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Tigu AB, Munteanu R, Moldovan C, Rares D, Kegyes D, Tomai R, Moisoiu V, Ghiaur G, Tomuleasa C, Einsele H, Gulei D, Croce CM. Therapeutic advances in the targeting of ROR1 in hematological cancers. Cell Death Discov 2024; 10:471. [PMID: 39551787 PMCID: PMC11570672 DOI: 10.1038/s41420-024-02239-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/19/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) are key cell surface receptors involved in cell communication and signal transduction, with great importance in cell growth, differentiation, survival, and metabolism. Dysregulation of RTKs, such as EGFR, VEGFR, HER2 or ROR, could lead to various diseases, particularly cancers. ROR1 has emerged as a promising target in hematological malignancies. The development of ROR1 targeted therapies is continuously growing leading to remarkable novel therapeutical approaches using mAbs, antibody-drug conjugates, several small molecules or CAR T cells which have shown encouraging preclinical results. In the hematological field, mAbs, small molecules, BiTEs or CAR T cell therapies displayed promising outcomes with the clinical trials data encouraging the use of anti-ROR1 therapies. This paper aims to offer a comprehensive analysis of the current landscape of ROR1-targeted therapies in hematological malignancies marking the innovative approaches with promising preclinical and clinical. Offering a better understanding of structural and functional aspects of ROR1 could lead to new perspectives in targeting a wide spectrum of malignancies.
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Affiliation(s)
- Adrian-Bogdan Tigu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania
| | - Raluca Munteanu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania
| | - Cristian Moldovan
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania
| | - Drula Rares
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David Kegyes
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania
| | - Radu Tomai
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania
| | - Vlad Moisoiu
- Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Gabriel Ghiaur
- Division of Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Ciprian Tomuleasa
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania.
| | - Hermann Einsele
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania
- Department of Medicine, University of Würzburg, Würzburg, Germany
| | - Diana Gulei
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania
| | - Carlo M Croce
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
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2
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Shinde PP, Chitkara D, Mittal A. Downregulation of microRNA-29b in cancer and fibrosis: molecular insights and clinical implications. Drug Discov Today 2024; 29:104190. [PMID: 39322175 DOI: 10.1016/j.drudis.2024.104190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 09/04/2024] [Accepted: 09/18/2024] [Indexed: 09/27/2024]
Abstract
MicroRNA-29b (miR-29b) is known for its therapeutic potential as an antifibrotic and anticancer agent. In fibrotic conditions, miR-29b inhibits fibrogenesis by downregulating crucial regulators such as collagens, extracellular matrix proteins and the transforming growth factor-β pathway. Similarly, in cancer, it acts as a tumor suppressor by downregulating various oncogenes and signaling pathways involved in cancer progression, such as Wnt-β-catenin, p38-mitogen-activated protein kinase and nuclear factor-κB. However, the upregulation of these pathways suppresses miR-29b, contributing to fibrosis and cancer development. Preclinical research and clinical trials have shown that delivering exogenous miR-29b mimics can restore its expression, attenuating tumorigenesis and fibrogenesis. This review discusses miR-29b's potential and its possible therapeutic development for cancer and fibrotic disorders.
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Affiliation(s)
- Pratik Pramod Shinde
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333 031, India
| | - Deepak Chitkara
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333 031, India
| | - Anupama Mittal
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333 031, India.
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3
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Garbayo E, El Moukhtari SH, Rodríguez-Nogales C, Agirre X, Rodriguez-Madoz JR, Rodriguez-Marquez P, Prósper F, Couvreur P, Blanco-Prieto MJ. RNA-loaded nanoparticles for the treatment of hematological cancers. Adv Drug Deliv Rev 2024; 214:115448. [PMID: 39303823 DOI: 10.1016/j.addr.2024.115448] [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: 02/19/2024] [Revised: 06/07/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024]
Abstract
Hematological cancers encompass a diverse group of malignancies affecting the blood, bone marrow, lymph nodes, and spleen. These disorders present unique challenges due to their complex etiology and varied clinical manifestations. Despite significant advancements in understanding and treating hematological malignancies, innovative therapeutic approaches are continually sought to enhance patient outcomes. This review highlights the application of RNA nanoparticles (RNA-NPs) in the treatment of hematological cancers. We delve into detailed discussions on in vitro and preclinical studies involving RNA-NPs for adult patients, as well as the application of RNA-NPs in pediatric hematological cancer. The review also addresses ongoing clinical trials involving RNA-NPs and explores the emerging field of CAR-T therapy engineered by RNA-NPs. Finally, we discuss the challenges still faced in translating RNA-NP research to clinics.
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Affiliation(s)
- Elisa Garbayo
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain
| | - Souhaila H El Moukhtari
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain
| | - Carlos Rodríguez-Nogales
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain
| | - Xabier Agirre
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Juan R Rodriguez-Madoz
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Paula Rodriguez-Marquez
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Felipe Prósper
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain; Departmento de Hematología and CCUN, Clínica Universidad de Navarra, University of Navarra, Avenida Pío XII 36, 31008 Pamplona, Spain
| | - Patrick Couvreur
- Institut Galien Paris-Sud, UMR CNRS 8612, Université Paris-Saclay, Orsay Cedex, France.
| | - María J Blanco-Prieto
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain.
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Tarab-Ravski D, Stotsky-Oterin L, Elisha A, Kundoor GR, Ramishetti S, Hazan-Halevy I, Haas H, Peer D. The future of genetic medicines delivered via targeted lipid nanoparticles to leukocytes. J Control Release 2024; 376:286-302. [PMID: 39401676 DOI: 10.1016/j.jconrel.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 10/19/2024]
Abstract
Genetic medicines hold vast therapeutic potential, offering the ability to silence or induce gene expression, knock out genes, and even edit DNA fragments. Applying these therapeutic modalities to leukocytes offers a promising path for treating various conditions yet overcoming the obstacles of specific and efficient delivery to leukocytes remains a major bottleneck in their clinical translation. Lipid nanoparticles (LNPs) have emerged as the leading delivery system for nucleic acids due to their remarkable versatility and ability to improve their in vivo stability, pharmacokinetics, and therapeutic benefits. Equipping LNPs with targeting moieties can promote their specific cellular uptake and internalization to leukocytes, making targeted LNPs (tLNPs) an inseparable part of developing leukocyte-targeted gene therapy. However, despite the significant advancements in research, genetic medicines for leukocytes using targeted delivery approaches have not been translated into the clinic yet. Herein, we discuss the important aspects of designing tLNPs and highlight the considerations for choosing an appropriate bioconjugation strategy and targeting moiety. Furthermore, we provide our insights on limiting challenges and identify key areas for further research to advance these exciting therapies for patient care.
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Affiliation(s)
- Dana Tarab-Ravski
- Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise, Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel; Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Lior Stotsky-Oterin
- Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise, Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel; Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Aviad Elisha
- Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise, Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel; Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Govinda Reddy Kundoor
- Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise, Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel; Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | | | - Inbal Hazan-Halevy
- Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise, Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel; Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Heinrich Haas
- NeoVac Ltd. 127 Olympic Ave., OX14 4SA, Milton Park, Oxfordshire, UK; Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg-University, Mainz, Germany
| | - Dan Peer
- Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise, Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel; Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.
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5
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Sivaganesh V, Ta TM, Peethambaran B. Pentagalloyl Glucose (PGG) Exhibits Anti-Cancer Activity against Aggressive Prostate Cancer by Modulating the ROR1 Mediated AKT-GSK3β Pathway. Int J Mol Sci 2024; 25:7003. [PMID: 39000112 PMCID: PMC11241829 DOI: 10.3390/ijms25137003] [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: 05/09/2024] [Revised: 06/24/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Androgen-receptor-negative, androgen-independent (ARneg-AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted prostate cancer therapy. In this study, we identify that Penta-O-galloyl-β-D-glucose (PGG), a plant-derived gallotannin small molecule inhibitor, modulates ROR1-mediated oncogenic signaling and mitigates prostate cancer phenotypes. Results indicate that ROR1 protein levels were elevated in the highly aggressive ARneg-AI PC3 cancer cell line. PGG was selectively cytotoxic to PC3 cells and induced apoptosis of PC3 (IC50 of 31.64 µM) in comparison to normal prostate epithelial RWPE-1 cells (IC50 of 74.55 µM). PGG was found to suppress ROR1 and downstream oncogenic pathways in PC3 cells. These molecular phenomena were corroborated by reduced migration, invasion, and cell cycle progression of PC3 cells. PGG minimally and moderately affected RWPE-1 and ARneg-AI DU145, respectively, which may be due to these cells having lower levels of ROR1 expression in comparison to PC3 cells. Additionally, PGG acted synergistically with the standard chemotherapeutic agent docetaxel to lower the IC50 of both compounds about five-fold (combination index = 0.402) in PC3 cells. These results suggest that ROR1 is a key oncogenic driver and a promising target in aggressive prostate cancers that lack a targetable androgen receptor. Furthermore, PGG may be a selective and potent anti-cancer agent capable of treating ROR1-expressing prostate cancers.
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Affiliation(s)
- Vignesh Sivaganesh
- Department of Biology, Saint Joseph’s University, 600 S 43rd St, Philadelphia, PA 19104, USA; (V.S.); (T.M.T.)
- Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, 4170 City Ave, Philadelphia, PA 19131, USA
| | - Tram M. Ta
- Department of Biology, Saint Joseph’s University, 600 S 43rd St, Philadelphia, PA 19104, USA; (V.S.); (T.M.T.)
| | - Bela Peethambaran
- Department of Biology, Saint Joseph’s University, 600 S 43rd St, Philadelphia, PA 19104, USA; (V.S.); (T.M.T.)
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6
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Bayraktar R, Fontana B, Calin GA, Nemeth K. miRNA Biology in Chronic Lymphocytic Leukemia. Semin Hematol 2024; 61:181-193. [PMID: 38724414 DOI: 10.1053/j.seminhematol.2024.03.001] [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: 11/27/2023] [Revised: 02/23/2024] [Accepted: 03/11/2024] [Indexed: 07/13/2024]
Abstract
microRNAs (miRNAs) are a class of small non-coding RNAs that play a crucial regulatory role in fundamental biological processes and have been implicated in various diseases, including cancer. The first evidence of the cancer-related function of miRNAs was discovered in chronic lymphocytic leukemia (CLL) in the early 2000s. Alterations in miRNA expression have since been shown to strongly influence the clinical course, prognosis, and response to treatment in patients with CLL. Therefore, the identification of specific miRNA alterations not only enhances our understanding of the molecular mechanisms underlying CLL but also holds promise for the development of novel diagnostic and therapeutic strategies. This review aims to provide a comprehensive summary of the current knowledge and recent insights into miRNA dysregulation in CLL, emphasizing its pivotal roles in disease progression, including the development of the lethal Richter syndrome, and to provide an update on the latest translational research in this field.
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Affiliation(s)
- Recep Bayraktar
- Translational Molecular Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Beatrice Fontana
- Translational Molecular Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - George A Calin
- Translational Molecular Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX; The RNA Interference and Non-coding RNA Center, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kinga Nemeth
- Translational Molecular Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX.
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7
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Wu ZL, Wang Y, Jia XY, Wang YG, Wang H. Receptor tyrosine kinase-like orphan receptor 1: A novel antitumor target in gastrointestinal cancers. World J Clin Oncol 2024; 15:603-613. [PMID: 38835843 PMCID: PMC11145958 DOI: 10.5306/wjco.v15.i5.603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/20/2024] [Accepted: 04/17/2024] [Indexed: 05/21/2024] Open
Abstract
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the type I receptor tyrosine kinase family. ROR1 is pivotal in embryonic development and cancer, and serves as a biomarker and therapeutic target. It has soluble and membrane-bound subtypes, with the latter highly expressed in tumors. ROR1 is conserved throughout evolution and may play a role in the development of gastrointestinal cancer through multiple signaling pathways and molecular mechanisms. Studies suggest that overexpression of ROR1 may increase tumor invasiveness and metastasis. Additionally, ROR1 may regulate the cell cycle, stem cell characteristics, and interact with other signaling pathways to affect cancer progression. This review explores the structure, expression and role of ROR1 in the development of gastrointestinal cancers. It discusses current antitumor strategies, outlining challenges and prospects for treatment.
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Affiliation(s)
- Zheng-Long Wu
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
- Department of Oncology, Zhejiang Xiaoshan Hospital, Hangzhou 311201, Zhejiang Province, China
| | - Ying Wang
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Xiao-Yuan Jia
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Yi-Gang Wang
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Hui Wang
- Department of Oncology, Zhejiang Xiaoshan Hospital, Hangzhou 311201, Zhejiang Province, China
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Sciaccotta R, Gangemi S, Penna G, Giordano L, Pioggia G, Allegra A. Potential New Therapies "ROS-Based" in CLL: An Innovative Paradigm in the Induction of Tumor Cell Apoptosis. Antioxidants (Basel) 2024; 13:475. [PMID: 38671922 PMCID: PMC11047475 DOI: 10.3390/antiox13040475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/09/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm.
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Affiliation(s)
- Raffaele Sciaccotta
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (R.S.); (G.P.); (L.G.)
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| | - Giuseppa Penna
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (R.S.); (G.P.); (L.G.)
| | - Laura Giordano
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (R.S.); (G.P.); (L.G.)
| | - Giovanni Pioggia
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy;
| | - Alessandro Allegra
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (R.S.); (G.P.); (L.G.)
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9
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Zhang X, Wang H, Zhang Y, Wang X. Advances in epigenetic alterations of chronic lymphocytic leukemia: from pathogenesis to treatment. Clin Exp Med 2024; 24:54. [PMID: 38492089 PMCID: PMC10944427 DOI: 10.1007/s10238-023-01268-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 12/01/2023] [Indexed: 03/18/2024]
Abstract
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with alterations in genetic expression and epigenetic modifications. In recent years, the new insight into epigenetics in the pathogenesis of CLL has been developed considerably, including DNA methylation, histone modification, RNA methylation, non-coding RNAs as well as chromatin remodeling. Epigenetic modification regulates various processes such as stem cell biology, cell growth, and tumorigenesis without altering gene sequence. Growing evidence indicates that the disturbance of gene expression profiles which were regulated by epigenetic modifications exerts vital roles in the development and progress in CLL, which provides novel perspectives to explore the etiology of CLL. In addition, the integration with epigenetic therapeutic targets and the in-depth understanding of epigenetic therapy contribute to develop new therapeutic strategies for CLL. Herein, the present review discusses the advances of epigenetic alterations in the pathogenesis, diagnosis, and prognostic assessment of CLL patients and also highlights existing and emerging agents targeting epigenetic regulators.
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Affiliation(s)
- Xin Zhang
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Hua Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Ya Zhang
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Taishan Scholars Program of Shandong Province, Jinan, 250021, Shandong, China.
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
- Taishan Scholars Program of Shandong Province, Jinan, 250021, Shandong, China.
- Branch of National Clinical Research Center for Hematologic Diseases, Jinan, 250021, Shandong, China.
- National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China.
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10
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Mouawad N, Ruggeri E, Capasso G, Martinello L, Visentin A, Frezzato F, Trentin L. How receptor tyrosine kinase-like orphan receptor 1 meets its partners in chronic lymphocytic leukemia. Hematol Oncol 2024; 42:e3250. [PMID: 38949887 DOI: 10.1002/hon.3250] [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: 10/12/2023] [Revised: 12/29/2023] [Accepted: 01/02/2024] [Indexed: 07/03/2024]
Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in western societies, recognized by clinical and molecular heterogeneity. Despite the success of targeted therapies, acquired resistance remains a challenge for relapsed and refractory CLL, as a consequence of mutations in the target or the upregulation of other survival pathways leading to the progression of the disease. Research on proteins that can trigger such pathways may define novel therapies for a successful outcome in CLL such as the receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 is a signaling receptor for Wnt5a, with an important role during embryogenesis. The aberrant expression on CLL cells and several types of tumors, is involved in cell proliferation, survival, migration as well as drug resistance. Antibody-based immunotherapies and small-molecule compounds emerged to target ROR1 in preclinical and clinical studies. Efforts have been made to identify new prognostic markers having predictive value to refine and increase the detection and management of CLL. ROR1 can be considered as an attractive target for CLL diagnosis, prognosis, and treatment. It can be clinically effective alone and/or in combination with current approved agents. In this review, we summarize the scientific achievements in targeting ROR1 for CLL diagnosis, prognosis, and treatment.
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MESH Headings
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Humans
- Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
- Prognosis
- Molecular Targeted Therapy
- Animals
- Biomarkers, Tumor/metabolism
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Affiliation(s)
- Nayla Mouawad
- Hematology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Edoardo Ruggeri
- Hematology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Guido Capasso
- Hematology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Leonardo Martinello
- Hematology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Andrea Visentin
- Hematology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Federica Frezzato
- Hematology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Livio Trentin
- Hematology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
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11
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Ali A, Mahla SB, Reza V, Hossein A, Bahareh K, Mohammad H, Fatemeh S, Mostafa AB, Leili R. MicroRNAs: Potential prognostic and theranostic biomarkers in chronic lymphocytic leukemia. EJHAEM 2024; 5:191-205. [PMID: 38406506 PMCID: PMC10887358 DOI: 10.1002/jha2.849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 12/13/2023] [Accepted: 12/29/2023] [Indexed: 02/27/2024]
Abstract
Small noncoding ribonucleic acids called microRNAs coordinate numerous critical physiological and biological processes such as cell division, proliferation, and death. These regulatory molecules interfere with the function of many genes by binding the 3'-UTR region of target mRNAs to inhibit their translation or even degrade them. Given that a large proportion of miRNAs behave as either tumor suppressors or oncogenes, any genetic or epigenetic aberration changeing their structure and/or function could initiate tumor formation and development. An example of such cancers is chronic lymphocytic leukemia (CLL), the most prevalent adult leukemia in Western nations, which is caused by unregulated growth and buildup of defective cells in the peripheral blood and lymphoid organs. Genetic alterations at cellular and molecular levels play an important role in the occurrence and development of CLL. In this vein, it was noted that the development of this disease is noticeably affected by changes in the expression and function of miRNAs. Many studies on miRNAs have shown that these molecules are pivotal in the prognosis of different cancers, including CLL, and their epigenetic alterations (e.g., methylation) can predict disease progression and response to treatment. Furthermore, miRNAs are involved in the development of drug resistance in CLL, and targeting these molecules can be considered a new therapeutic approach for the treatment of this disease. MiRNA screening can offer important information on the etiology and development of CLL. Considering the importance of miRNAs in gene expression regulation, their application in the diagnosis, prognosis, and treatment of CLL is reviewed in this paper.
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Affiliation(s)
- Afgar Ali
- Research Center for Hydatid Disease in IranKerman University of Medical SciencesKermanIran
| | - Sattarzadeh Bardsiri Mahla
- Stem Cells and Regenerative Medicine Innovation CenterKerman University of Medical SciencesKermanIran
- Department of Hematology and Laboratory Sciences, Faculty of Allied Medical SciencesKerman University of Medical SciencesKermanIran
| | - Vahidi Reza
- Research Center for Hydatid Disease in IranKerman University of Medical SciencesKermanIran
| | - Arezoomand Hossein
- Department of Hematology and Laboratory Sciences, Faculty of Allied Medical SciencesKerman University of Medical SciencesKermanIran
| | - Kashani Bahareh
- Department of Medical Genetics, School of MedicineTehran University of Medical SciencesTehranIran
| | - Hosseininaveh Mohammad
- Research Center for Hydatid Disease in IranKerman University of Medical SciencesKermanIran
| | - Sharifi Fatemeh
- Research Center of Tropical and Infectious DiseasesKerman University of Medical SciencesKermanIran
| | - Amopour Bahnamiry Mostafa
- Department of Research and Development, Production and Research ComplexPasteur Institute of IranTehranIran
| | - Rouhi Leili
- Student Research CommitteeKerman University of Medical SciencesKermanIran
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12
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Chiang CL, Ma Y, Hou YC, Pan J, Chen SY, Chien MH, Zhang ZX, Hsu WH, Wang X, Zhang J, Li H, Sun L, Fallen S, Lee I, Chen XY, Chu YS, Zhang C, Cheng TS, Jiang W, Kim BYS, Reategui E, Lee R, Yuan Y, Liu HC, Wang K, Hsiao M, Huang CYF, Shan YS, Lee AS, James Lee L. Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer. Nat Commun 2023; 14:6692. [PMID: 37872156 PMCID: PMC10593751 DOI: 10.1038/s41467-023-42402-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 10/10/2023] [Indexed: 10/25/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours.
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Affiliation(s)
- Chi-Ling Chiang
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
- Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Yifan Ma
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Ya-Chin Hou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Junjie Pan
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Sin-Yu Chen
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Ming-Hsien Chien
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Zhi-Xuan Zhang
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Wei-Hsiang Hsu
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Xinyu Wang
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Jingjing Zhang
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Hong Li
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Lili Sun
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
| | | | - Inyoul Lee
- Institute of Systems Biology, Seattle, WA, 98109, USA
| | - Xing-Yu Chen
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Yeh-Shiu Chu
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Chi Zhang
- College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA
| | - Tai-Shan Cheng
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Wen Jiang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Betty Y S Kim
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Eduardo Reategui
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Robert Lee
- College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA
| | - Yuan Yuan
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Hsiao-Chun Liu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Kai Wang
- Institute of Systems Biology, Seattle, WA, 98109, USA
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
| | - Andrew S Lee
- Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518055, China.
- School of Chemical Biology and Biochemistry, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
| | - L James Lee
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA.
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
- Spot Biosystems Ltd., Palo Alto, CA, 94305, USA.
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13
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Autore F, Ramassone A, Stirparo L, Pagotto S, Fresa A, Innocenti I, Visone R, Laurenti L. Role of microRNAs in Chronic Lymphocytic Leukemia. Int J Mol Sci 2023; 24:12471. [PMID: 37569845 PMCID: PMC10419063 DOI: 10.3390/ijms241512471] [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: 07/05/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia in adults, with a highly variable clinical course. Improvement in the knowledge of the molecular pathways behind this disease has led to the development of increasingly specific therapies, such as BCR signaling inhibitors and BCL-2 inhibitors. In this context, the emerging role of microRNAs (miRNAs) in CLL pathophysiology and their possible application in therapy is worth noting. MiRNAs are one of the most important regulatory molecules of gene expression. In CLL, they can act both as oncogenes and tumor suppressor genes, and the deregulation of specific miRNAs has been associated with prognosis, progression, and drug resistance. In this review, we describe the role of the miRNAs that primarily impact the disease, and how these miRNAs could be used as therapeutic tools. Certainly, the use of miRNAs in clinical practice is still limited in CLL. Many issues still need to be solved, particularly regarding their biological and safety profile, even if several studies have suggested their efficacy on the disease, alone or in combination with other drugs.
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Affiliation(s)
- Francesco Autore
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Alice Ramassone
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
| | - Luca Stirparo
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Sara Pagotto
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, 66100 Chieti, Italy
| | - Alberto Fresa
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Idanna Innocenti
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Rosa Visone
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, 66100 Chieti, Italy
| | - Luca Laurenti
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
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14
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Hay J, Tarafdar A, Holroyd AK, Moka HA, Dunn KM, Alshayeb A, Lloyd BH, Cassels J, Malik N, Khan AF, Sou I, Lees J, Almuhanna HNB, Kalakonda N, Slupsky JR, Michie AM. PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling. Cancers (Basel) 2022; 14:cancers14236006. [PMID: 36497487 PMCID: PMC9735720 DOI: 10.3390/cancers14236006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/22/2022] [Accepted: 11/30/2022] [Indexed: 12/13/2022] Open
Abstract
B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model.
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Affiliation(s)
- Jodie Hay
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Paul O’Gorman Leukaemia Research Centre, Gartnavel General Hospital, 21 Shelley Road, Glasgow G12 0ZD, UK
| | - Anuradha Tarafdar
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Ailsa K. Holroyd
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Hothri A. Moka
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Karen M. Dunn
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Paul O’Gorman Leukaemia Research Centre, Gartnavel General Hospital, 21 Shelley Road, Glasgow G12 0ZD, UK
| | - Alzahra Alshayeb
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
| | - Bryony H. Lloyd
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
| | - Jennifer Cassels
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Paul O’Gorman Leukaemia Research Centre, Gartnavel General Hospital, 21 Shelley Road, Glasgow G12 0ZD, UK
| | - Natasha Malik
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Ashfia F. Khan
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - IengFong Sou
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Jamie Lees
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Paul O’Gorman Leukaemia Research Centre, Gartnavel General Hospital, 21 Shelley Road, Glasgow G12 0ZD, UK
| | - Hassan N. B. Almuhanna
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Paul O’Gorman Leukaemia Research Centre, Gartnavel General Hospital, 21 Shelley Road, Glasgow G12 0ZD, UK
| | - Nagesh Kalakonda
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
| | - Joseph R. Slupsky
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
| | - Alison M. Michie
- School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Paul O’Gorman Leukaemia Research Centre, Gartnavel General Hospital, 21 Shelley Road, Glasgow G12 0ZD, UK
- Correspondence: ; Tel.: +44-(0)141-301-7885
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15
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Abstract
Since its initial identification in 1992 as a possible class 1 cell-surface receptor without a known parent ligand, receptor tyrosine kinase-like orphan receptor 1 (ROR1) has stimulated research, which has made apparent its significance in embryonic development and cancer. Chronic lymphocytic leukemia (CLL) was the first malignancy found to have distinctive expression of ROR1, which can help distinguish leukemia cells from most noncancer cells. Aside from its potential utility as a diagnostic marker or target for therapy, ROR1 also factors in the pathophysiology of CLL. This review is a report of the studies that have elucidated the expression, biology, and evolving strategies for targeting ROR1 that hold promise for improving the therapy of patients with CLL or other ROR1-expressing malignancies.
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Affiliation(s)
- Thomas J. Kipps
- Center for Novel Therapeutics, Moores Cancer Center, Department of Medicine, University of California, San Diego, La Jolla, CA
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16
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Goswami S, Chiang CL, Zapolnik K, Nunes J, Ventura A, Mo X, Xie Z, Lee LJ, Baskar S, Rader C, Byrd JC, Phelps M, Bhatnagar B, Muthusamy N. ROR1 targeted immunoliposomal delivery of OSU-2S shows selective cytotoxicity in t(1;19)(q23;p13) translocated B-cell acute lymphoblastic leukemia. Leuk Res 2022; 118:106872. [PMID: 35640397 PMCID: PMC10029232 DOI: 10.1016/j.leukres.2022.106872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 05/02/2022] [Accepted: 05/19/2022] [Indexed: 10/18/2022]
Affiliation(s)
- Swagata Goswami
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Chi-Ling Chiang
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Kevan Zapolnik
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jessica Nunes
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Ann Ventura
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Xiaokui Mo
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Zhiliang Xie
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - L James Lee
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA
| | - Sivasubramanian Baskar
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - John C Byrd
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mitch Phelps
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Bhavana Bhatnagar
- Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Natarajan Muthusamy
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Role of Nano-miRNAs in Diagnostics and Therapeutics. Int J Mol Sci 2022; 23:ijms23126836. [PMID: 35743278 PMCID: PMC9223810 DOI: 10.3390/ijms23126836] [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: 05/11/2022] [Revised: 06/15/2022] [Accepted: 06/17/2022] [Indexed: 12/26/2022] Open
Abstract
MicroRNAs (miRNA) are key regulators of gene expression, controlling different biological processes such as cellular development, differentiation, proliferation, metabolism, and apoptosis. The relationships between miRNA expression and the onset and progression of different diseases, such as tumours, cardiovascular and rheumatic diseases, and neurological disorders, are well known. A nanotechnology-based approach could match miRNA delivery and detection to move beyond the proof-of-concept stage. Different kinds of nanotechnologies can have a major impact on the diagnosis and treatment of miRNA-related diseases such as cancer. Developing novel methodologies aimed at clinical practice represents a big challenge for the early diagnosis of specific diseases. Within this context, nanotechnology represents a wide emerging area at the forefront of research over the last two decades, whose potential has yet to be fully attained. Nanomedicine, derived from nanotechnology, can exploit the unique properties of nanometer-sized particles for diagnostic and therapeutic purposes. Through nanomedicine, specific treatment to counteract only cancer-cell proliferation will be improved, while leaving healthy cells intact. In this review, we dissect the properties of different nanocarriers and their roles in the early detection and treatment of cancer.
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18
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Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond. Cancers (Basel) 2022; 14:cancers14122997. [PMID: 35740661 PMCID: PMC9221163 DOI: 10.3390/cancers14122997] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/14/2022] [Accepted: 06/14/2022] [Indexed: 11/20/2022] Open
Abstract
Simple Summary Mutations of the NOTCH1 gene are a validated prognostic marker in chronic lymphocytic leukemia and a potential predictive marker for anti-CD20-based therapies. At present, the most frequent pathological alteration of the NOTCH1 gene is due to somatic genetic mutations, which have a multifaceted functional impact. However, beside NOTCH1 mutations, other factors may lead to activation of the NOTCH1 pathway, and these include mutations of FBXW7, MED12, SPEN, SF3B1 as well as other B-cell pathways. Understanding the preferential strategies though which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL. Abstract The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated protein ultimately operates as a nuclear transcriptional co-factor, whose stability is finely regulated. The Notch pathway has gained growing attention in chronic lymphocytic leukemia (CLL) because of the high rate of somatic mutations of the NOTCH1 gene. In CLL, NOTCH1 mutations represent a validated prognostic marker and a potential predictive marker for anti-CD20-based therapies, as pathological alterations of the Notch pathway can provide significant growth and survival advantage to neoplastic clone. However, beside NOTCH1 mutation, other events have been demonstrated to perturb the Notch pathway, namely somatic mutations of upstream, or even apparently unrelated, proteins such as FBXW7, MED12, SPEN, SF3B1, as well as physiological signals from other pathways such as the B-cell receptor. Here we review these mechanisms of activation of the NOTCH1 pathway in the context of CLL; the resulting picture highlights how multiple different mechanisms, that might occur under specific genomic, phenotypic and microenvironmental contexts, ultimately result in the same search for proliferative and survival advantages (through activation of MYC), as well as immune escape and therapy evasion (from anti-CD20 biological therapies). Understanding the preferential strategies through which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL.
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19
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Zoulikha M, He W. Targeted Drug Delivery for Chronic Lymphocytic Leukemia. Pharm Res 2022; 39:441-461. [DOI: 10.1007/s11095-022-03214-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 02/21/2022] [Indexed: 02/06/2023]
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Tarab-Ravski D, Stotsky-Oterin L, Peer D. Delivery strategies of RNA therapeutics to leukocytes. J Control Release 2022; 342:362-371. [PMID: 35041904 DOI: 10.1016/j.jconrel.2022.01.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/31/2021] [Accepted: 01/10/2022] [Indexed: 12/27/2022]
Abstract
Harnessing RNA-based therapeutics for cancer, inflammation, and viral diseases is hindered by poor delivery of therapeutic RNA molecules. Targeting leukocytes to treat these conditions holds great promise, as they are key participants in their initiation, drug response, and treatment. The various extra- and intra-cellular obstacles that impediment the clinical implementation of therapeutic RNA can be overcome by utilizing drug delivery systems. However, delivery of therapeutic RNA to leukocytes poses an even greater challenge as these cells are difficult to reach and transfect upon systemic administration. This review briefly describes the existing successful delivery strategies that efficiently target leukocytes in vivo and discuss their potential clinical applicability.
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Affiliation(s)
- Dana Tarab-Ravski
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel
| | - Lior Stotsky-Oterin
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Dan Peer
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.
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21
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Nanoparticle-Based Modification of the DNA Methylome: A Therapeutic Tool for Atherosclerosis? CARDIOGENETICS 2022. [DOI: 10.3390/cardiogenetics12010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Cardiovascular epigenomics is a relatively young field of research, yet it is providing novel insights into gene regulation in the atherosclerotic arterial wall. That information is already pointing to new avenues for atherosclerosis (AS) prevention and therapy. In parallel, advances in nanoparticle (NP) technology allow effective targeting of drugs and bioactive molecules to the vascular wall. The partnership of NP technology and epigenetics in AS is just beginning and promises to produce novel exciting candidate treatments. Here, we briefly discuss the most relevant recent advances in the two fields. We focus on AS and DNA methylation, as the DNA methylome of that condition is better understood in comparison with the rest of the cardiovascular disease field. In particular, we review the most recent advances in NP-based delivery systems and their use for DNA methylome modification in inflammation. We also address the promises of DNA methyltransferase inhibitors for prevention and therapy. Furthermore, we emphasize the unique challenges in designing therapies that target the cardiovascular epigenome. Lastly, we touch the issue of human exposure to industrial NPs and its impact on the epigenome as a reminder of the undesired effects that any NP-based therapy must avoid to be apt for secondary prevention of AS.
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22
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The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia. Blood Adv 2021; 5:3152-3162. [PMID: 34424320 DOI: 10.1182/bloodadvances.2020003276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 04/18/2021] [Indexed: 11/20/2022] Open
Abstract
Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody-based therapies. Herein we describe a humanized, first-in-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR1+ malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR1+ leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR1+ hematologic malignancies.
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23
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Anelli L, Zagaria A, Specchia G, Musto P, Albano F. Dysregulation of miRNA in Leukemia: Exploiting miRNA Expression Profiles as Biomarkers. Int J Mol Sci 2021; 22:ijms22137156. [PMID: 34281210 PMCID: PMC8269043 DOI: 10.3390/ijms22137156] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 12/14/2022] Open
Abstract
Micro RNAs (miRNAs) are a class of small non-coding RNAs that have a crucial role in cellular processes such as differentiation, proliferation, migration, and apoptosis. miRNAs may act as oncogenes or tumor suppressors; therefore, they prevent or promote tumorigenesis, and abnormal expression has been reported in many malignancies. The role of miRNA in leukemia pathogenesis is still emerging, but several studies have suggested using miRNA expression profiles as biomarkers for diagnosis, prognosis, and response to therapy in leukemia. In this review, the role of miRNAs most frequently involved in leukemia pathogenesis is discussed, focusing on the class of circulating miRNAs, consisting of cell-free RNA molecules detected in several body fluids. Circulating miRNAs could represent new potential non-invasive diagnostic and prognostic biomarkers of leukemia that are easy to isolate and characterize. The dysregulation of some miRNAs involved in both myeloid and lymphoid leukemia, such as miR-155, miR-29, let-7, and miR-15a/miR-16-1 clusters is discussed, showing their possible employment as therapeutic targets.
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Affiliation(s)
- Luisa Anelli
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
| | - Antonella Zagaria
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
| | - Giorgina Specchia
- School of Medicine, University of Bari ‘Aldo Moro’, 70100 Bari, Italy;
| | - Pellegrino Musto
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
| | - Francesco Albano
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
- Correspondence: ; Tel.: +39(0)-80-547-8031; Fax: +39-(0)80-559-3471
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24
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Chiang CL, Cheng MH, Lin CH. From Nanoparticles to Cancer Nanomedicine: Old Problems with New Solutions. NANOMATERIALS 2021; 11:nano11071727. [PMID: 34209111 PMCID: PMC8308137 DOI: 10.3390/nano11071727] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/12/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022]
Abstract
Anticancer nanomedicines have been studied over 30 years, but fewer than 10 formulations have been approved for clinical therapy today. Despite abundant options of anticancer drugs, it remains challenging to have agents specifically target cancer cells while reducing collateral toxicity to healthy tissue. Nanocompartments that can be selective toward points deeply within malignant tissues are a promising concept, but the heterogeneity of tumor tissue, inefficiency of cargo loading and releasing, and low uniformity of manufacture required from preclinical to commercialization are major obstacles. Technological advances have been made in this field, creating engineered nanomaterials with improved uniformity, flexibility of cargo loading, diversity of surface modification, and less inducible immune responses. This review highlights the developmental process of approved nanomedicines and the opportunities for novel materials that combine insights of tumors and nanotechnology to develop a more effective nanomedicine for cancer patients.
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Affiliation(s)
- Chi-Ling Chiang
- Comprehensive Cancer Center, Division of Hematology, Ohio State University, Columbus, OH 43202, USA;
- NSEC Center for Affordable Nanoengineering of Polymeric Biomedical Devices, Ohio State University, Columbus, OH 43202, USA
| | - Ming-Huei Cheng
- Center of Lymphedema Microsurgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan;
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Chih-Hsin Lin
- Graduate Institute of Nanomedicine and Medical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence:
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25
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Sharma S, Pavlasova GM, Seda V, Cerna KA, Vojackova E, Filip D, Ondrisova L, Sandova V, Kostalova L, Zeni PF, Borsky M, Oppelt J, Liskova K, Kren L, Janikova A, Pospisilova S, Fernandes SM, Shehata M, Rassenti LZ, Jaeger U, Doubek M, Davids MS, Brown JR, Mayer J, Kipps TJ, Mraz M. miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors. Blood 2021; 137:2481-2494. [PMID: 33171493 PMCID: PMC7610744 DOI: 10.1182/blood.2020005627] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022] Open
Abstract
B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.
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MESH Headings
- Adenine/analogs & derivatives
- Adenine/pharmacology
- Adult
- Aged
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- CD40 Antigens/genetics
- CD40 Antigens/metabolism
- Female
- Follow-Up Studies
- Gene Expression Regulation, Neoplastic
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Male
- MicroRNAs/genetics
- Middle Aged
- Piperidines/pharmacology
- Prognosis
- Proto-Oncogene Proteins c-bcr/antagonists & inhibitors
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- Survival Rate
- TNF Receptor-Associated Factor 4/genetics
- TNF Receptor-Associated Factor 4/metabolism
- Tumor Cells, Cultured
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Affiliation(s)
- Sonali Sharma
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Gabriela Mladonicka Pavlasova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Vaclav Seda
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Katerina Amruz Cerna
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Eva Vojackova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Daniel Filip
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Laura Ondrisova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Veronika Sandova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Lenka Kostalova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Pedro F Zeni
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Marek Borsky
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jan Oppelt
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Kvetoslava Liskova
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Leos Kren
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Andrea Janikova
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Sarka Pospisilova
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Stacey M Fernandes
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Medhat Shehata
- Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; and
| | - Laura Z Rassenti
- Moores Cancer Center, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Ulrich Jaeger
- Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; and
| | - Michael Doubek
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Matthew S Davids
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jennifer R Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jiri Mayer
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Thomas J Kipps
- Moores Cancer Center, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Marek Mraz
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
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26
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Heydarzadeh S, Ranjbar M, Karimi F, Seif F, Alivand MR. Overview of host miRNA properties and their association with epigenetics, long non-coding RNAs, and Xeno-infectious factors. Cell Biosci 2021; 11:43. [PMID: 33632341 PMCID: PMC7905430 DOI: 10.1186/s13578-021-00552-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 02/06/2021] [Indexed: 12/19/2022] Open
Abstract
MicroRNA-derived structures play impressive roles in various biological processes. So dysregulation of miRNAs can lead to different human diseases. Recent studies have extended our comprehension of the control of miRNA function and features. Here, we overview some remarkable miRNA properties that have potential implications for the miRNA functions, including different variants of a miRNA called isomiRs, miRNA arm selection/arm switching, and the effect of these factors on miRNA target selection. Besides, we review some aspects of miRNA interactions such as the interaction between epigenetics and miRNA (different miRNAs and their related processing enzymes are epigenetically regulated by multiple DNA methylation enzymes. moreover, DNA methylation could be controlled by diverse mechanisms related to miRNAs), direct and indirect crosstalk between miRNA and lnc (Long Non-Coding) RNAs as a further approach to conduct intercellular regulation called "competing endogenous RNA" (ceRNA) that is involved in the pathogenesis of different diseases, and the interaction of miRNA activities and some Xeno-infectious (virus/bacteria/parasite) factors, which result in modulation of the pathogenesis of infections. This review provides some related studies to a better understanding of miRNA involvement mechanisms and overcoming the complexity of related diseases that may be applicable and useful to prognostic, diagnostic, therapeutic purposes and personalized medicine in the future.
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Affiliation(s)
- Samaneh Heydarzadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Ranjbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farokh Karimi
- Department of Biotechnology, Faculty of Science, University of Maragheh, Maragheh, Iran
| | - Farhad Seif
- Department of Immunology and Allergy, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran
- Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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27
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Raue R, Frank AC, Syed SN, Brüne B. Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment. Int J Mol Sci 2021; 22:ijms22042210. [PMID: 33672261 PMCID: PMC7926641 DOI: 10.3390/ijms22042210] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.
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Affiliation(s)
- Rebecca Raue
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
| | - Ann-Christin Frank
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
| | - Shahzad Nawaz Syed
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
- Correspondence: (S.N.S.); (B.B.); Tel.: +49-69-6301-7424 (B.B.)
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (R.R.); (A.-C.F.)
- Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, 60596 Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany
- Correspondence: (S.N.S.); (B.B.); Tel.: +49-69-6301-7424 (B.B.)
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28
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Katsaraki K, Karousi P, Artemaki PI, Scorilas A, Pappa V, Kontos CK, Papageorgiou SG. MicroRNAs: Tiny Regulators of Gene Expression with Pivotal Roles in Normal B-Cell Development and B-Cell Chronic Lymphocytic Leukemia. Cancers (Basel) 2021; 13:cancers13040593. [PMID: 33546241 PMCID: PMC7913321 DOI: 10.3390/cancers13040593] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 01/01/2023] Open
Abstract
Simple Summary The involvement of miRNAs in physiological cellular processes has been well documented. The development of B cells, which is dictated by a miRNA-transcription factor regulatory network, suggests a typical process partly orchestrated by miRNAs. Besides their contribution in normal hematopoiesis, miRNAs have been severally reported to be implicated in hematological malignancies, a typical example of which is B-cell chronic lymphocytic leukemia (B-CLL). Numerous studies have attempted to highlight the regulatory role of miRNAs in B-CLL or establish some of them as molecular biomarkers or therapeutic targets. Thus, a critical review summarizing the current knowledge concerning the multifaceted role of miRNAs in normal B-cell development and B-CLL progression, prognosis, and therapy, is urgent. Moreover, this review aims to highlight important miRNAs in both normal B-cell development and B-CLL and discuss future perspectives concerning their regulatory potential and establishment in clinical practice. Abstract MicroRNAs (miRNAs) represent a class of small non-coding RNAs bearing regulatory potency. The implication of miRNAs in physiological cellular processes has been well documented so far. A typical process orchestrated by miRNAs is the normal B-cell development. A stage-specific expression pattern of miRNAs has been reported in the developmental procedure, as well as interactions with transcription factors that dictate B-cell development. Besides their involvement in normal hematopoiesis, miRNAs are severally implicated in hematological malignancies, a typical paradigm of which is B-cell chronic lymphocytic leukemia (B-CLL). B-CLL is a highly heterogeneous disease characterized by the accumulation of abnormal B cells in blood, bone marrow, lymph nodes, and spleen. Therefore, timely, specific, and sensitive assessment of the malignancy is vital. Several studies have attempted to highlight the remarkable significance of miRNAs as regulators of gene expression, biomarkers for diagnosis, prognosis, progression, and therapy response prediction, as well as molecules with potential therapeutic utility. This review seeks to outline the linkage between miRNA function in normal and malignant hematopoiesis by demonstrating the main benchmarks of the implication of miRNAs in the regulation of normal B-cell development, and to summarize the key findings about their value as regulators, biomarkers, or therapeutic targets in B-CLL.
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Affiliation(s)
- Katerina Katsaraki
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (K.K.); (P.K.); (P.I.A.); (A.S.)
| | - Paraskevi Karousi
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (K.K.); (P.K.); (P.I.A.); (A.S.)
| | - Pinelopi I. Artemaki
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (K.K.); (P.K.); (P.I.A.); (A.S.)
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (K.K.); (P.K.); (P.I.A.); (A.S.)
| | - Vasiliki Pappa
- Second Department of Internal Medicine and Research Unit, University General Hospital “Attikon”, 12462 Athens, Greece;
| | - Christos K. Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (K.K.); (P.K.); (P.I.A.); (A.S.)
- Correspondence: (C.K.K.); (S.G.P.); Tel.: +30-210-727-4616 (C.K.K.); +30-210-583-2519 (S.G.P.)
| | - Sotirios G. Papageorgiou
- Second Department of Internal Medicine and Research Unit, University General Hospital “Attikon”, 12462 Athens, Greece;
- Correspondence: (C.K.K.); (S.G.P.); Tel.: +30-210-727-4616 (C.K.K.); +30-210-583-2519 (S.G.P.)
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29
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Han JS, Kim SE, Jin JQ, Park NR, Lee JY, Kim HL, Lee SB, Yang SW, Lim DJ. Tear-Derived Exosome Proteins Are Increased in Patients with Thyroid Eye Disease. Int J Mol Sci 2021; 22:ijms22031115. [PMID: 33498689 PMCID: PMC7866068 DOI: 10.3390/ijms22031115] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/14/2021] [Accepted: 01/20/2021] [Indexed: 12/14/2022] Open
Abstract
Exosomes contain proteins, lipids, RNA, and DNA that mediate intercellular signaling. Exosomes can contribute to the pathological processes of various diseases, although their roles in ocular diseases are unclear. We aimed to isolate exosomes from tear fluids (TF) of patients with Thyroid eye disease (TED) and analyze the exosomal proteins. TFs were collected from eight patients with TED and eight control subjects. The number of TF exosomes were measured using nanoparticle-tracking analysis. The expression of specific proteins in the purified exosome pellets were analyzed using a Proteome Profiler Array Kit. Cultured normal orbital fibroblasts were incubated with TF exosomes from patients with TED and control subjects, and changes in inflammatory cytokine levels were compared. TF exosomes from TED patients showed more exosomes than the control subjects. The expression levels of exosomal proteins vitamin D-binding (VDB) protein, C-reactive protein (CRP), chitinase 3-like 1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and vascular adhesion molecule-1 (VCAM-1) were significantly increased in patients with TED, compared to those of controls. Orbital fibroblasts exposed to TF exosomes from patients with TED showed significantly higher levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) production than those treated with control TF exosomes. Specific proteins showed higher expression in exosomes from TED patients, implying that they may play keys roles in TED pathogenesis.
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Affiliation(s)
- Jeong-Sun Han
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.-S.H.); (J.-Q.J.)
| | - Sung Eun Kim
- Department of Ophthalmology and Visual Science, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.E.K.); (N.R.P.)
| | - Jun-Qing Jin
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.-S.H.); (J.-Q.J.)
| | - Na Ri Park
- Department of Ophthalmology and Visual Science, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.E.K.); (N.R.P.)
| | - Ji-Young Lee
- Department of Pathology, Institute of Hansen’s Disease, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.-Y.L.); (S.-B.L.)
| | - Hong Lim Kim
- Integrative Research Support Center, Laboratory of Electron Microscope, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Seong-Beom Lee
- Department of Pathology, Institute of Hansen’s Disease, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.-Y.L.); (S.-B.L.)
| | - Suk-Woo Yang
- Department of Ophthalmology and Visual Science, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.E.K.); (N.R.P.)
- Correspondence: (S.-W.Y.); (D.-J.L.); Tel.: +82-2-2258-6009 (D.-J.L.)
| | - Dong-Jun Lim
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.-S.H.); (J.-Q.J.)
- Correspondence: (S.-W.Y.); (D.-J.L.); Tel.: +82-2-2258-6009 (D.-J.L.)
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30
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Shen J, Lu Z, Wang J, Zhang T, Yang J, Li Y, Liu G, Zhang X. Advances of Nanoparticles for Leukemia Treatment. ACS Biomater Sci Eng 2020; 6:6478-6489. [PMID: 33320613 DOI: 10.1021/acsbiomaterials.0c01040] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Leukemia is a liquid tumor caused by a hematopoietic stem cell malignant clone, which seriously affects the normal function of the hematopoietic system. Conventional drugs have poor therapeutic effects due to their poor specificity and stability. With the development of nanotechnology, nonviral nanoparticles bring hope for the efficient treatment of leukemia. Nanoparticles are easily modified. They can be designed to target lesion sites and control drug release. Thereby, nanoparticles can improve the effects of drugs and reduce side effects. This review mainly focuses on and summarizes the current research progress of nanoparticles to deliver different leukemia therapeutic drugs, as to demonstrate the potential of nanoparticles in leukemia treatment.
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Affiliation(s)
- Jie Shen
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China.,School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Zhiguo Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China.,School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Jianze Wang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Tianlu Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Jun Yang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Yan Li
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Guiying Liu
- Department of Pediatrics, Capital Medical University Affiliated Beijing Anzhen Hospital, Beijing, 100029, PR China
| | - Xin Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China
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Kraus L, Ma L, Yang Y, Nguyen F, Hoy RC, Okuno T, Khan M, Mohsin S. Cortical Bone Derived Stem Cells Modulate Cardiac Fibroblast Response via miR-18a in the Heart After Injury. Front Cell Dev Biol 2020; 8:494. [PMID: 32656212 PMCID: PMC7324629 DOI: 10.3389/fcell.2020.00494] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/25/2020] [Indexed: 12/29/2022] Open
Abstract
The adult heart following injury such as a myocardial infarction forms a fibrotic scar associated with transformation of resident cardiac fibroblasts into myofibroblast, accelerating cardiac remodeling and dysfunction. Cell therapies provide a novel direction for the enhancement of cardiac structure and function but remain poorly described in terms of the effect on resident cardiac fibroblasts. We have shown cortical bone derived stem cells (CBSCs) exhibit an ability to repair the heart after myocardial injury together with reduced scar formation. Nevertheless, whether CBSCs possess ability to modulate resident fibroblast response after myocardial injury remains untested.
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Affiliation(s)
- Lindsay Kraus
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Lena Ma
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Yijun Yang
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Faustina Nguyen
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Robert C Hoy
- Center for Metabolic Disease, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Tomoko Okuno
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Mohsin Khan
- Center for Metabolic Disease, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Sadia Mohsin
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
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Zhou Q, Zhou S, Wang H, Li Y, Xiao X, Yang J. Stable silencing of ROR1 regulates cell cycle, apoptosis, and autophagy in a lung adenocarcinoma cell line. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:1108-1120. [PMID: 32509086 PMCID: PMC7270672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 04/14/2020] [Indexed: 06/11/2023]
Abstract
Lung cancer has the highest mortality and recurrence rate among cancers in the world. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been widely recognized for its role in promoting the growth and metastasis of lung cancer, but its comprehensive role and molecular mechanisms in regulating cell cycle, apoptosis, and autophagy remain unclear. In this study, a series of ROR1-stably silenced monoclonal clones from lung adenocarcinoma cell lines PC9, PC9erlo, and NCI-H1975 were successfully selected and confirmed by qRT-PCR, western blot, and flow cytometry, and used as cell models in the following assays. Our study clearly shows that blocking ROR1 significantly downregulates cell cycle-inducing molecules such as CDK4 and Cyclin E1, and anti-apoptotic molecules such as Bcl-XL and Bcl-2, while it markedly upregulates pro-apoptotic molecules such as Bak, Caspase-3, and Caspase-7, which extends our previous observation on the molecular mechanism of ROR1-mediated tumor growth in lung adenocarcinoma. Our data also show that silencing ROR1 promotes autophagy since the key molecules involved in autophagy including ATG7, ATG12, BNIP3L, LC3A, LC3B, and NBS1 were up-regulated. We further screened key phosphokinase signaling pathways downstream of ROR1 in lung adenocarcinoma by a human phospho-kinase array. Our data indicate that blocking ROR1 could deactivate Akt, then activate GSK-3α/β by de-phosphorylation, and finally deactivate mTOR. In this way blocking ROR1 could effectively regulate the cell cycle, apoptosis, and autophagy in lung cancer.
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Affiliation(s)
- Qi Zhou
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine Chengdu 611137, Sichuan, P. R. China
| | - Shiyi Zhou
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine Chengdu 611137, Sichuan, P. R. China
| | - Huili Wang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine Chengdu 611137, Sichuan, P. R. China
| | - Yanping Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine Chengdu 611137, Sichuan, P. R. China
| | - Xiaoqian Xiao
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine Chengdu 611137, Sichuan, P. R. China
| | - Jiahui Yang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine Chengdu 611137, Sichuan, P. R. China
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Nanocarriers as Magic Bullets in the Treatment of Leukemia. NANOMATERIALS 2020; 10:nano10020276. [PMID: 32041219 PMCID: PMC7075174 DOI: 10.3390/nano10020276] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/30/2020] [Accepted: 02/01/2020] [Indexed: 12/21/2022]
Abstract
Leukemia is a type of hematopoietic stem/progenitor cell malignancy characterized by the accumulation of immature cells in the blood and bone marrow. Treatment strategies mainly rely on the administration of chemotherapeutic agents, which, unfortunately, are known for their high toxicity and side effects. The concept of targeted therapy as magic bullet was introduced by Paul Erlich about 100 years ago, to inspire new therapies able to tackle the disadvantages of chemotherapeutic agents. Currently, nanoparticles are considered viable options in the treatment of different types of cancer, including leukemia. The main advantages associated with the use of these nanocarriers summarized as follows: i) they may be designed to target leukemic cells selectively; ii) they invariably enhance bioavailability and blood circulation half-life; iii) their mode of action is expected to reduce side effects. FDA approval of many nanocarriers for treatment of relapsed or refractory leukemia and the desired results extend their application in clinics. In the present review, different types of nanocarriers, their capability in targeting leukemic cells, and the latest preclinical and clinical data are discussed.
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