - Shihori Tanabe
- Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Horacio Cabral
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
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25
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Fang G, Lu H, Rodriguez de la Fuente L, Law AMK, Lin G, Jin D, Gallego‐Ortega D. Mammary Tumor Organoid Culture in Non-Adhesive Alginate for Luminal Mechanics and High-Throughput Drug Screening. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2102418. [PMID: 34494727 PMCID: PMC8564453 DOI: 10.1002/advs.202102418] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/25/2021] [Indexed: 05/14/2023]
Abstract
Mammary tumor organoids have become a promising in vitro model for drug screening and personalized medicine. However, the dependency on the basement membrane extract (BME) as the growth matrices limits their comprehensive application. In this work, mouse mammary tumor organoids are established by encapsulating tumor pieces in non-adhesive alginate. High-throughput generation of organoids in alginate microbeads is achieved utilizing microfluidic droplet technology. Tumor pieces within the alginate microbeads developed both luminal- and solid-like structures and displayed a high similarity to the original fresh tumor in cellular phenotypes and lineages. The mechanical forces of the luminal organoids in the alginate capsules are analyzed with the theory of the thick-wall pressure vessel (TWPV) model. The luminal pressure of the organoids increase with the lumen growth and can reach 2 kPa after two weeks' culture. Finally, the mammary tumor organoids are treated with doxorubicin and latrunculin A to evaluate their application as a drug screening platform. It is found that the drug response is related to the luminal size and pressures of organoids. This high-throughput culture for mammary tumor organoids may present a promising tool for preclinical drug target validation and personalized medicine.
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Affiliation(s)
- Guocheng Fang
- Institute for Biomedical Materials and DevicesSchool of Mathematical and Physical SciencesUniversity of Technology SydneyBroadway UltimoSydneyNew South Wales2007Australia
| | - Hongxu Lu
- Institute for Biomedical Materials and DevicesSchool of Mathematical and Physical SciencesUniversity of Technology SydneyBroadway UltimoSydneyNew South Wales2007Australia
| | - Laura Rodriguez de la Fuente
- St. Vincent's Clinical SchoolFaculty of MedicineUniversity of New South Wales SydneyDarlinghurstNew South Wales2010Australia
- Garvan Institute of Medical Research384 Victoria StreetDarlinghurstNew South Wales2010Australia
| | - Andrew M. K. Law
- St. Vincent's Clinical SchoolFaculty of MedicineUniversity of New South Wales SydneyDarlinghurstNew South Wales2010Australia
- Garvan Institute of Medical Research384 Victoria StreetDarlinghurstNew South Wales2010Australia
| | - Gungun Lin
- Institute for Biomedical Materials and DevicesSchool of Mathematical and Physical SciencesUniversity of Technology SydneyBroadway UltimoSydneyNew South Wales2007Australia
| | - Dayong Jin
- Institute for Biomedical Materials and DevicesSchool of Mathematical and Physical SciencesUniversity of Technology SydneyBroadway UltimoSydneyNew South Wales2007Australia
- UTS‐SUSTech Joint Research Centre for Biomedical Materials and DevicesDepartment of Biomedical EngineeringSouthern University of Science and TechnologyShenzhenGuangdong518055China
| | - David Gallego‐Ortega
- Institute for Biomedical Materials and DevicesSchool of Mathematical and Physical SciencesUniversity of Technology SydneyBroadway UltimoSydneyNew South Wales2007Australia
- St. Vincent's Clinical SchoolFaculty of MedicineUniversity of New South Wales SydneyDarlinghurstNew South Wales2010Australia
- Garvan Institute of Medical Research384 Victoria StreetDarlinghurstNew South Wales2010Australia
- School of Biomedical EngineeringFaculty of EngineeringUniversity of Technology SydneyBroadway UltimoSydneyNew South Wales2007Australia
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26
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Satija G, Sharma B, Madan A, Iqubal A, Shaquiquzzaman M, Akhter M, Parvez S, Khan MA, Alam MM. Benzimidazole based derivatives as anticancer agents: Structure activity relationship analysis for various targets. J Heterocycl Chem 2021. [DOI: 10.1002/jhet.4355] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Garvit Satija
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
| | - Barkha Sharma
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
| | - Anish Madan
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
| | - Ashif Iqubal
- Department of Pharmacology School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
| | - Mohammad Shaquiquzzaman
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
| | - Mymoona Akhter
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
| | - Suhel Parvez
- Department of Toxicology School of Chemical and Life Sciences, Jamia Hamdard New Delhi India
| | - Mohammad Ahmed Khan
- Department of Pharmacology School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
| | - Mohammad Mumtaz Alam
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India
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27
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Hossain SM, Lynch-Sutherland CF, Chatterjee A, Macaulay EC, Eccles MR. Can Immune Suppression and Epigenome Regulation in Placenta Offer Novel Insights into Cancer Immune Evasion and Immunotherapy Resistance? EPIGENOMES 2021; 5:16. [PMID: 34968365 PMCID: PMC8594685 DOI: 10.3390/epigenomes5030016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/18/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is the second leading cause of mortality and morbidity in the developed world. Cancer progression involves genetic and epigenetic alterations, accompanied by aggressive changes, such as increased immune evasion, onset of metastasis, and drug resistance. Similar to cancer, DNA hypomethylation, immune suppression, and invasive cell behaviours are also observed in the human placenta. Mechanisms that lead to the acquisition of invasive behaviour, immune evasion, and drug and immunotherapy resistance are presently under intense investigations to improve patient outcomes. Here, we review current knowledge regarding the similarities between immune suppression and epigenome regulation, including the expression of repetitive elements (REs), endogenous retroviruses (ERVs) and transposable elements (TEs) in cells of the placenta and in cancer, which are associated with changes in immune regulation and invasiveness. We explore whether immune suppression and epigenome regulation in placenta offers novel insights into immunotherapy resistance in cancer, and we also discuss the implications and the knowledge gaps relevant to these findings, which are rapidly being accrued in these quite disparate research fields. Finally, we discuss potential linkages between TE, ERV and RE activation and expression, regarding mechanisms of immune regulation in placenta and cancer. A greater understanding of the role of immune suppression and associated epigenome regulation in placenta could help to elucidate some comparable mechanisms operating in cancer, and identify potential new therapeutic targets for treating cancer.
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Affiliation(s)
- Sultana Mehbuba Hossain
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (S.M.H.); (C.F.L.-S.); (A.C.); (E.C.M.)
| | - Chiemi F. Lynch-Sutherland
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (S.M.H.); (C.F.L.-S.); (A.C.); (E.C.M.)
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (S.M.H.); (C.F.L.-S.); (A.C.); (E.C.M.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland 1010, New Zealand
| | - Erin C. Macaulay
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (S.M.H.); (C.F.L.-S.); (A.C.); (E.C.M.)
| | - Michael R. Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (S.M.H.); (C.F.L.-S.); (A.C.); (E.C.M.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland 1010, New Zealand
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28
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Mukherjee S, Yadav G, Kumar R. Recent trends in stem cell-based therapies and applications of artificial intelligence in regenerative medicine. World J Stem Cells 2021; 13:521-541. [PMID: 34249226 PMCID: PMC8246250 DOI: 10.4252/wjsc.v13.i6.521] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/22/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells are undifferentiated cells that can self-renew and differentiate into diverse types of mature and functional cells while maintaining their original identity. This profound potential of stem cells has been thoroughly investigated for its significance in regenerative medicine and has laid the foundation for cell-based therapies. Regenerative medicine is rapidly progressing in healthcare with the prospect of repair and restoration of specific organs or tissue injuries or chronic disease conditions where the body’s regenerative process is not sufficient to heal. In this review, the recent advances in stem cell-based therapies in regenerative medicine are discussed, emphasizing mesenchymal stem cell-based therapies as these cells have been extensively studied for clinical use. Recent applications of artificial intelligence algorithms in stem cell-based therapies, their limitation, and future prospects are highlighted.
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Affiliation(s)
- Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Garima Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
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29
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The Molecular Basis of Different Approaches for the Study of Cancer Stem Cells and the Advantages and Disadvantages of a Three-Dimensional Culture. Molecules 2021; 26:molecules26092615. [PMID: 33947095 PMCID: PMC8124970 DOI: 10.3390/molecules26092615] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/13/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) are a rare tumor subpopulation with high differentiation, proliferative and tumorigenic potential compared to the remaining tumor population. CSCs were first discovered by Bonnet and Dick in 1997 in acute myeloid leukemia. The identification and isolation of these cells in this pioneering study were carried out through the flow cytometry, exploiting the presence of specific cell surface molecular markers (CD34+/CD38−). In the following years, different strategies and projects have been developed for the study of CSCs, which are basically divided into surface markers assays and functional assays; some of these techniques also allow working with a cellular model that better mimics the tumor architecture. The purpose of this mini review is to summarize and briefly describe all the current methods used for the identification, isolation and enrichment of CSCs, describing, where possible, the molecular basis, the advantages and disadvantages of each technique with a particular focus on those that offer a three-dimensional culture.
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Khan T, Cabral H. Abnormal Glycosylation of Cancer Stem Cells and Targeting Strategies. Front Oncol 2021; 11:649338. [PMID: 33889547 PMCID: PMC8056457 DOI: 10.3389/fonc.2021.649338] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cell (CSCs) are deemed as one of the main reasons of tumor relapse due to their resistance to standard therapies. Numerous intracellular signaling pathways along with extracellular features are crucial in regulating CSCs properties, such as heterogeneity, plasticity and differentiation. Aberrant glycosylation of these cellular signaling pathways and markers of CSCs have been directly correlated with maintaining survival, self-renewal and extravasation properties. In this review, we highlight the importance of glycosylation in promoting stemness character of CSCs, and present strategies for targeting abnormal glycosylation to eliminate the resistant CSC population.
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Affiliation(s)
| | - Horacio Cabral
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
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Song SS, Huang S, Park S. Association of Polygenetic Risk Scores Related to Cell Differentiation and Inflammation with Thyroid Cancer Risk and Genetic Interaction with Dietary Intake. Cancers (Basel) 2021; 13:1510. [PMID: 33805984 PMCID: PMC8038131 DOI: 10.3390/cancers13071510] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/19/2021] [Accepted: 03/23/2021] [Indexed: 12/28/2022] Open
Abstract
The incidence of thyroid cancer continues to increase steadily, and this increasing incidence cannot be attributed solely to the overdiagnosis of microcarcinoma or technical advancements in detection methods and may also depend on environmental and genetic factors. However, the impacts and interactions of genetic and environmental factors remain controversial, and they may differ in Eastern and Western countries. The study's purpose was to identify single nucleotide polymorphisms of genes related to cell differentiation and inflammation to influence thyroid cancer incidence and determine interactions with lifestyles in a large city hospital-based cohort. Genetic variants were selected by genome-wide association study with thyroid cancer participants (case; n = 495) and controls without cancers (n = 56,439). SNPs having gene-gene interactions were selected by generalized multifactor dimensionality reduction. Polygenic risk scores (PRSs) were generated by summing the number of selected SNP risk alleles. PRSs of the best model included 6 SNPs, that is, DIRC3_rs6759952, GAP43_rs13059137, NRG1_rs7834206, PROM1_rs72616195, LRP1B_rs1369535, and LOC100507065_rs11175834. Participants with a high-PRS had a higher thyroid cancer risk by 3.9-fold than those with a low-PRS. The following variables were related to an increased thyroid cancer risk; female (OR = 4.21), high white blood cell count (OR = 4.03), and high energy (OR = 7.00), low alcohol (OR = 4.11), and high seaweed (OR = 4.02) intakes. These variables also interacted with PRS to influence thyroid cancer risk. Meat/noodle diet patterns interacted with PRSs to increase thyroid cancer risk (p = 0.0023). In conclusion, women with a high-PRS associated with cell differentiation and inflammation were at an elevated thyroid cancer risk. Daily energy, seaweeds, and alcohol intake interacted with PRS for thyroid cancer risk. These results could be applied to personalized nutrition plans to reduce the risk of thyroid cancer.
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Affiliation(s)
- Sang Shin Song
- Obesity/Diabetes Research Center, Department of Food and Nutrition, Hoseo University, Asan 31499, Korea;
| | - ShaoKai Huang
- Department of Bio-Convergence System, Hoseo University, Asan 31499, Korea;
| | - Sunmin Park
- Obesity/Diabetes Research Center, Department of Food and Nutrition, Hoseo University, Asan 31499, Korea;
- Department of Bio-Convergence System, Hoseo University, Asan 31499, Korea;
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