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Shamsul Kamal AA, Fakiruddin KS, Bobbo KA, Ling KH, Vidyadaran S, Abdullah S. Engineered Mesenchymal Stem Cells as Treatment for Cancers: Opportunities, Clinical Applications and Challenges. Malays J Med Sci 2024; 31:56-82. [PMID: 39416732 PMCID: PMC11477465 DOI: 10.21315/mjms2024.31.5.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 06/27/2024] [Indexed: 10/19/2024] Open
Abstract
The insufficient and unspecific target of classical chemotherapies often leads to therapy resistance and cancer recurrence. Over the past decades, discoveries about mesenchymal stem cell (MSC) biology have provided new potential approaches to improve cancer therapy. Researchers have utilised the multipotent, regenerative and immunosuppressive qualities of MSCs and tropisms towards inflammatory, hypoxic and malignant sites in various therapeutic applications. Although MSC-based therapies have generally been demonstrated safe, their effectiveness remains limited when these cells are used alone. However, through genetic engineering, researchers have proven that MSCs can be modified to have specialised delivery roles to increase their therapeutic efficacy in cancer treatment. They can be made to overexpress therapeutic proteins through viral or non-viral genetic modification, which enhances their innate properties. Nevertheless, these engineering strategies must be optimised to increase therapeutic efficacy and targeting effectiveness while minimising any loss of MSC function. This review underscores the cutting-edge methods for engineering MSCs, discusses their promise and the difficulties in translating them into clinical settings, and offers some prospective suggestions for the future on achieving their full therapeutic potential.
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Affiliation(s)
- Aishah Amirah Shamsul Kamal
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Kamal Shaik Fakiruddin
- Haematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Selangor, Malaysia
| | - Khadijat Abubakar Bobbo
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - King Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Selangor, Malaysia
| | - Sharmili Vidyadaran
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Syahril Abdullah
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysia Genome and Vaccine Institute, National Institutes of Biotechnology Malaysia, Selangor, Malaysia
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2
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Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, Ramezani M. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med Res Rev 2024; 44:1596-1661. [PMID: 38299924 DOI: 10.1002/med.22023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 11/28/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Gil-Chinchilla JI, Zapata AG, Moraleda JM, García-Bernal D. Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects. Biomolecules 2024; 14:734. [PMID: 39062449 PMCID: PMC11275142 DOI: 10.3390/biom14070734] [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: 05/08/2024] [Revised: 06/11/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.
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Affiliation(s)
- Jesús I. Gil-Chinchilla
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
| | - Agustín G. Zapata
- Department of Cell Biology, Complutense University, 28040 Madrid, Spain;
| | - Jose M. Moraleda
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Medicine, University of Murcia, 30120 Murcia, Spain
| | - David García-Bernal
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Biochemistry, Molecular Biology and Immunology, University of Murcia, 30120 Murcia, Spain
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Kim Y, Choi J, Kim EH, Park W, Jang H, Jang Y, Chi S, Kweon D, Lee K, Kim SH, Yang Y. Design of PD-L1-Targeted Lipid Nanoparticles to Turn on PTEN for Efficient Cancer Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309917. [PMID: 38520717 PMCID: PMC11165541 DOI: 10.1002/advs.202309917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 03/15/2024] [Indexed: 03/25/2024]
Abstract
Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue-specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor-targeting peptides into the LNPs; the programmed death ligand 1 (PD-L1) binding peptides are conjugated to PEGylated lipids via a copper-free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD-L1 proteins, which leads to the uptake of LNPs into PD-L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN-deficient triple-negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy-mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor-targeted LNPs for mRNA-based cancer therapy.
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Affiliation(s)
- Yelee Kim
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Jiwoong Choi
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Eun Hye Kim
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Wonbeom Park
- Department of Integrative BiotechnologySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Hochung Jang
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Division of Bio‐Medical Science and TechnologyKIST SchoolKorea University of Science and TechnologySeoul02792Republic of Korea
| | - Yeongji Jang
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Sung‐Gil Chi
- Department of Life SciencesKorea UniversitySeoul02841Republic of Korea
| | - Dae‐Hyuk Kweon
- Department of Integrative BiotechnologySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Kyuri Lee
- College of Pharmacy and Research Institute of Pharmaceutical SciencesGyeongsang National UniversityJinju52828Republic of Korea
| | - Sun Hwa Kim
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
| | - Yoosoo Yang
- Biomedical Research DivisionKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Division of Bio‐Medical Science and TechnologyKIST SchoolKorea University of Science and TechnologySeoul02792Republic of Korea
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Karami Fath M, Bagherzadeh Torbati SM, Saqagandomabadi V, Yousefi Afshar O, Khalilzad M, Abedi S, Moliani A, Daneshdoust D, Barati G. The therapeutic effect of MSCs and their extracellular vesicles on neuroblastoma. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2024; 187:51-60. [PMID: 38373516 DOI: 10.1016/j.pbiomolbio.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/04/2023] [Accepted: 02/16/2024] [Indexed: 02/21/2024]
Abstract
Neuroblastoma is a common inflammatory-related cancer during infancy. Standard treatment modalities including surgical interventions, high-dose chemotherapy, radiotherapy, and immunotherapy are not able to increase survival rate and reduce tumor relapse in high-risk patients. Mesenchymal stem cells (MSCs) are known for their tumor-targeting and immunomodulating properties. MSCs could be engineered to express anticancer agents (i.e., growth factors, cytokines, pro-apoptotic agents) or deliver oncolytic viruses in the tumor microenvironment. As many functions of MSCs are mediated through their secretome, researchers have tried to use extracellular vesicles (EVs) from MSCs for targeted therapy of neuroblastoma. Here, we reviewed the studies to figure out whether the use of MSCs could be worthwhile in neuroblastoma therapy or not. Native MSCs have shown a promoting or inhibiting role in cancers including neuroblastoma. Therefore, MSCs are proposed as a vehicle to deliver anticancer agents such as oncolytic viruses to the neuroblastoma tumor microenvironment. Although modified MSCs or their EVs have been shown to suppress the tumorigenesis of neuroblastoma, further pre-clinical and clinical studies are required to come to a conclusion.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | | | - Vahid Saqagandomabadi
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | | | - Mohammad Khalilzad
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Abedi
- Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Afshin Moliani
- Isfahan Medical Students Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Danyal Daneshdoust
- Faculty of Medicine, Babol University of Medical Sciences, Mazandaran, Iran
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Wang J, Zhang X, Chen H, Ren H, Zhou M, Zhao Y. Engineered stem cells by emerging biomedical stratagems. Sci Bull (Beijing) 2024; 69:248-279. [PMID: 38101962 DOI: 10.1016/j.scib.2023.12.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/24/2023] [Accepted: 11/09/2023] [Indexed: 12/17/2023]
Abstract
Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders. As the safety of stem cell transplantation having been demonstrated in numerous clinical trials, various kinds of stem cells are currently utilized in medical applications. Despite the achievements, the therapeutic benefits of stem cells for diseases are limited, and the data of clinical researches are unstable. To optimize tthe effectiveness of stem cells, engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities, paving the way for the next generation of stem cell therapies. This review offers a detailed analysis of engineered stem cells, including their clinical applications and potential for future development. We begin by briefly introducing the recent advances in the production of stem cells (induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs)). Furthermore, we present the latest developments of engineered strategies in stem cells, including engineered methods in molecular biology and biomaterial fields, and their application in biomedical research. Finally, we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications.
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Affiliation(s)
- Jinglin Wang
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; Division of Hepatobiliary Surgery and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Xiaoxuan Zhang
- Division of Hepatobiliary Surgery and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Hanxu Chen
- Division of Hepatobiliary Surgery and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Haozhen Ren
- Division of Hepatobiliary Surgery and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
| | - Min Zhou
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
| | - Yuanjin Zhao
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; Division of Hepatobiliary Surgery and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China; Shenzhen Research Institute, Southeast University, Shenzhen 518038, China.
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7
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Saadh MJ, Alhuthali HM, Gonzales Aníbal O, Asenjo-Alarcón JA, Younus DG, Alhili A, Adhab ZH, Alsalmi O, Gharib AF, Pecho RDC, Akhavan-Sigari R. Mesenchymal stem cells and their extracellular vesicles in urological cancers: Prostate, bladder, and kidney. Cell Biol Int 2024; 48:3-19. [PMID: 37947445 DOI: 10.1002/cbin.12098] [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: 07/19/2023] [Revised: 08/31/2023] [Accepted: 10/12/2023] [Indexed: 11/12/2023]
Abstract
Mesenchymal stem cells (MSCs) are recognized for their remarkable ability to differentiate into multiple cell types. They are also known to possess properties that can fight cancer, leading to attempts to modify MSCs for use in anticancer treatments. However, MSCs have also been found to participate in pathways that promote tumor growth. Many studies have been conducted to explore the potential of MSCs for clinical applications, but the results have been inconclusive, possibly due to the diverse nature of MSC populations. Furthermore, the conflicting roles of MSCs in inhibiting tumors and promoting tumor growth hinder their adaptation to anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in urological cancers such as bladder, prostate, and renal are not as well established, and data comparing them are still limited. MSCs hold significant promise as a vehicle for delivering anticancer agents and suicide genes to tumors. Presently, numerous studies have concentrated on the products derived from MSCs, such as extracellular vesicles (EVs), as a form of cell-free therapy. This work aimed to review and discuss the current knowledge of MSCs and their EVs in urological cancer therapy.
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Affiliation(s)
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | | | | | - Ahmed Alhili
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Ohud Alsalmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Amal F Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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8
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Taeb S, Rostamzadeh D, Mafi S, Mofatteh M, Zarrabi A, Hushmandi K, Safari A, Khodamoradi E, Najafi M. Update on Mesenchymal Stem Cells: A Crucial Player in Cancer Immunotherapy. Curr Mol Med 2024; 24:98-113. [PMID: 36573062 DOI: 10.2174/1566524023666221226143814] [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: 05/17/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 12/28/2022]
Abstract
The idea of cancer immunotherapy has spread, and it has made tremendous progress with the advancement of new technology. Immunotherapy, which serves to assist the natural defenses of the body in eradicating cancerous cells, is a remarkable achievement that has revolutionized both cancer research and cancer treatments. Currently, the use of stem cells in immunotherapy is widespread and shares a special characteristic, including cancer cell migration, bioactive component release, and immunosuppressive activity. In the context of cancer, mesenchymal stem cells (MSCs) are rapidly being identified as vital stromal regulators of tumor progression. MSCs therapy has been implicated in treating a wide range of diseases, including bone damage, autoimmune diseases, and particularly hematopoietic abnormalities, providing stem cell-based therapy with an extra dimension. Moreover, the implication of MSCs does not have ethical concerns, and the complications known in pluripotent and totipotent stem cells are less common in MSCs. MSCs have a lot of distinctive characteristics that, when coupled, make them excellent for cellular-based immunotherapy and as vehicles for gene and drug delivery in a variety of inflammations and malignancies. MSCs can migrate to the inflammatory site and exert immunomodulatory responses via cell-to-cell contacts with lymphocytes by generating soluble substances. In the current review, we discuss the most recent research on the immunological characteristics of MSCs, their use as immunomodulatory carriers, techniques for approving MSCs to adjust their immunological contour, and their usages as vehicles for delivering therapeutic as well as drugs and genes engineered to destroy tumor cells.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Sahar Mafi
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohammad Mofatteh
- Sir William Dunn School of Pathology, Medical Sciences Division, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom
- Lincoln College, University of Oxford, Turl Street, Oxford OX1 3DR, United Kingdom
| | - Ali Zarrabi
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Arash Safari
- Department of Radiology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Ghaleh HEG, Vakilzadeh G, Zahiri A, Farzanehpour M. Investigating the potential of oncolytic viruses for cancer treatment via MSC delivery. Cell Commun Signal 2023; 21:228. [PMID: 37667271 PMCID: PMC10478302 DOI: 10.1186/s12964-023-01232-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/16/2023] [Indexed: 09/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted considerable interest as a promising approach for cancer treatment due to their ability to undergo tumor-trophic migration. MSCs possess the unique ability to selectively migrate to tumors, making them an excellent candidate for targeted delivery of oncolytic viruses (OVs) to treat isolated tumors and metastatic malignancies. OVs have attracted attention as a potential treatment for cancer due to their ability to selectively infect and destroy tumor cells while sparing normal cells. In addition, OVs can induce immunogenic cell death and contain curative transgenes in their genome, making them an attractive candidate for cancer treatment in combination with immunotherapies. In combination with MSCs, OVs can modulate the tumor microenvironment and trigger anti-tumor immune responses, making MSC-releasing OVs a promising approach for cancer treatment. This study reviews researches on the use of MSC-released OVs as a novel method for treating cancer. Video Abstract.
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Affiliation(s)
| | - Gazal Vakilzadeh
- Applied Virology Research Center, Baqiyatallah University of Medical sciences, Tehran, Iran
| | - Ali Zahiri
- Students Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdieh Farzanehpour
- Applied Virology Research Center, Baqiyatallah University of Medical sciences, Tehran, Iran.
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10
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Wang Y, Shao W. Innate Immune Response to Viral Vectors in Gene Therapy. Viruses 2023; 15:1801. [PMID: 37766208 PMCID: PMC10536768 DOI: 10.3390/v15091801] [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: 07/12/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
Viral vectors play a pivotal role in the field of gene therapy, with several related drugs having already gained clinical approval from the EMA and FDA. However, numerous viral gene therapy vectors are currently undergoing pre-clinical research or participating in clinical trials. Despite advancements, the innate response remains a significant barrier impeding the clinical development of viral gene therapy. The innate immune response to viral gene therapy vectors and transgenes is still an important reason hindering its clinical development. Extensive studies have demonstrated that different DNA and RNA sensors can detect adenoviruses, adeno-associated viruses, and lentiviruses, thereby activating various innate immune pathways such as Toll-like receptor (TLR), cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), and retinoic acid-inducible gene I-mitochondrial antiviral signaling protein (RLR-MAVS). This review focuses on elucidating the mechanisms underlying the innate immune response induced by three widely utilized viral vectors: adenovirus, adeno-associated virus, and lentivirus, as well as the strategies employed to circumvent innate immunity.
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Affiliation(s)
| | - Wenwei Shao
- Academy of Medical Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin 300072, China;
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Karami Fath M, Moayedi Banan Z, Barati R, Mohammadrezakhani O, Ghaderi A, Hatami A, Ghiabi S, Zeidi N, Asgari K, Payandeh Z, Barati G. Recent advancements to engineer mesenchymal stem cells and their extracellular vesicles for targeting and destroying tumors. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 178:1-16. [PMID: 36781149 DOI: 10.1016/j.pbiomolbio.2023.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 02/13/2023]
Abstract
Mesenchymal stem cells (MSCs) have the ability to migrate into tumor sites and release growth factors to modulate the tumor microenvironment. MSC therapy have shown a dual role in cancers, promoting or inhibiting. However, MSCs could be used as a carrier of anticancer agents for targeted tumor therapy. Recent technical improvements also allow engineering MSCs to improve tumor-targeting properties, protect anticancer agents, and decrease the cytotoxicity of drugs. While some of MSC functions are mediated through their secretome, MSCs-derived extracellular vesicles (EVs) are also proposed as a possible viechle for cancer therapy. EVs allow efficient loading of anticancer agents and have an intrinsic ability to target tumor cells, making them suitable for targeted therapy of tumors. In addition, the specificity and selectivity of EVs to the tumor sites could be enhanced by surface modification. In this review, we addressed the current approaches used for engineering MSCs and EVs to effectively target tumor sites and deliver anticancer agents.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Zahra Moayedi Banan
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Barati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Omid Mohammadrezakhani
- Faculty of Pharmacy, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran
| | - Aliasghar Ghaderi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hatami
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shamim Ghiabi
- Department of Medical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Zeidi
- Division of Pharmaceutical Science, Long Island University, Brooklyn, NY, USA
| | - Katayoon Asgari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
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12
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Improving the Transduction Efficiency and Antitumor Effect of Conditionally Replicative Adenovirus by Application of 6-cyclohexyl Methyl-β-D-maltoside. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28020528. [PMID: 36677587 PMCID: PMC9862058 DOI: 10.3390/molecules28020528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 01/06/2023]
Abstract
As a tumor-targeting oncolytic adenovirus (Ad), conditionally replicating adenovirus (CRAd) can access the cell interior by binding to coxsackievirus-Ad receptors (CARs) and specifically replicate and destroy cancer cells without lethal effects on normal cells. The transduction efficiency of CRAd is highly dependent on the number of CARs on the cell membrane. However, not all tumor cells highly express CARs; therefore, improving the transduction efficiency of CRAd is beneficial for improving its antitumor effect. In this study, 6-cyclohexyl methyl-β-D-maltoside (6-β-D), as maltoside transfection agent, showed several advantages, including high transfection efficiency, low toxicity, and potential for intensive use and easy operation. With pretreatment of cancer cells with low concentration of 6-β-D (≤5 μg/mL), the transduction efficiency of "model" Ad (eGFP-Ad) was improved 18-fold compared to eGFP-Ad alone. 6-β-D improved the antitumor effect of CRAd while being safe for normal cells, in which treatment with 6-β-D helped the lethal effects of CRAd at a multiplicity-of-infection ratio of 10 (MOI 10) achieve the oncolytic outcomes of MOI 50. This means that if CRAd is combined with 6-β-D, the amount of CRAd used in clinical practice could be greatly reduced without diminishing its curative effect or exposing patients to the potential side effects of high-titer CRAd. Finally, the underlying mechanism of antitumor effect of CRAd + 6-β-D was primarily investigated, and we found that 6-β-D increased the virus's replication in cancer cells at the early stage of infection and activated the apoptosis signaling pathway at the late stage of the cell cycle. This research will provide an effective technical reference for further improving Ad-mediated cancer gene therapy in clinical practice.
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13
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Complexing the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T with Cationic Nanoparticles Enhances Viral Infection and Spread in Prostate and Pancreatic Cancer Models. Int J Mol Sci 2022; 23:ijms23168884. [PMID: 36012152 PMCID: PMC9408166 DOI: 10.3390/ijms23168884] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Oncolytic adenoviruses (OAd) can be employed to efficiently eliminate cancer cells through multiple mechanisms of action including cell lysis and immune activation. Our OAds, AdΔΔ and Ad-3∆-A20T, selectively infect, replicate in, and kill adenocarcinoma cells with the added benefit of re-sensitising drug-resistant cells in preclinical models. Further modifications are required to enable systemic delivery in patients due to the rapid hepatic elimination and neutralisation by blood factors and antibodies. Here, we show data that support the use of coating OAds with gold nanoparticles (AuNPs) as a possible new method of virus modification to help augment tumour uptake. The pre-incubation of cationic AuNPs with AdΔΔ, Ad-3∆-A20T and wild type adenovirus (Ad5wt) was performed prior to infection of prostate/pancreatic cancer cell lines (22Rv, PC3, Panc04.03, PT45) and a pancreatic stellate cell line (PS1). Levels of viral infection, replication and cell viability were quantified 24–72 h post-infection in the presence and absence of AuNPs. Viral spread was assessed in organotypic cultures. The presence of AuNPs significantly increased the uptake of Ad∆∆, Ad-3∆-A20T and Ad5wt in all the cell lines tested (ranging from 1.5-fold to 40-fold), compared to virus alone, with the greatest uptake observed in PS1, a usually adenovirus-resistant cell line. Pre-coating the AdΔΔ and Ad-3∆-A20T with AuNPs also increased viral replication, leading to enhanced cell killing, with maximal effect in the most virus-insensitive cells (from 1.4-fold to 5-fold). To conclude, the electrostatic association of virus with cationic agents provides a new avenue to increase the dose in tumour lesions and potentially protect the virus from detrimental blood factor binding. Such an approach warrants further investigation for clinical translation.
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14
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Rahimi Tesiye M, Abrishami Kia Z, Rajabi-Maham H. Mesenchymal stem cells and prostate cancer: A concise review of therapeutic potentials and biological aspects. Stem Cell Res 2022; 63:102864. [PMID: 35878578 DOI: 10.1016/j.scr.2022.102864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/06/2022] [Accepted: 07/08/2022] [Indexed: 11/09/2022] Open
Abstract
Prostate cancer (PCa) arises from a cancer stem or progenitor cell with homogenous characteristics, especially among the aging men population. Over the past decade, the increasing PCa incidence has led to significant changes in both disease diagnosis and treatment. Recently, the therapeutic aspects of stem cells in many cancers, including PCa, have been debatable. The new generation of PCa studies seek to present definitive treatments with reduced therapeutic side effects. Since discovering unique properties of stem cells in modulating immunity, selective migration to inflammatory regions, and secretion of various growth factors, they have been a promising therapeutic target. The existing properties of stem cell therapy bring new opportunities for cancer inhibition: transferring chemotherapeutics, activating prodrugs, affecting the expression of genes involved in cancer, genetically modifying the production of anti-cancer compounds, proteins, and/or deriving extracellular vesicles (EVs) containing therapeutic agents from stem cells. However, their dual properties in carcinogenicity as well as their ability to inhibit cancer result in particular limitations studying them after administration. A clear understanding of the interaction between MSCs and the prostate cancer microenvironment will provide crucial information in revealing the precise applications and new practical protocols for clinical use of these cells..
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Affiliation(s)
- Maryam Rahimi Tesiye
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Zahra Abrishami Kia
- Faculty of Physical Education and Sport Sciences, University of Mazandaran, Babolsar, Iran.
| | - Hassan Rajabi-Maham
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
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15
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Chen C, Li YL, Lv FL, Xu LD, Huang YW. Surface Display of Peptides Corresponding to the Heptad Repeat 2 Domain of the Feline Enteric Coronavirus Spike Protein on Bacillus subtilis Spores Elicits Protective Immune Responses Against Homologous Infection in a Feline Aminopeptidase-N-Transduced Mouse Model. Front Immunol 2022; 13:925922. [PMID: 35837396 PMCID: PMC9273865 DOI: 10.3389/fimmu.2022.925922] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/23/2022] [Indexed: 11/22/2022] Open
Abstract
Although feline coronavirus (FCoV) infection is extremely common in cats, there are currently few effective treatments. A peptide derived from the heptad repeat 2 (HR2) domain of the coronavirus (CoV) spike protein has shown effective for inhibition of various human and animal CoVs in vitro, but further use of FCoV-HR2 in vivo has been limited by lack of practical delivery vectors and small animal infection model. To overcome these technical challenges, we first constructed a recombinant Bacillus subtilis (rBSCotB-HR2P) expressing spore coat protein B (CotB) fused to an HR2-derived peptide (HR2P) from a serotype II feline enteric CoV (FECV). Immunogenic capacity was evaluated in mice after intragastric or intranasal administration, showing that recombinant spores could trigger strong specific cellular and humoral immune responses. Furthermore, we developed a novel mouse model for FECV infection by transduction with its primary receptor (feline aminopeptidase N) using an E1/E3-deleted adenovirus type 5 vector. This model can be used to study the antiviral immune response and evaluate vaccines or drugs, and is an applicable choice to replace cats for the study of FECV. Oral administration of rBSCotB-HR2P in this mouse model effectively protected against FECV challenge and significantly reduced pathology in the digestive tract. Owing to its safety, low cost, and probiotic features, rBSCotB-HR2P is a promising oral vaccine candidate for use against FECV/FCoV infection in cats.
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Affiliation(s)
- Chu Chen
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Ya-Li Li
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Fang-Li Lv
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Ling-Dong Xu
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Yao-Wei Huang, ; Ling-Dong Xu,
| | - Yao-Wei Huang
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- *Correspondence: Yao-Wei Huang, ; Ling-Dong Xu,
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16
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Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185:114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 12/16/2022]
Abstract
The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.
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17
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Mesenchymal Stem Cells and their Derived Exosomes Promote Malignant Phenotype of Polyploid Non-Small-Cell Lung Cancer Cells through AMPK Signaling Pathway. Anal Cell Pathol 2022; 2022:8708202. [PMID: 35419253 PMCID: PMC9001126 DOI: 10.1155/2022/8708202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/09/2022] [Accepted: 03/15/2022] [Indexed: 12/20/2022] Open
Abstract
Chemotherapy is an important method for the treatment of non-small-cell lung cancer (NSCLC), but it can lead to side effects and polyploid cancer cells. The polyploid cancer cells can live and generate daughter cancer cells via budding. Mesenchymal stem cells (MSCs) are pluripotent stem cells with repair and regeneration functions and can resist tissue damage caused by tumor therapy. This study is aimed at investigating the effects of MSCs and their derived exosomes on the biological characteristics of polyploid NSCLC cells and the potential mechanisms. We found that MSC conditioned medium (CM), MSCs, and MSC-exosomes had no effect on cell proliferation of the polyploid A549 and H1299 cells. Compared with the control group, MSCs and MSC-exosomes significantly promoted epithelial mesenchymal transformation, cell migration, antiapoptosis, and autophagy in the polyploid A549 and H1299 by activating AMPK signaling pathway, but no significant changes were observed in MSC-CM treatment. These results revealed that MSCs and MSC-exosomes promoted malignant phenotype of polyploid NSCLC cells through the AMPK signaling pathway.
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18
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Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, Mazzucato M, Agostini F. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J Stem Cells 2022; 14:54-75. [PMID: 35126828 PMCID: PMC8788179 DOI: 10.4252/wjsc.v14.i1.54] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.
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Affiliation(s)
- Carla Vicinanza
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Elisabetta Lombardi
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Da Ros
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Miriam Marangon
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Cristina Durante
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Mario Mazzucato
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Agostini
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
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19
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Chen Y, Hu S, Shu Y, Qi Z, Zhang B, Kuang Y, Ma J, Cheng P. Antifibrotic Therapy Augments the Antitumor Effects of Vesicular Stomatitis Virus Via Reprogramming Tumor Microenvironment. Hum Gene Ther 2021; 33:237-249. [PMID: 34405694 DOI: 10.1089/hum.2021.048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Solid tumors are characterized by abundant extracellular matrix originating from cancer-associated fibroblasts (CAFs). High collagen content can trigger the collapse of vascular system in the tumor and form physical barrier that eventually impedes the penetration of drug particles and cytotoxic immune cells. Moreover, CAFs is able to promote the enrichment of tumor-associated macrophages (TAMs) and differentiation of myeloid-derived suppressor cells (MDSCs) that work in concert to develop a highly immunosuppressive tumor microenvironment (TME). In this study, we investigated if halofuginone, an antifibrotic drug, can augment the therapeutic effects of oncolytic vesicular stomatitis virus (VSV). The results revealed that halofuginone significantly disrupts the collagen network in tumors and promotes the distribution of VSV and infiltration of CD8+ T cells (p < 0.0001). Combined treatment of VSV and halofuginone also modulates the immunosuppressive TME via deletion of TAM, MDSCs, and regulatory T cells (Tregs). Collectively, the combination therapy remarkably inhibits the tumor growth in multiple murine models and prolongs survival of mice. The results demonstrate the clinical potential of halofuginone in combination with oncolytic virus.
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Affiliation(s)
- Yanwei Chen
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Shichuan Hu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yongheng Shu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Zhongbing Qi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Bin Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yueting Kuang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jinhu Ma
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
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20
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Gonzalez-Pastor R, Hernandez Y, Gimeno M, de Martino A, Man YS, Hallden G, Quintanilla M, de la Fuente JM, Martin-Duque P. Coating an adenovirus with functionalized gold nanoparticles favors uptake, intracellular trafficking and anti-cancer therapeutic efficacy. Acta Biomater 2021; 134:593-604. [PMID: 34325075 DOI: 10.1016/j.actbio.2021.07.047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022]
Abstract
Adenoviral (Ad) vectors have proven to be important tools for gene and cell therapy, although some issues still need to be addressed, such as undesired interactions with blood components and off-target sequestration that ultimately hamper efficacy. In the past years, several organic and inorganic materials have been developed to reduce immunogenicity and improve biodistribution of Ad vectors. Here we investigated the influence of the functionalization of 14 nm PEGylated gold nanoparticles (AuNPs) with quaternary ammonium groups and an arginine-glycine-aspartic acid (RGD)-motif on the uptake and biodistribution of Ad vectors. We report the formation of Ad@AuNPs complexes that promote cell attachment and uptake, independently of the presence of the coxsackievirus and adenovirus receptor (CAR) and αvβ3 and αvβ5 integrins, significantly improving transduction without limiting Ad bioactivity. Besides, the presence of the RGD peptide favors tumor targeting and decreases Ad sequestration in the liver. Additionally, tumor delivery of a coated Ad vector expressing the human sodium iodide symporter (hNIS) by mesenchymal stem cells induces increased accumulation of radioactive iodine (131I) and tumor volume reduction compared to naked Ad-hNIS, highlighting the promising potential of our coating formulation in cancer gene therapy. STATEMENT OF SIGNIFICANCE: Modification of adenoviral vectors with lipids and polymers can reduce interactions with blood components and increase tumor accumulation; however, increased toxicity and reduced transduction efficiency were indicated. Coating with gold nanoparticles has proven to be a successful strategy for increasing the efficiency of transduction of receptor-defective cell lines. Here we explore the contribution of cell surface receptors on the mechanisms of entry of Ad vectors coated with gold nanoparticles in cell lines with varying degrees of resistance to infection. The enhancement of the anti-tumoral effect shown in this work provides new evidence for the potential of our formulation.
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21
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Glioblastoma Therapy: Rationale for a Mesenchymal Stem Cell-based Vehicle to Carry Recombinant Viruses. Stem Cell Rev Rep 2021; 18:523-543. [PMID: 34319509 DOI: 10.1007/s12015-021-10207-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2021] [Indexed: 12/12/2022]
Abstract
Evasion of growth suppression is among the prominent hallmarks of cancer. Phosphatase and tensin homolog (PTEN) and p53 tumor-suppressive pathways are compromised in most human cancers, including glioblastoma (GB). Hence, these signaling pathways are an ideal point of focus for novel cancer therapeutics. Recombinant viruses can selectivity kill cancer cells and carry therapeutic genes to tumors. Specifically, oncolytic viruses (OV) have been successfully employed for gene delivery in GB animal models and showed potential to neutralize immunosuppression at the tumor site. However, the associated systemic immunogenicity, inefficient transduction of GB cells, and inadequate distribution to metastatic tumors have been the major bottlenecks in clinical studies. Mesenchymal stem cells (MSCs), with tumor-tropic properties and immune privilege, can improve OVs targeting. Remarkably, combining the two approaches can address their individual issues. Herein, we summarize findings to advocate the reactivation of tumor suppressors p53 and PTEN in GB treatment and use MSCs as a "Trojan horse" to carry oncolytic viral cargo to disseminated tumor beds. The integration of MSCs and OVs can emerge as the new paradigm in cancer treatment.
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22
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Hassanzadeh A, Altajer AH, Rahman HS, Saleh MM, Bokov DO, Abdelbasset WK, Marofi F, Zamani M, Yaghoubi Y, Yazdanifar M, Pathak Y, Chartrand MS, Jarahian M. Mesenchymal Stem/Stromal Cell-Based Delivery: A Rapidly Evolving Strategy for Cancer Therapy. Front Cell Dev Biol 2021; 9:686453. [PMID: 34322483 PMCID: PMC8311597 DOI: 10.3389/fcell.2021.686453] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapy has become an attractive and advanced scientific research area in the context of cancer therapy. This interest is closely linked to the MSC-marked tropism for tumors, suggesting them as a rational and effective vehicle for drug delivery for both hematological and solid malignancies. Nonetheless, the therapeutic application of the MSCs in human tumors is still controversial because of the induction of several signaling pathways largely contributing to tumor progression and metastasis. In spite of some evidence supporting that MSCs may sustain cancer pathogenesis, increasing proofs have indicated the suppressive influences of MSCs on tumor cells. During the last years, a myriad of preclinical and some clinical studies have been carried out or are ongoing to address the safety and efficacy of the MSC-based delivery of therapeutic agents in diverse types of malignancies. A large number of studies have focused on the MSC application as delivery vehicles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemotherapeutic drug such as gemcitabine (GCB), paclitaxel (PTX), and doxorubicin (DOX), prodrugs such as 5-fluorocytosine (5-FC) and ganciclovir (GCV), and immune cell-activating cytokines along with oncolytic virus. In the current review, we evaluate the latest findings rendering the potential of MSCs to be employed as potent gene/drug delivery vehicle for inducing tumor regression with a special focus on the in vivo reports performed during the last two decades.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Sciences, University of Anbar, Ramadi, Iraq
| | - Dmitry O. Bokov
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Yoda Yaghoubi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Yashwant Pathak
- Professor and Associate Dean for Faculty Affairs, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
- Adjunct Professor, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
| | | | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
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23
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Mercer-Smith AR, Findlay IA, Bomba HN, Hingtgen SD. Intravenously Infused Stem Cells for Cancer Treatment. Stem Cell Rev Rep 2021; 17:2025-2041. [PMID: 34138421 DOI: 10.1007/s12015-021-10192-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2021] [Indexed: 01/14/2023]
Abstract
Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be engineered to secrete cytotoxic products, loaded with oncolytic viruses or nanoparticles containing small molecule drugs, or conjugated with immunotherapies. Herein we describe these preclinical and clinical studies, discuss the distribution and migration of stem cells following intravenous infusion, and examine both the limitations of and the methods to improve the migration and therapeutic efficacy of tumoritropic, therapeutic stem cells.
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Affiliation(s)
- Alison R Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Ingrid A Findlay
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Hunter N Bomba
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA. .,Department of Neurosurgery, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA.
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24
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McKenna MK, Englisch A, Brenner B, Smith T, Hoyos V, Suzuki M, Brenner MK. Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity. Mol Ther 2021; 29:1808-1820. [PMID: 33571680 DOI: 10.1016/j.ymthe.2021.02.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 01/05/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022] Open
Abstract
The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy: incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.
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Affiliation(s)
- Mary K McKenna
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Alexander Englisch
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
| | - Benjamin Brenner
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd., Evanston, IL 60208, USA
| | - Tyler Smith
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Valentina Hoyos
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Masataka Suzuki
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Malcolm K Brenner
- Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA.
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Muhammad T, Sakhawat A, Khan AA, Huang H, Khan HR, Huang Y, Wang J. Aloperine in combination with therapeutic adenoviral vector synergistically suppressed the growth of non-small cell lung cancer. J Cancer Res Clin Oncol 2020; 146:861-874. [PMID: 32088783 DOI: 10.1007/s00432-020-03157-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/13/2020] [Indexed: 12/25/2022]
Abstract
PURPOSE Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and ranked top in terms of incidence and mortality in men and women. Recently, improvements in treatment approaches for NSCLC have reported, but still, there is a need to devise innovative treatment strategies, especially to manage the advanced and metastatic stage of NSCLC. Aloperine (ALO), an herbal alkaloid, has exerted anti-cancer effects in many cancers. However, the use of any chemotherapeutic agents is dose limited due to possible adverse effects and drug-resistance issues. Therefore, a combination of chemotherapy with viral-based targeted gene therapy may provide a novel treatment strategy for NSCLC. METHODS/RESULTS In this study, the results of the MTT and flow cytometry-based assays showed that Aloperine-Adbic (adenoviral vector expressing p14ARF/p53) combined treatment on NSCLC cells synergistically produced anti-proliferative effects, induced apoptosis, and arrested cell cycle at the G1 phase. Furthermore, the expression analysis suggested that the p53/p21 pathway might contribute to achieving aforesaid cytotoxic effects. The ALO-Adbic combined treatment prolonged the percent survival of NSCLC xenograft models. CONCLUSION In conclusion, ALO-Adbic combination can produce synergistic anti-cancer effects at low doses, and may offer a more effective and less toxic new treatment strategy for NSCLC.
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Affiliation(s)
- Tahir Muhammad
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100022, China
| | - Ali Sakhawat
- Beijing Institute of Technology, Beijing, 100124, China
| | - Aamir Ali Khan
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100022, China
| | - Hua Huang
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100022, China
| | | | - Yinghui Huang
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100022, China
| | - Juan Wang
- College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100022, China.
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26
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Hadryś A, Sochanik A, McFadden G, Jazowiecka-Rakus J. Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses. Eur J Pharmacol 2020; 874:172991. [PMID: 32044323 DOI: 10.1016/j.ejphar.2020.172991] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 01/09/2020] [Accepted: 02/04/2020] [Indexed: 12/13/2022]
Abstract
Progress in genetic engineering led to the emergence of some viruses as potent anticancer therapeutics. These oncolytic viruses combine self-amplification with dual antitumor action: oncolytic (destruction of cancer cells) and immunostimulatory (eliciting acquired antitumor response against cancer epitopes). As any other viruses, they trigger antiviral response upon systemic administration. Mesenchymal stem cells are immature cells capable of self-renewing and differentiating into many cell types that belong to three germinal layers. Due to their inherent tumor tropism mesenchymal stem cells loaded with oncolytic virus can improve delivery of the therapeutic cargo to cancer sites. Shielding of oncolytic viral construct from antiviral host immune response makes these cells prospective delivery vehicles to even hard-to-reach metastatic neoplastic foci. Use of mesenchymal stem cells has been criticized by some investigators as limiting proliferative abilities of primary cells and increasing the risk of malignant transformation, as well as attenuating therapeutic responses. However, majority of preclinical studies indicate safety and efficacy of mesenchymal stem cells used as carriers of oncolytic viruses. In view of contradictory postulates, the debate continues. The review discusses mesenchymal stem cells as carriers for delivery of genetically engineered oncolytic constructs and focuses on systemic approach to oncoviral treatment of some deadly neoplasms.
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Affiliation(s)
- Agata Hadryś
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland; Institute of Chemistry, University of Silesia, Poland.
| | - Aleksander Sochanik
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland.
| | - Grant McFadden
- Biodesign Institute, Arizona State University, Tempe, AZ, USA.
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Attia N, Mashal M. Mesenchymal Stem Cells: The Past Present and Future. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1312:107-129. [PMID: 33159306 DOI: 10.1007/5584_2020_595] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The biomedical applications of mesenchymal stem cells (MSCs) have gained expanding attention over the past three decades. MSCs are easily obtained from various tissue types (e.g. bone marrow, fat, cord blood, etc.), are capable of self-renewal, and could be induced to differentiate into several cell lineages for countless biomedical applications. In addition, when transplanted, MSCs are not detected by immune surveillance, thus do not lead to graft rejection. Moreover, they can home towards affected tissues and induce their therapeutic effect in a cell-base and/or a cell-free manner. These properties, and many others, have made MSCs appealing therapeutic cell candidates (for cell and/or gene therapy) in myriad clinical conditions. However, similar to any other therapeutic tool, MSCs still have their own limitations and grey areas that entail more research for better understanding and optimization. Herein, we present a brief overview of various pre-clinical/clinical applications of MSCs in regenerative medicine and discuss limitations and future challenges.
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Affiliation(s)
- Noha Attia
- Department of Basic Sciences, The American University of Antigua-College of Medicine, Coolidge, Antigua and Barbuda. .,The Center of research and evaluation, The American University of Antigua-College of Medicine, Coolidge, Antigua and Barbuda. .,Histology and Cell Biology Department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt. .,NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
| | - Mohamed Mashal
- The Center of research and evaluation, The American University of Antigua-College of Medicine, Coolidge, Antigua and Barbuda.,NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
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Ouyang X, Wang X, Kraatz HB, Ahmadi S, Gao J, Lv Y, Sun X, Huang Y. A Trojan horse biomimetic delivery strategy using mesenchymal stem cells for PDT/PTT therapy against lung melanoma metastasis. Biomater Sci 2019; 8:1160-1170. [PMID: 31848537 DOI: 10.1039/c9bm01401b] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Mesenchymal stem cell (MSC)-based biomimetic delivery has been actively explored for drug accumulation and penetration into tumors by taking advantage of the tumor-tropic and penetration properties of MSCs. In this work, we further demonstrated the feasibility of MSC-mediated nano drug delivery, which was characterized by the "Trojan horse"-like transport via an endocytosis-exocytosis-endocytosis process between MSCs and cancer cells. Chlorin e6 (Ce6)-conjugated polydopamine nanoparticles (PDA-Ce6) were developed and loaded into the MSCs. Phototherapeutic agents are safe to the MSCs, and their very low dark toxicity causes no impairment of the inherent properties of MSCs, including tumor-homing ability. The MSCs loaded with PDA-Ce6 (MSC-PDA-Ce6) were able to target and penetrate into tumors and exocytose 60% of the payloads in 72 h. The released PDA-Ce6 NPs could penetrate deep and be re-endocytosed by the cancer cells. MSC-PDA-Ce6 tended to accumulate in the lungs and delivered PDA-Ce6 into the tumors after intravenous injection in the mouse model with lung melanoma metastasis. Phototoxicity can be selectively triggered in the tumors by sequentially treating with near-infrared irradiation to induce photodynamic therapy (PDT) and photothermal therapy (PTT). The MSC-based biomimetic delivery of PDA-Ce6 nanoparticles is a potential method for dual phototherapy against lung melanoma metastasis.
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Affiliation(s)
- Xumei Ouyang
- Department of Pharmacy, Zhejiang University City College, Hangzhou 310015, China. and Department of Pharmacy, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325035, China and Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiaoling Wang
- Department of Pharmacy, Zhejiang University City College, Hangzhou 310015, China. and Department of Pharmacy, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325035, China
| | - Heinz-Bernhard Kraatz
- Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada
| | - Soha Ahmadi
- Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada
| | - Jianqing Gao
- Department of Pharmacy, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yuanyuan Lv
- Department of Pharmacy, Zhejiang University City College, Hangzhou 310015, China.
| | - Xiaoyi Sun
- Department of Pharmacy, Zhejiang University City College, Hangzhou 310015, China.
| | - Yongzhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai, 201203, China.
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Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death. Cancers (Basel) 2019; 11:cancers11121975. [PMID: 31817939 PMCID: PMC6966515 DOI: 10.3390/cancers11121975] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 12/24/2022] Open
Abstract
Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of selectivity they have for tumour cells over healthy cells. Over the past decade, research has demonstrated the existence of numerous proteins which have an intrinsic tumour-specific toxicity, several of which originate from viruses. These tumour-selective viral proteins, although from distinct backgrounds, have several similar and interesting properties. Though the mechanism(s) of action of these proteins are not fully understood, it is possible that they can manipulate several cell death modes in cancer exemplifying the intricate interplay between these pathways. This review will discuss our current knowledge on the topic and outstanding questions, as well as deliberate the potential for viral proteins to progress into the clinic as successful cancer therapeutics.
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