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1
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Rahimian S, Mirkazemi K, Kamalinejad A, Doroudian M. Exosome-based advances in pancreatic cancer: The potential of mesenchymal stem cells. Crit Rev Oncol Hematol 2025; 207:104594. [PMID: 39732301 DOI: 10.1016/j.critrevonc.2024.104594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/28/2024] [Accepted: 12/08/2024] [Indexed: 12/30/2024] Open
Abstract
Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), is one of the most challenging clinical conditions due to its late-stage diagnosis and poor survival rates. Mesenchymal stem cells (MSCs), used for targeted therapies, are being explored as a promising treatment because of their tumor-homing properties and potential contributions to the pancreatic cancer microenvironment. Understanding these interactions is crucial for developing effective treatments. In this study, we investigated how MSCs exhibit tropism towards tumors, influence the microenvironment through paracrine effects, and serve as potential drug delivery vehicles. We also examined their role in progression and therapeutic resistance in pancreatic cancer therapy. The cytotoxic effects of certain compounds on tumor cells, the use of genetically modified MSCs as drug carriers, and the potential of exosomal biomarkers like miRNAs and riRNAs for diagnosis and monitoring of pancreatic cancer were analyzed. Overall, MSC-based therapies, coupled with insights into tumor-stromal interactions, offer new avenues for improving outcomes in pancreatic cancer treatment. Additionally, the use of MSC-based therapies in clinical trials is discussed. While MSCs show promising potential for pancreatic cancer monitoring, diagnosis, and treatment, results so far have been limited.
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Affiliation(s)
- Sana Rahimian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Kimia Mirkazemi
- Faculty of Science, University of Amsterdam, Amsterdam, the Netherlands
| | - Armita Kamalinejad
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
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2
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Liu X, Hyun Kim J, Li X, Liu R. Application of mesenchymal stem cells exosomes as nanovesicles delivery system in the treatment of breast cancer. Int J Pharm 2024; 666:124732. [PMID: 39304093 DOI: 10.1016/j.ijpharm.2024.124732] [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: 05/28/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
As people's living standards continue to improve and human life span expectancy increases, the incidence and mortality rates of breast cancer are continuously rising. Early detection of breast cancer and targeted therapy for different breast cancer subtypes can significantly reduce the mortality rate and alleviate the suffering of patients. Exosomes are extracellular vesicles secreted by various cells in the body. They participate in physiological and pathological responses by releasing active substances and play an important role in regulating intercellular communication. In recent years, research on exosomes has gradually expanded, and their special membrane structure and targetable characteristics are being increasingly applied in various clinical studies. Mesenchymal stem cells (MSCs)-derived exosomes play an important role in regulating the progression of breast cancer. In this review, we summarize the current treatment methods for breast cancer, the connection between MSCs, exosomes, and breast cancer, as well as the application of exosomes derived from MSCs from different sources in cancer treatment. We highlight how the rational design of modified MSCs-derived exosomes (MSCs-Exos) delivery systems can overcome the uncertainties of stem cell therapy and overcome the clinical translation challenges of nanomaterials. This work aims to promote future research on the application of MSCs-Exos in breast cancer treatment.
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Affiliation(s)
- Xiaofan Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - June Hyun Kim
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea
| | - Xuemei Li
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China.
| | - Rui Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea.
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3
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Wang KN, Li ZZ, Zhou K, Liu B, Rao L, Bu LL. Cell Membrane-Coated Nanoparticles for Dental, Oral, and Craniofacial Diseases. RESEARCH (WASHINGTON, D.C.) 2024; 7:0478. [PMID: 39296987 PMCID: PMC11409001 DOI: 10.34133/research.0478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/26/2024] [Accepted: 08/29/2024] [Indexed: 09/21/2024]
Abstract
Dental, oral, and craniofacial diseases can substantially impact the quality of human life, thereby posing a serious public health concern. Although conventional therapies such as surgery have solved these problems largely, the prognosis of patients is not always satisfactory. Cell membrane-coated nanoparticles (CMCNPs) carry nanodrugs with the help of natural cell membranes, therefore utilizing their remarkable ability to interface and interact with their surrounding environment. These nanoparticles have demonstrated substantial advantages in drug targeting, prolonging blood circulation time, penetrating biofilms, and immune escape. With the assistance of CMCNPs, the therapeutic effects of dental, oral, and craniofacial diseases can reach a higher level. CMCNPs have been applied for dental, oral, and craniofacial diseases for various conditions such as head and neck cancer, periodontal disease, and oral biosignal detection. For the therapies of head and neck cancer, CMCNPs have been widely utilized as a tool of chemotherapy, phototherapy, and immunotherapy, while yet to be exploited in imaging technique. In the end, we summarized the challenges and prospectives of CMCNPs for dental, oral, and craniofacial diseases: large-scale production with uniform standards and high quantity, extensive application directions in dental, oral, and craniofacial regions (implant, endodontics), and the promotion of its clinical application.
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Affiliation(s)
- Kang-Ning Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zi-Zhan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Kan Zhou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral & Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Lang Rao
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Lin-Lin Bu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral & Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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4
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Coccè V, Missaglia S, Martegani E, Tavian D, Doneda L, Manfredi B, Alessandri G, Corradini C, Giannì A, Ciusani E, Paino F, Pessina A. Early Adipogenesis and Upregulation of UCP1 in Mesenchymal Stromal Cells Stimulated by Devitalized Microfragmented Fat (MiFAT). J Lipids 2024; 2024:1318186. [PMID: 39297160 PMCID: PMC11410402 DOI: 10.1155/2024/1318186] [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: 01/31/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/21/2024] Open
Abstract
Adipose tissue is mainly composed by adipocytes. Moreover, mesenchymal stromal/stem cells (MSCs), macrophages, endothelial cells, and extracellular matrix components are present. The variety of molecules as cytokines and growth factors of its structure very rich in blood vessel makes it also similar to a true endocrine organ that however needs still to be fully investigated. In our study, we used human lipoaspirate to obtain mechanically microfragmented fat (MiFAT) which was washed and then devitalized by freezing-thawing cycles. In our experiments, thawed MiFAT was used to stimulate cultures of MSCs from two different sources (adipose tissue and gingiva papilla) in comparison with a traditional stimulation in vitro obtained by culturing MSCs with adipogenic medium. MSCs stimulated with MiFAT showed a very early production of lipid droplets, after only 3 days, that correlated with an increased expression of adipokines. Furthermore, a significant upregulation of PPAR gamma 1 alpha coactivator (PPARGC1A) was observed with an overexpression of uncoupling protein 1 (UCP1) that suggest a pattern of differentiation compatible with the beige-brown fat.
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Affiliation(s)
- Valentina Coccè
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
| | - Sara Missaglia
- Laboratory of Cellular Biochemistry and Molecular Biology CRIBENS Università Cattolica del Sacro Cuore, Milan, Italy
- Department of Psychology Università Cattolica del Sacro Cuore, Milan, Italy
| | - Eleonora Martegani
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
| | - Daniela Tavian
- Laboratory of Cellular Biochemistry and Molecular Biology CRIBENS Università Cattolica del Sacro Cuore, Milan, Italy
- Department of Psychology Università Cattolica del Sacro Cuore, Milan, Italy
| | - Luisa Doneda
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
| | - Barbara Manfredi
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
| | - Giulio Alessandri
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
| | - Costantino Corradini
- Department of Biomedical Surgical and Dental Sciences Sports Trauma Researches Center University of Milan c/o 1st Division of Orthopedics and Traumatology Orthopedic Center Pini CTO-ASST Gaetano Pini, Milan, Italy
| | - Aldo Giannì
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
- Maxillo-Facial and Dental Unit Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico 20122, Milan, Italy
| | - Emilio Ciusani
- Department of Diagnostics and Technology Fondazione IRCCS Istituto Neurologico "C.Besta", Milano, Italy
| | - Francesca Paino
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
| | - Augusto Pessina
- CRC StaMeTec Department of Biomedical Surgical and Dental Sciences University of Milan 20122, Milan, Italy
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5
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Mahadiuzzaman ASM, Dain Md Opo FA, Alkarim S. Stem cell-based targeted therapy in pancreatic cancer: Current approaches and future prospects. Tissue Cell 2024; 89:102449. [PMID: 38924893 DOI: 10.1016/j.tice.2024.102449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 05/22/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
Despite recent improvements in oncology, diagnosis, and therapy, pancreatic cancer remains extremely difficult to cure due to its aggressive growth pattern with early invasion and distant metastases, chemoresistance, and a lack of effective screening modalities for early detection. Here, novel therapeutic approaches for treating pancreatic cancer are urgently needed. Recently, stem cells have drawn a lot of interest as a possible treatment for pancreatic cancer due to their ability to locate tumors. Though research over the last few decades has revealed some very exciting and promising new treatment approaches, the clinical success of these stem-cell based anti-cancer medicines has been quite limited. The most effective stem cell-mediated therapeutic options will only be available with a deeper understanding of the intricate molecular biology underlying pancreatic cancer and the subsequent identification of cancer stem cells as a novel target that promotes the growth of the cancer and resistance to chemotherapy. This review will highlight the stem cell based anti-cancer therapy targeting pancreatic cancer stem cells and different molecular signaling pathways. A particular focus will be on the therapeutic potential of naïve Stem cells, anti-cancer drug loaded stem cells, genetically engineered stem cells and exosomal miRNA released by stem cells in pancreatic cancer treatment. Similarly, the role of nanotechnology in stem cell based anticancer therapy will be further discussed to better implementation of these cell-based cancer therapy.
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Affiliation(s)
- A S M Mahadiuzzaman
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - F A Dain Md Opo
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Saleh Alkarim
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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6
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Starska-Kowarska K. Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies. Cells 2024; 13:1270. [PMID: 39120301 PMCID: PMC11311692 DOI: 10.3390/cells13151270] [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: 06/08/2024] [Revised: 07/11/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.
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Affiliation(s)
- Katarzyna Starska-Kowarska
- Department of Physiology, Pathophysiology and Clinical Immunology, Department of Clinical Physiology, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; ; Tel.: +48-42-2725237
- Department of Otorhinolaryngology, EnelMed Center Expert, Lodz, Drewnowska 58, 91-001 Lodz, Poland
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7
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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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8
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Padinharayil H, George A. Small extracellular vesicles: Multi-functional aspects in non-small cell lung carcinoma. Crit Rev Oncol Hematol 2024; 198:104341. [PMID: 38575042 DOI: 10.1016/j.critrevonc.2024.104341] [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: 07/05/2023] [Revised: 03/13/2024] [Accepted: 03/28/2024] [Indexed: 04/06/2024] Open
Abstract
Extracellular vesicles (EVs) impact normal and pathological cellular signaling through bidirectional trafficking. Exosomes, a subset of EVs possess biomolecules including proteins, lipids, DNA fragments and various RNA species reflecting a speculum of their parent cells. The involvement of exosomes in bidirectional communication and their biological constituents substantiate its role in regulating both physiology and pathology, including multiple cancers. Non-small cell lung cancer (NSCLC) is the most common lung cancers (85%) with high incidence, mortality and reduced overall survival. Lack of efficient early diagnostic and therapeutic tools hurdles the management of NSCLC. Interestingly, the exosomes from body fluids similarity with parent cells or tissue offers a potential future multicomponent tool for the early diagnosis of NSCLC. The structural twinning of exosomes with a cell/tissue and the competitive tumor derived exosomes in tumor microenvironment (TME) promotes the unpinning horizons of exosomes as a drug delivery, vaccine, and therapeutic agent. Exosomes in clinical point of view assist to trace: acquired resistance caused by various therapeutic agents, early diagnosis, progression, and surveillance. In an integrated approach, EV biomarkers offer potential cutting-edge techniques for the detection and diagnosis of cancer, though the purification, characterization, and biomarker identification processes for the translational research regarding EVs need further optimization.
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Affiliation(s)
- Hafiza Padinharayil
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur-05, Kerala, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur-05, Kerala, India.
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9
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Coccè V, Bonelli M, La Monica S, Alfieri R, Doneda L, Martegani E, Alessandri G, Lagrasta CA, Giannì A, Sordi V, Petrella F, Roncoroni L, Paino F, Pessina A. Mesenchymal stromal cells loaded with Paclitaxel (PacliMES) a potential new therapeutic approach on mesothelioma. Biochem Pharmacol 2023; 214:115678. [PMID: 37399948 DOI: 10.1016/j.bcp.2023.115678] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/19/2023] [Accepted: 06/29/2023] [Indexed: 07/05/2023]
Abstract
Malignant pleural mesothelioma is an asbestos-related tumor originating in mesothelial cells of the pleura that poorly responds to chemotherapeutic approaches. Adult mesenchymal stromal cells derived either from bone marrow or from adipose tissue may be considered a good model for cell-based therapy, a treatment which has experienced significant interest in recent years. The present study confirms that Paclitaxel is effective on mesothelioma cell proliferation in 2D and 3D in vitro cultures, and that 80,000 mesenchymal stromal cells loaded with Paclitaxel inhibit tumor growth at a higher extent than Paclitaxel alone. An in vivo approach to treat in situ mesothelioma xenografts using a minimal amount of 106 mesenchymal stromal cells loaded with Paclitaxel showed the same efficacy of a systemic administration of 10 mg/kg of Paclitaxel. These data strongly support drug delivery system by mesenchymal stromal cells as a useful approach against many solid tumors. We look with interest at the favourable opinion recently expressed by the Italian Drug Agency on the procedure for the preparation of mesenchymal stromal cells loaded with Paclitaxel in large-scale bioreactor systems and their storage until clinical use. This new Advanced Medicinal Therapy Product, already approved for a Phase I clinical trial on mesothelioma patients, could pave the way for mesenchymal stromal cells use as drug delivery system on other solid tumors for adjuvant therapy associated with surgery and radiotherapy.
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Affiliation(s)
- Valentina Coccè
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Mara Bonelli
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Silvia La Monica
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Luisa Doneda
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Eleonora Martegani
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Giulio Alessandri
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | | | - Aldo Giannì
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Hospital, 20132 Milan, Italy
| | - Francesco Petrella
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; Department of Thoracic Surgery, IRCCS European Institute of Oncology, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Leda Roncoroni
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; Center for Prevention and Diagnosis of Celiac Disease, Gastroenterology and Endoscopy Unit. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Francesca Paino
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Augusto Pessina
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
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10
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Giuli L, Santopaolo F, Pallozzi M, Pellegrino A, Coppola G, Gasbarrini A, Ponziani FR. Cellular therapies in liver and pancreatic diseases. Dig Liver Dis 2023; 55:563-579. [PMID: 36543708 DOI: 10.1016/j.dld.2022.11.013] [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: 08/11/2022] [Revised: 10/21/2022] [Accepted: 11/22/2022] [Indexed: 04/29/2023]
Abstract
Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine.
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Affiliation(s)
- Lucia Giuli
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Pallozzi
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Pellegrino
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
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11
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Cordani N, Lisini D, Coccè V, Paglia G, Meanti R, Cerrito MG, Tettamanti P, Bonaffini L, Paino F, Alessandri G, Marcianti A, Giannì A, Villa C, Mauri M, Mologni L, Torsello A, Pessina A, Cazzaniga ME. Conditioned Medium of Mesenchymal Stromal Cells Loaded with Paclitaxel Is Effective in Preclinical Models of Triple-Negative Breast Cancer (TNBC). Int J Mol Sci 2023; 24:ijms24065864. [PMID: 36982938 PMCID: PMC10058623 DOI: 10.3390/ijms24065864] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a very aggressive disease even in its early stages and is characterized by a severe prognosis. Neoadjuvant chemotherapy is one of the milestones of treatment, and paclitaxel (PTX) is among the most active drugs used in this setting. However, despite its efficacy, peripheral neuropathy occurs in approximately 20-25% of cases and represents the dose-limiting toxicity of this drug. New deliverable strategies to ameliorate drug delivery and reduce side effects are keenly awaited to improve patients' outcomes. Mesenchymal stromal cells (MSCs) have recently been demonstrated as promising drug delivery vectors for cancer treatment. The aim of the present preclinical study is to explore the possibility of a cell therapy approach based on the use of MSCs loaded with PTX to treat TNBC-affected patients. For this purpose, we in vitro evaluated the viability, migration and colony formation of two TNBC cell lines, namely, MDA-MB-231 and BT549, treated with MSC-PTX conditioned medium (MSC-CM PTX) in comparison with both CM of MSCs not loaded with PTX (CTRL) and free PTX. We observed stronger inhibitory effects on survival, migration and tumorigenicity for MSC-CM PTX than for CTRL and free PTX in TNBC cell lines. Further studies will provide more information about activity and potentially open the possibility of using this new drug delivery vector in the context of a clinical study.
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Affiliation(s)
- Nicoletta Cordani
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | - Daniela Lisini
- Cell Therapy Production Unit-UPTC, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Valentina Coccè
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Giuseppe Paglia
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | - Ramona Meanti
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | | | - Pietro Tettamanti
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Luca Bonaffini
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | - Francesca Paino
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Giulio Alessandri
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Angela Marcianti
- Cell Therapy Production Unit-UPTC, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Aldo Giannì
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
- Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Chiara Villa
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | - Mario Mauri
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | - Luca Mologni
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | - Antonio Torsello
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
| | - Augusto Pessina
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Marina Elena Cazzaniga
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy
- Phase 1 Research Centre, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi 33, 20900 Monza, Italy
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12
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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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The Role of Mesenchymal Stem Cells and Exosomes in Tumor Development and Targeted Antitumor Therapies. Stem Cells Int 2023; 2023:7059289. [PMID: 36824409 PMCID: PMC9943627 DOI: 10.1155/2023/7059289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 01/17/2023] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can be isolated from various tissues in adults and differentiated into cells of the osteoblasts, adipocytes, chondrocytes, and myocytes. Recruitments of MSCs towards tumors have a crucial contribution to tumor development. However, the role of MSCs in the tumor microenvironment is uncertain. In addition, due to its tropism to the tumor and low immunogenic properties, more and more pieces of evidence indicate that MSCs may be an ideal carrier for antitumor biologics such as cytokines, chemotherapeutic agents, and oncolytic viruses. Here, we review the existing knowledge on the anti- and protumorigenic effect of MSCs and their extracellular vesicles and exosomes, the role of MSCs, and their extracellular vesicles and exosomes as antitumor vectors.
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14
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Ma Z, Hua J, Liu J, Zhang B, Wang W, Yu X, Xu J. Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges. Int J Mol Sci 2023; 24:3559. [PMID: 36834969 PMCID: PMC9966548 DOI: 10.3390/ijms24043559] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 02/01/2023] [Indexed: 02/12/2023] Open
Abstract
Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer.
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Affiliation(s)
- Zhilong Ma
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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15
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Microcapsule-Based Dose-Dependent Regulation of the Lifespan and Behavior of Adipose-Derived MSCs as a Cell-Mediated Delivery System: In Vitro Study. Int J Mol Sci 2022; 24:ijms24010292. [PMID: 36613737 PMCID: PMC9820487 DOI: 10.3390/ijms24010292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
The development of “biohybrid” drug delivery systems (DDS) based on mesenchymal stem/stromal cells (MSCs) is an important focus of current biotechnology research, particularly in the areas of oncotheranostics, regenerative medicine, and tissue bioengineering. However, the behavior of MSCs at sites of inflammation and tumor growth is relevant to potential tumor transformation, immunosuppression, the inhibition or stimulation of tumor growth, metastasis, and angiogenesis. Therefore, the concept was formulated to control the lifespan of MSCs for a specific time sufficient for drug delivery to the target tissue by varying the number of internalized microcontainers. The current study addressed the time-dependent in vitro assessment of the viability, migration, and division of human adipose-derived MSCs (hAMSCs) as a function of the dose of internalized polyelectrolyte microcapsules prepared using a layer-by-layer technique. Polystyrene sulfonate (PSS)—poly(allylamine hydrochloride) (PAH)-coated spherical micrometer-sized (diameter ~2−3 µm) vaterite (CaCO3) microcapsules (PAH-PSS)6 with the capping PSS layer were prepared after dissolution of the CaCO3 core template. The Cell-IQ phase contrast imaging results showed that hAMSCs internalized all (PAH-PSS)6 microcapsules saturating the intercellular medium (5−90 particles per cell). A strong (r > 0.7) linear dose-dependent and time-dependent (up to 8 days) regression was observed between the in vitro decrease in cell viability and the number of internalized microvesicles. The approximate time-to-complete-death of hAMSCs at different concentrations of microcapsules in culture was 428 h (1:5 ratio), 339 h (1:10), 252 h (1:20), 247 h (1:45), and 170 h (1:90 ratio). By varying the number of microcontainers loaded into the cells (from 1:10 to 1:90), a dose-dependent exponential decrease in both the movement rate and division rate of hAMSCs was observed. A real-time cell analysis (RTCA) of the effect of (PAH-PSS)6 microcapsules (from 1:5 to 1:20) on hAMSCs also showed a dose- and time-dependent decrease in cell longevity after a 50h study at ratios of 1:10 and 1:20. The incorporation of microcapsules (1:5, 1:20, and 1:45) resulted in a dose-dependent increase in 24−48 h secretion of GRO-α (CXCL1), MIF, and SDF-1α (CXCL12) chemokines in hAMSC culture. In turn, the normalization or inhibition of chemokine secretion occurred after 72 h, except for MIF levels below 5−20 microcapsules, which were internalized by MSCs. Thus, the proposed concept of controlling the lifespan of MSC-based DDS using a dose of internalized PAH-PSS microcapsules could be useful for biomedical applications. (PAH-PSS)6 microcapsule ratios of 1:5 and 1:10 have little effect on the lifespan of hAMSCs for a long time (up to 14−18 days), which can be recommended for regenerative therapy and tissue bioengineering associated with low oncological risk. The microcapsule ratios of 1:20 and 1:45 did not significantly restrict the migratory activity of hAMSCs-based DDS during the time interval required for tissue delivery (up to 4−5 days), followed by cell death after 10 days. Therefore, such doses of microcapsules can be used for hAMSC-based DDS in oncotheranostics.
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16
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Babajani A, Manzari-Tavakoli A, Jamshidi E, Tarasi R, Niknejad H. Anti-cancer effects of human placenta-derived amniotic epithelial stem cells loaded with paclitaxel on cancer cells. Sci Rep 2022; 12:18148. [PMID: 36307463 PMCID: PMC9616866 DOI: 10.1038/s41598-022-22562-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/17/2022] [Indexed: 12/31/2022] Open
Abstract
Available therapeutic strategies for cancers have developed side effects, resistance, and recurrence that cause lower survival rates. Utilizing targeted drug delivery techniques has opened up new hopes for increasing the efficacy of cancer treatment. The current study aimed to investigate the appropriate condition of primming human amniotic epithelial cells (hAECs) with paclitaxel as a dual therapeutic approach consisting of inherent anticancer features of hAECs and loaded paclitaxel. The effects of paclitaxel on the viability of hAECs were evaluated to find an appropriate loading period. The possible mechanism of hAECs paclitaxel resistance was assessed using verapamil. Afterward, the loading and releasing efficacy of primed hAECs were evaluated by HPLC. The anti-neoplastic effects and apoptosis as possible mechanism of conditioned media of paclitaxel-loaded hAECs were assessed on breast and cervical cancer cell lines. hAECs are highly resistant to cytotoxic effects of paclitaxel in 24 h. Evaluating the role of P-glycoproteins in hAECs resistance showed that they do not participate in hAECs resistance. The HPLC demonstrated that hAECs uptake/release paclitaxel with optimum efficacy in 8000 ng/ml treatment. Assessing the anti-proliferative effect of primed hAECs condition media on cancer cells showed that the secretome induced 3.3- and 4.8-times more potent effects on MCF-7 and HeLa, respectively, and enhanced the apoptosis process. These results suggest that hAECs could possibly be used as a drug delivery system for cancer treatment. Besides, inherent anticancer effects of hAECs were preserved during the modification process. Synergistic anticancer effects of paclitaxel and hAECs can be translated into clinical practice, which would be evaluated in the future studies.
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Affiliation(s)
- Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asma Manzari-Tavakoli
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Jamshidi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roghayeh Tarasi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Szewc M, Radzikowska-Bűchner E, Wdowiak P, Kozak J, Kuszta P, Niezabitowska E, Matysiak J, Kubiński K, Masłyk M. MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents-A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives. Int J Mol Sci 2022; 23:2745. [PMID: 35269887 PMCID: PMC8911180 DOI: 10.3390/ijms23052745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure.
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Affiliation(s)
- Monika Szewc
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Elżbieta Radzikowska-Bűchner
- Department of Plastic, Reconstructive and Maxillary Surgery, Central Clinical Hospital MSWiA, 02-507 Warsaw, Poland;
| | - Paulina Wdowiak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Joanna Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Piotr Kuszta
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Ewa Niezabitowska
- Department of Urology and Urological Oncology, Multidisciplinary Hospital in Lublin, 20-400 Lublin, Poland;
| | - Joanna Matysiak
- Department of Chemistry, University of Life Sciences in Lublin, 20-950 Lublin, Poland;
| | - Konrad Kubiński
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
| | - Maciej Masłyk
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
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18
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Bellei B, Migliano E, Picardo M. Research update of adipose tissue-based therapies in regenerative dermatology. Stem Cell Rev Rep 2022; 18:1956-1973. [PMID: 35230644 DOI: 10.1007/s12015-022-10328-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2022] [Indexed: 12/09/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) have a spontaneous propensity to support tissue homeostasis and regeneration. Among the several sources of MSCs, adipose-derived tissue stem cells (ADSCs) have received major interest due to the higher mesenchymal stem cells concentration, ease, and safety of access. However, since a significant part of the natural capacity of ADSCs to repair damaged tissue is ascribable to their secretory activity that combines mitogenic factors, cytokines, chemokines, lipids, and extracellular matrix components, several studies focused on cell-free strategies. Furthermore, adipose cell-free derivatives are becoming more attractive especially for non-volumizing purposes, such as most dermatological conditions. However, when keratinocytes, fibroblasts, melanocytes, adipocytes, and hair follicle cells might not be locally sourced, graft of materials containing concentrated ADSCs is preferred. The usage of extracellular elements of adipose tissue aims to promote a self-autonomous regenerative microenvironment in the receiving area restoring physiological homeostasis. Hence, ADSCs or their paracrine activity are currently being studied in several dermatological settings including wound healing, skin fibrosis, burn, and aging.The present work analyzing both preclinical and clinical experiences gives an overview of the efficacy of adipose tissue-derivatives like autologous fat, the stromal vascular fraction (SVF), purified ADSCs, secretome and extracellular matrix graft in the field of regenerative medicine for the skin.
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Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy.
| | - Emilia Migliano
- Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy
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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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Limongi T, Susa F, Marini M, Allione M, Torre B, Pisano R, di Fabrizio E. Lipid-Based Nanovesicular Drug Delivery Systems. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:3391. [PMID: 34947740 PMCID: PMC8707227 DOI: 10.3390/nano11123391] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/07/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022]
Abstract
In designing a new drug, considering the preferred route of administration, various requirements must be fulfilled. Active molecules pharmacokinetics should be reliable with a valuable drug profile as well as well-tolerated. Over the past 20 years, nanotechnologies have provided alternative and complementary solutions to those of an exclusively pharmaceutical chemical nature since scientists and clinicians invested in the optimization of materials and methods capable of regulating effective drug delivery at the nanometer scale. Among the many drug delivery carriers, lipid nano vesicular ones successfully support clinical candidates approaching such problems as insolubility, biodegradation, and difficulty in overcoming the skin and biological barriers such as the blood-brain one. In this review, the authors discussed the structure, the biochemical composition, and the drug delivery applications of lipid nanovesicular carriers, namely, niosomes, proniosomes, ethosomes, transferosomes, pharmacosomes, ufasomes, phytosomes, catanionic vesicles, and extracellular vesicles.
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Hamilton G, Teufelsbauer M. Adipose-derived stromal/stem cells and extracellular vesicles for cancer therapy. Expert Opin Biol Ther 2021; 22:67-78. [PMID: 34236014 DOI: 10.1080/14712598.2021.1954156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Mesenchymal stromal/stem cells (MSCs) hold great perspective for the therapy of a host of diseases due to regenerative and anti-inflammatory properties by differentiation into diverse cell populations, homing to damaged tissue regions, paracrine effects, and release of extracellular vesicles. AREAS COVERED This review describes the isolation, characterization, and potential use of MSCs and ADSCs for benign and malignant diseases. The MSCs may be administered as whole cells or in form of their secretome that is held responsible for most of their beneficial effects. A special constituent of the paracrine components are the extracellular vesicles (EVs) that carry a biologically potent cargo of proteins, cytokines, and RNA. EXPERT OPINION The applications of MSCs and ADSCs are amply documented and have been investigated in preclinical models and many unregulated and a few controlled trials. Larger numbers of MSCs and ADSCs can be obtained for allogeneic transfer but imply difficulties including perseverance of the cells in vivo and possible differentiation into harmful cell types. MSC-derived cell-free preparations are easier to handle and manufacture for various applications. Especially, with the help of bioreactors, EVs can be obtained in excessive numbers and preloaded or charged with proteins, cytokines, and regulatory RNA specimen to treat inflammatory diseases and cancer.
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Affiliation(s)
- Gerhard Hamilton
- Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria.,Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Maryana Teufelsbauer
- Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria.,Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
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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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Raghav PK, Mann Z. Cancer stem cells targets and combined therapies to prevent cancer recurrence. Life Sci 2021; 277:119465. [PMID: 33831426 DOI: 10.1016/j.lfs.2021.119465] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/01/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) control the dynamics of tumorigenesis by self-renewal ability and differentiation potential. These properties contribute towards tumor malignancy, metastasis, cellular heterogeneity, and immune escape, which are regulated by multiple signaling pathways. The CSCs are chemoresistant and cause cancer recurrence, generally recognized as a small side-population that eventually leads to tumor relapse. Despite many treatment options available, none can be considered entirely efficient due to a lack of specificity and dose limitation. This review primarily highlights the processes involved in CSCs development and maintenance. Secondly, the current effective therapies based on stem cells, cell-free therapies that involve exosomes and miRNAs, and photodynamic therapy have been discussed. Also, the inhibitors that specifically target various signaling pathways, which can be used in combination to control CSCs kinetics have been highlighted. Conclusively, this comprehensive review is a detailed study of recently developed novel treatment strategies that will facilitate in coming up with better-targeted approaches against CSCs.
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Affiliation(s)
| | - Zoya Mann
- Independent Researcher, New Delhi, India
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24
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Tan B, Tang Q, Zhong Y, Wei Y, He L, Wu Y, Wu J, Liao J. Biomaterial-based strategies for maxillofacial tumour therapy and bone defect regeneration. Int J Oral Sci 2021; 13:9. [PMID: 33727527 PMCID: PMC7966790 DOI: 10.1038/s41368-021-00113-9] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/13/2020] [Accepted: 01/17/2021] [Indexed: 02/07/2023] Open
Abstract
Issues caused by maxillofacial tumours involve not only dealing with tumours but also repairing jaw bone defects. In traditional tumour therapy, the systemic toxicity of chemotherapeutic drugs, invasive surgical resection, intractable tumour recurrence, and metastasis are major threats to the patients' lives in the clinic. Fortunately, biomaterial-based intervention can improve the efficiency of tumour treatment and decrease the possibility of recurrence and metastasis, suggesting new promising antitumour therapies. In addition, maxillofacial bone tissue defects caused by tumours and their treatment can negatively affect the physiological and psychological health of patients, and investment in treatment can result in a multitude of burdens to society. Biomaterials are promising options because they have good biocompatibility and bioactive properties for stimulation of bone regeneration. More interestingly, an integrated material regimen that combines tumour therapy with bone repair is a promising treatment option. Herein, we summarized traditional and biomaterial-mediated maxillofacial tumour treatments and analysed biomaterials for bone defect repair. Furthermore, we proposed a promising and superior design of dual-functional biomaterials for simultaneous tumour therapy and bone regeneration to provide a new strategy for managing maxillofacial tumours and improve the quality of life of patients in the future.
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Affiliation(s)
- Bowen Tan
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Quan Tang
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yongjin Zhong
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yali Wei
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Linfeng He
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanting Wu
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiabao Wu
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jinfeng Liao
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Centre for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
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25
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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26
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Tarasov VV, Svistunov AA, Chubarev VN, Dostdar SA, Sokolov AV, Brzecka A, Sukocheva O, Neganova ME, Klochkov SG, Somasundaram SG, Kirkland CE, Aliev G. Extracellular vesicles in cancer nanomedicine. Semin Cancer Biol 2021; 69:212-225. [PMID: 31421263 DOI: 10.1016/j.semcancer.2019.08.017] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 07/22/2019] [Accepted: 08/13/2019] [Indexed: 02/06/2023]
Abstract
To date, a lot of nanotechnological optitions are available for targeted drug delivery. Extracellular vesicles (EVs) are membrane structures that cells use for storage, transport, communication, and signaling. Recent research has focused on EVs as natural nanoparticles for drug delivery. This review sheds light on the application of EVs in cancer therapy, such as targeted chemotherapy, gene therapy, and vaccine development. Aspects of biogenesis, isolation, targeting, and loading of EVs are discussed in detail.
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Affiliation(s)
- Vadim V Tarasov
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Andrey A Svistunov
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Vladimir N Chubarev
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Samira A Dostdar
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Alexander V Sokolov
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Anna Brzecka
- Department of Pulmonology and Lung Cancer, Wroclaw Medical University, Wroclaw, Poland
| | - Olga Sukocheva
- College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, Australia
| | - Margarita E Neganova
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia
| | - Sergey G Klochkov
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia
| | | | - Cecil E Kirkland
- Department of Biological Sciences, Salem University, Salem, WV, USA
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia; Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia; GALLY International Research Institute, 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA.
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27
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Giannasi C, Niada S, Magagnotti C, Ragni E, Andolfo A, Brini AT. Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles. Stem Cell Res Ther 2020; 11:521. [PMID: 33272318 PMCID: PMC7711257 DOI: 10.1186/s13287-020-02035-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In the last years, several clinical trials have proved the safety and efficacy of adipose-derived stem/stromal cells (ASC) in contrasting osteoarthritis (OA). Since ASC act mainly through paracrine mechanisms, their secretome (conditioned medium, CM) represents a promising therapeutic alternative. ASC-CM is a complex cocktail of proteins, nucleic acids, and lipids released as soluble factors and/or conveyed into extracellular vesicles (EV). Here, we investigate its therapeutic potential in an in vitro model of OA. METHODS Human articular chondrocytes (CH) were induced towards an OA phenotype by 10 ng/ml TNFα in the presence of either ASC-CM or EV, both deriving from 5 × 105 cells, to evaluate the effect on hypertrophic, catabolic, and inflammatory markers. RESULTS Given the same number of donor cells, our data reveal a higher therapeutic potential of ASC-CM compared to EV alone that was confirmed by its enrichment in chondroprotective factors among which TIMP-1 and -2 stand out. In details, only ASC-CM significantly decreased MMP activity (22% and 29% after 3 and 6 days) and PGE2 expression (up to 40% at day 6) boosted by the inflammatory cytokine. Conversely, both treatments down-modulated of ~ 30% the hypertrophic marker COL10A1. CONCLUSIONS These biological and molecular evidences of ASC-CM beneficial action on CH with an induced OA phenotype may lay the basis for its future clinical translation as a cell-free therapeutic in the management of OA.
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Affiliation(s)
- Chiara Giannasi
- Laboratorio di Applicazioni Biotecnologiche, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
| | - Stefania Niada
- Laboratorio di Applicazioni Biotecnologiche, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Cinzia Magagnotti
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Enrico Ragni
- Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Annapaola Andolfo
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Anna Teresa Brini
- Laboratorio di Applicazioni Biotecnologiche, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.,Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
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28
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Coccè V, Bonomi A, Cavicchini L, Sisto F, Giannì A, Farronato G, Alessandri G, Petrella F, Sordi V, Parati E, Bondiolotti G, Paino F, Pessina A. Paclitaxel Priming of TRAIL Expressing Mesenchymal Stromal Cells (MSCs-TRAIL) Increases Antitumor Efficacy of Their Secretome. Curr Cancer Drug Targets 2020; 21:CCDT-EPUB-111520. [PMID: 33200709 DOI: 10.2174/1568009620666201116112153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 09/07/2020] [Accepted: 09/16/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Adipose tissue derived MSCs engineered with the tumor necrosis factor-related apoptosis-inducing ligand protein (MSCs-TRAIL) have a significant anticancer activity. MSCs, without any genetic modifications, exposed to high doses of chemotherapeutic agents are able to uptake the drug and release it in amount affecting tumor proliferation. The purpose of this study was to verify the ability of MSCs-TRAIL to uptake and release paclitaxel (PTX) by providing an increased antitumor efficacy. METHODS MSCs and MSCs-TRAIL were tested for their sensitivity to Paclitaxel (PTX) by MTT assay and the cells were loaded with PTX according to a standardized procedure. The secretome was analysed by HPLC for the presence of PTX, microarray assay for soluble TRAIL (s-TRAIL) and tested for in vitro anticancer activity. RESULTS MSCs-TRAIL were resistant to PTX and able to incorporate and then release the drug. The secretion of s-TRAIL by PTX loaded MSCs-TRAIL was not inhibited and the PTX delivery together with s-TRAIL secretion resulted into an increased antitumor efficacy of cell secretoma as tested in vitro on human pancreatic carcinoma (CFPAC-1) and glioblastoma (U87-MG). CONCLUSIONS Our result is the first demonstration of the possible merging of two new MSCs therapy approaches based on genetic manipulation and drug delivery. If confirmed in vivo, this could potentiate the efficacy of MSCs-TRAIL and strongly contribute to reduce the toxicity due to the systemic treatment of PTX.
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Affiliation(s)
- Valentina Coccè
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy
| | - Arianna Bonomi
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy
| | - Loredana Cavicchini
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy
| | - Francesca Sisto
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy
| | - Aldo Giannì
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy
| | - Giampietro Farronato
- Department of Biomedical, Surgical and Dental Sciences, Unit of Orthodontics and Paediatric Dentistry, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano. Italy
| | - Giulio Alessandri
- Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan. Italy
| | - Francesco Petrella
- Department of Oncology and Hematology, University of Milan, Milan. Italy
| | - Valeria Sordi
- San Raffaele Diabetes Research Institute; San Raffaele Scientific Institute, Milan. Italy
| | - Eugenio Parati
- Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan. Italy
| | - Gianpietro Bondiolotti
- Department of Medical Biotechnology and Translational Medicine, University of Milan. Italy
| | - Francesca Paino
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy
| | - Augusto Pessina
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy
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Louault K, Li RR, DeClerck YA. Cancer-Associated Fibroblasts: Understanding Their Heterogeneity. Cancers (Basel) 2020; 12:E3108. [PMID: 33114328 PMCID: PMC7690906 DOI: 10.3390/cancers12113108] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 10/12/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023] Open
Abstract
The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming and therapeutic resistance. Nevertheless, their role is not fully understood, and is sometimes controversial due to their heterogeneity. CAFs are heterogeneous in their origin, phenotype, function and presence within tumors. As a result, strategies to target CAFs in cancer therapy have been hampered by the difficulties in better defining the various populations of CAFs and by the lack of clear recognition of their specific function in cancer progression. This review discusses how a greater understanding of the heterogeneous nature of CAFs could lead to better approaches aimed at their use or at their targeting in the treatment of cancer.
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Affiliation(s)
- Kévin Louault
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Rong-Rong Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA;
| | - Yves A. DeClerck
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
- Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
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30
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Shi Q, Huo N, Wang X, Yang S, Wang J, Zhang T. Exosomes from oral tissue stem cells: biological effects and applications. Cell Biosci 2020; 10:108. [PMID: 32944222 PMCID: PMC7490964 DOI: 10.1186/s13578-020-00471-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
As natural nanoparticles, exosomes are a type of extracellular vesicles that are enclosed by a lipid bilayer and contain various cargos, including miRNA, mRNA, DNA and proteins. Exosomes have rapidly gained attention as a highly promising cell-free therapy. Because the cargo of exosomes changes with the changes in parent cells and status, exosomes from different types of cells may exhibit different biological effects. Considering the particularity of oral tissue stem cells, their exosomes were isolated and used to examine their related biological functions and the possibility of replacing stem cells. A variety of exosomes of oral tissue stem cells were studied, and the results revealed many special biological characteristics of these exosomes and their parent cells, especially immunomodulation, osteogenesis, odontogenesis, neuroprotection, nerve regeneration, wound healing, skin regeneration and vascularization. The oral tissue stem cell exosomes may be loaded with drugs or genes and act as tools for tumor treatment. The relevant results showed that exosomes from oral tissue stem cells were potent therapeutic tools. The present review focuses on the biological function and application of oral tissue stem cell-derived exosomes.
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Affiliation(s)
- Quan Shi
- Institute of Stomatology, First Medical Center, Chinese PLA General Hospital, Beijing, 100853 China
| | - Na Huo
- Institute of Stomatology, First Medical Center, Chinese PLA General Hospital, Beijing, 100853 China
| | - Xing Wang
- Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001 China.,Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, 030001 China
| | - Shuo Yang
- Institute of Stomatology, First Medical Center, Chinese PLA General Hospital, Beijing, 100853 China
| | - Juncheng Wang
- Institute of Stomatology, First Medical Center, Chinese PLA General Hospital, Beijing, 100853 China
| | - Tong Zhang
- Institute of Stomatology, First Medical Center, Chinese PLA General Hospital, Beijing, 100853 China
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31
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Babajani A, Soltani P, Jamshidi E, Farjoo MH, Niknejad H. Recent Advances on Drug-Loaded Mesenchymal Stem Cells With Anti-neoplastic Agents for Targeted Treatment of Cancer. Front Bioeng Biotechnol 2020; 8:748. [PMID: 32793565 PMCID: PMC7390947 DOI: 10.3389/fbioe.2020.00748] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/11/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs), as an undifferentiated group of adult multipotent cells, have remarkable antitumor features that bring them up as a novel choice to treat cancers. MSCs are capable of altering the behavior of cells in the tumor microenvironment, inducing an anti-inflammatory effect in tumor cells, inhibiting tumor angiogenesis, and preventing metastasis. Besides, MSCs can induce apoptosis and inhibit the proliferation of tumor cells. The ability of MSCs to be loaded with chemotherapeutic drugs and release them in the site of primary and metastatic neoplasms makes them a preferable choice as targeted drug delivery procedure. Targeted drug delivery minimizes unexpected side effects of chemotherapeutic drugs and improves clinical outcomes. This review focuses on recent advances on innate antineoplastic features of MSCs and the effect of chemotherapeutic drugs on viability, proliferation, and the regenerative capacity of various kinds of MSCs. It also discusses the efficacy and mechanisms of drug loading and releasing procedures along with in vivo and in vitro preclinical outcomes of antineoplastic effects of primed MSCs for clinical prospection.
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Affiliation(s)
- Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pegah Soltani
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Jamshidi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hadi Farjoo
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Automated Large-Scale Production of Paclitaxel Loaded Mesenchymal Stromal Cells for Cell Therapy Applications. Pharmaceutics 2020; 12:pharmaceutics12050411. [PMID: 32365861 PMCID: PMC7284468 DOI: 10.3390/pharmaceutics12050411] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 04/25/2020] [Accepted: 04/28/2020] [Indexed: 01/20/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) prepared as advanced therapies medicinal products (ATMPs) have been widely used for the treatment of different diseases. The latest developments concern the possibility to use MSCs as carrier of molecules, including chemotherapeutic drugs. Taking advantage of their intrinsic homing feature, MSCs may improve drugs localization in the disease area. However, for cell therapy applications, a significant number of MSCs loaded with the drug is required. We here investigate the possibility to produce a large amount of Good Manufacturing Practice (GMP)-compliant MSCs loaded with the chemotherapeutic drug Paclitaxel (MSCs-PTX), using a closed bioreactor system. Cells were obtained starting from 13 adipose tissue lipoaspirates. All samples were characterized in terms of number/viability, morphology, growth kinetics, and immunophenotype. The ability of MSCs to internalize PTX as well as the antiproliferative activity of the MSCs-PTX in vitro was also assessed. The results demonstrate that our approach allows a large scale expansion of cells within a week; the MSCs-PTX, despite a different morphology from MSCs, displayed the typical features of MSCs in terms of viability, adhesion capacity, and phenotype. In addition, MSCs showed the ability to internalize PTX and finally to kill cancer cells, inhibiting the proliferation of tumor lines in vitro. In summary our results demonstrate for the first time that it is possible to obtain, in a short time, large amounts of MSCs loaded with PTX to be used in clinical trials for the treatment of patients with oncological diseases.
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Li JN, Li W, Cao LQ, Liu N, Zhang K. Efficacy of mesenchymal stem cells in the treatment of gastrointestinal malignancies. World J Gastrointest Oncol 2020; 12:365-382. [PMID: 32368316 PMCID: PMC7191336 DOI: 10.4251/wjgo.v12.i4.365] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/03/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs), which are a kind of stem cell, possess an immune privileged nature, tumour homing features, and multi-lineage differentiation ability. MSCs have been studied in many fields, such as tissue engineering, nervous system diseases, and cancer treatment. In recent years, an increasing number of researchers have focused on the effects of MSCs on various kinds of tumours. However, the concrete anticancer efficacy of MSCs is still controversial. Gastrointestinal (GI) malignancies are the major causes of cancer-related death worldwide. The interactions of MSCs and GI cancer cells in specific conditions have attracted increasing attention. In this review, we introduce the characteristics of MSCs and analyse the effects of MSCs on GI malignancies, including gastric cancer, hepatoma, pancreatic cancer, and colorectal cancer. In addition, we also provide our perspectives on why MSCs may play different roles in GI malignancies and further research directions to increase the treatment efficacy of MSCs on GI malignancies.
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Affiliation(s)
- Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Wei Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Lan-Qing Cao
- Department of Pathology, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Ning Liu
- Department of Central Laboratory, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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Potentials of "stem cell-therapy" in pancreatic cancer: An update. Pancreatology 2019; 19:1034-1042. [PMID: 31668563 DOI: 10.1016/j.pan.2019.09.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 08/22/2019] [Accepted: 09/28/2019] [Indexed: 02/07/2023]
Abstract
In recent times, cell-therapies like T-activated cells, dendritic cells and natural killer cells have shown increasing promise in treating cancers as evidenced by both animal and human studies in the literature. In addition, stem cells are also being considered as potent anti-cancer agents since they act through multi-pronged approaches (chemokines, cytokines, paracrine action). In this review, we have attempted to discuss the inferences of studies that have used different sub-types of stem cells namely mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs) and neural stem cells (NSCs) in in-vitro/in-vivo mice and/or human studies as a treatment modality for pancreatic cancer. Pancreatic cancers are diagnosed in late/metastatic stages hence limiting its progress to partial/disease-free status. Recent literature supports evidences of stem cell therapy in pancreatic cancer with promising results; yet their impact remains inconclusive due to limited studies in human subjects. With reference to the treatment options for pancreatic cancer, the most studied sub-type of stem cells was HSCs as evident from the available clinical trials. The suggested mechanism of the HSC-transplantation is presumably via the graft-versus-tumor effect that elicits an anti-tumor immune response activated by the T-cell repertoires. On the other hand, the property of MSCs like tropism, migration to tumor site and activation of host immune cells by its secretome, appear to be able to regulate pancreatic tumor microenvironment. Further, drug delivery potential could be mediated via engineered MSCs to enhance the bioavailability of drug/prodrug at tumor site. Conclusively, stem cells have shown great potentials as next-generation therapeutic options.
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Chopra N, Dutt Arya B, Jain N, Yadav P, Wajid S, Singh SP, Choudhury S. Biophysical Characterization and Drug Delivery Potential of Exosomes from Human Wharton's Jelly-Derived Mesenchymal Stem Cells. ACS OMEGA 2019; 4:13143-13152. [PMID: 31460441 PMCID: PMC6705090 DOI: 10.1021/acsomega.9b01180] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 07/24/2019] [Indexed: 05/22/2023]
Abstract
Cell-derived exosomes (30-200 nm) as biological "nanocarriers" have attracted a great deal of interest for therapeutic applications due to their ability to internalize in in vivo biological systems (i.e., cells). Although they can be harvested from various sources including stem cells, yet an appropriate isolation and characterization protocol to obtain "pure" exosomal population is needed. For potential clinical applications, understanding the functional ability of exosomes and their purity, that is, free from microvesicles, apoptotic bodies, and protein aggregates, is a pre-requisite. To achieve high purity and yield of exosomes from human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) in the size range of 30-200 nm, we have performed and compared three isolation procedures: ultracentrifugation (UC), sucrose cushion (SC), and commercially available reagent (CR). The isolated exosomes were characterized using nanoparticle tracking analysis (NTA), field emission scanning electron microscopy (FESEM), and atomic force microscopy (AFM). Furthermore, to understand the therapeutic potential of the hWJ-MSC-derived exosomes (hWJ-ME) to target pancreatic tumor cells, the internalization efficacy has been evaluated on the MiaPaCa-2 cell lines using confocal microscopy and flow cytometry. The NTA results showed sucrose cushion to be an optimal method for exosome isolation with high purity (86.8%), as compared to UC (40.5%; p = 0.050) and CR (38%; p = 0.050). Optical analysis by FESEM and AFM revealed that SC-isolated exosomes presented a spherical morphology, whereas UC- and CR-isolated exosomes exhibited an uneven morphology. Furthermore, the data from confocal images and flow cytometry showed that hWJ-ME were internalized by MiaPaCa-2, demonstrating the feasibility of exosomes as a "potential nanocarrier". Thus, our study suggests that a combination of NTA (yield), AFM (dimensions), and FESEM (morphology and topography) could provide sensitive biophysical characterization of hWJ-ME. In the future, enriched exosomes could be used as a delivery vehicle to transport target-specific drugs or gene-silencing constructs to tumors.
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Affiliation(s)
- Neha Chopra
- Department
of Research, Sir Ganga Ram Hospital, Old Rajinder Nagar, Delhi 110060, India
- Department
of Biotechnology, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Braham Dutt Arya
- CSIR−National
Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi 110012, India
- Academy
of Scientific & Innovative Research (AcSIR), New Delhi 110025, India
| | - Namrata Jain
- Malvern
Panalytical Ltd., Enigma Business Park, Malvern WR14 1XZ, U.K.
| | - Poonam Yadav
- Department
of Research, Sir Ganga Ram Hospital, Old Rajinder Nagar, Delhi 110060, India
| | - Saima Wajid
- Department
of Biotechnology, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Surinder P. Singh
- CSIR−National
Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi 110012, India
- Academy
of Scientific & Innovative Research (AcSIR), New Delhi 110025, India
- E-mail: (S.P.S.)
| | - Sangeeta Choudhury
- Department
of Research, Sir Ganga Ram Hospital, Old Rajinder Nagar, Delhi 110060, India
- E-mail: (S.C.)
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Mesenchymal Stem Cells and Cancer: Clinical Challenges and Opportunities. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2820853. [PMID: 31205939 PMCID: PMC6530243 DOI: 10.1155/2019/2820853] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 03/19/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023]
Abstract
Stem cell-based therapies exhibit profound therapeutic potential for treating various human diseases, including cancer. Among the cell types that can be used for this purpose, mesenchymal stem cells (MSCs) are considered as promising source of stem cells in personalized cell-based therapies. The inherent tumor-tropic property of MSCs can be used to target cancer cells. Although the impacts of MSCs on tumor progression remain elusive, they have been genetically modified or engineered as targeted anticancer agents which could inhibit tumor growth by blocking different processes of tumor. In addition, there are close interactions between MSCs and cancer stem cells (CSCs). MSCs can regulate the growth of CSCs through paracrine mechanisms. This review aims to focus on the current knowledge about MSCs-based tumor therapies, the opportunities and challenges, as well as the prospective of its further clinical implications.
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Coccè V, Franzè S, Brini AT, Giannì AB, Pascucci L, Ciusani E, Alessandri G, Farronato G, Cavicchini L, Sordi V, Paroni R, Dei Cas M, Cilurzo F, Pessina A. In Vitro Anticancer Activity of Extracellular Vesicles (EVs) Secreted by Gingival Mesenchymal Stromal Cells Primed with Paclitaxel. Pharmaceutics 2019; 11:pharmaceutics11020061. [PMID: 30717104 PMCID: PMC6409699 DOI: 10.3390/pharmaceutics11020061] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/15/2019] [Accepted: 01/26/2019] [Indexed: 01/08/2023] Open
Abstract
Interdental papilla are an interesting source of mesenchymal stromal cells (GinPaMSCs), which are easy to isolate and expand in vitro. In our laboratory, GinPaMSCs were isolated, expanded, and characterized by studying their secretome before and after priming with paclitaxel (PTX). The secretome of GinPaMSCs did not affect the growth of cancer cell lines tested in vitro, whereas the secretome of GinPaMSCs primed with paclitaxel (GinPaMSCs/PTX) exerted a significant anticancer effect. GinPaMSCs were able to uptake and then release paclitaxel in amounts pharmacologically effective against cancer cells, as demonstrated in vitro by the direct activity of GinPaMSCs/PTX and their secretome against both human pancreatic carcinoma and squamous carcinoma cells. PTX was associated with extracellular vesicles (EVs) secreted by cells (EVs/PTX), suggesting that PTX is incorporated into exosomes during their biogenesis. The isolation of mesenchymal stromal cells (MSCs) from gingiva is less invasive than that from other tissues (such as bone marrow and fat), and GinPaMSCs provide an optimal substrate for drug-priming to obtain EVs/PTX having anticancer activity. This research may contribute to develop new strategies of cell-mediated drug delivery by EVs that are easy to store without losing function, and could have a superior safety profile in therapy.
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Affiliation(s)
- Valentina Coccè
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
| | - Silvia Franzè
- Department of Pharmaceutical Science, University of Milan, 20133 Milan, Italy.
| | - Anna Teresa Brini
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
- IRCCS Orthopedic Institute Galeazzi, 20161 Milan, Italy.
| | - Aldo Bruno Giannì
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
- Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy.
| | - Luisa Pascucci
- Department of Veterinary Medicine, University of Perugia, 06123 Perugia, Italy.
| | - Emilio Ciusani
- Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico "C. Besta", 20133 Milan, Italy.
| | - Giulio Alessandri
- Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, 20133 Milan, Italy.
| | - Giampietro Farronato
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
- Unit of Orthodontics and Paediatric Dentistry, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy.
| | - Loredana Cavicchini
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
| | - Rita Paroni
- Department of Health Sciences of the University of Milan, 20142 Milan, Italy.
| | - Michele Dei Cas
- Department of Health Sciences of the University of Milan, 20142 Milan, Italy.
| | - Francesco Cilurzo
- Department of Pharmaceutical Science, University of Milan, 20133 Milan, Italy.
| | - Augusto Pessina
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
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Marei HE, Casalbore P, Althani A, Coccè V, Cenciarelli C, Alessandri G, Brini AT, Parati E, Bondiolotti G, Pessina A. Human Olfactory Bulb Neural Stem Cells (Hu-OBNSCs) Can Be Loaded with Paclitaxel and Used to Inhibit Glioblastoma Cell Growth. Pharmaceutics 2019; 11:45. [PMID: 30669623 PMCID: PMC6358986 DOI: 10.3390/pharmaceutics11010045] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/11/2019] [Accepted: 01/16/2019] [Indexed: 12/20/2022] Open
Abstract
Exploitation of the potential ability of human olfactory bulb (hOB) cells to carry, release, and deliver an effective, targeted anticancer therapy within the central nervous system (CNS) milieu remains elusive. Previous studies have demonstrated the marked ability of several types of stem cells (such as mesenchymal stem cells (MSCs) to carry and release different anti-cancer agents such as paclitaxel (PTX). Herein we investigate the ability of human olfactory bulb neural stem cells (Hu-OBNSCs) to carry and release paclitaxel, producing effective cytotoxic effects against cancer cells. We isolated Hu-OBNSCs from the hOB, uploaded them with PTX, and studied their potential cytotoxic effects against cancer cells in vitro. Interestingly, the Hu-OBNSCs displayed a five-fold increase in their resistance to the cytotoxicity of PTX, and the PTX-uploaded Hu-OBNSCs were able to inhibit proliferation and invasion, and to trigger marked cytotoxic effects on glioblastoma multiforme (GBM) cancer cells, and Human Caucasian fetal pancreatic adenocarcinoma 1 (CFPAC-1) in vitro. Despite their ability to resist the cytotoxic activity of PTX, the mechanism by which Hu-OBNSCs acquire resistance to PTX is not yet explained. Collectively our data indicate the ability of the Hu-OBNSCs to resist PTX, and to trigger effective cytotoxic effects against GBM cancer cells and CFPAC-1. This indicates their potential to be used as a carrier/vehicle for targeted anti-cancer therapy within the CNS.
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Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35116, Egypt.
| | - Patrizia Casalbore
- Institute of Cell Biology and Neurobiology, National Research Council of Italy, 00015 Rome, Italy.
| | - Asmaa Althani
- Biomedical Research Center, Qatar University, Doha 2713, Qatar.
| | - Valentina Coccè
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
| | - Carlo Cenciarelli
- Institute of Translational Pharmacology, National Research Council of Italy, 00133 Rome, Italy.
| | - Giulio Alessandri
- Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, 20133 Milan, Italy.
| | - Anna T Brini
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy.
| | - Eugenio Parati
- Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, 20133 Milan, Italy.
| | - Gianpietro Bondiolotti
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
| | - Augusto Pessina
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20133 Milan, Italy.
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Chulpanova DS, Kitaeva KV, Tazetdinova LG, James V, Rizvanov AA, Solovyeva VV. Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment. Front Pharmacol 2018; 9:259. [PMID: 29615915 PMCID: PMC5869248 DOI: 10.3389/fphar.2018.00259] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 03/08/2018] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs), which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.
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Affiliation(s)
- Daria S Chulpanova
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Kristina V Kitaeva
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Leysan G Tazetdinova
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - Albert A Rizvanov
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Valeriya V Solovyeva
- OpenLab Gene and Cell Technologies, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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A Nonenzymatic and Automated Closed-Cycle Process for the Isolation of Mesenchymal Stromal Cells in Drug Delivery Applications. Stem Cells Int 2018. [PMID: 29531535 PMCID: PMC5838483 DOI: 10.1155/2018/4098140] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The adipose tissue is a good source of mesenchymal stromal cells that requires minimally invasive isolation procedures. To ensure reproducibility, efficacy, and safety for clinical uses, these procedures have to be in compliant with good manufacturing practices. Techniques for harvesting and processing human adipose tissue have rapidly evolved in the last years, and Lipogems® represents an innovative approach to obtain microfragmented adipose tissue in a short time, without expansion and/or enzymatic treatment. The aim of this study was to assess the presence of mesenchymal stromal cells in the drain bag of the device by using a prototype Lipogems processor to wash the lipoaspirate in standardized condition. We found that, besides oil and blood residues, the drain bag contained single isolated cells easy to expand and with the typical characteristics of mesenchymal stromal cells that can be loaded with paclitaxel to use for drug-delivery application. Our findings suggest the possibility to replace the drain bag with a "cell culture chamber" obtaining a new integrated device that, without enzymatic treatment, can isolate and expand mesenchymal stromal cells in one step with high good manufacturing practices compliance. This system could be used to obtain mesenchymal stromal cells for regenerative purposes and for drug delivery.
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Drug Loaded Gingival Mesenchymal Stromal Cells (GinPa-MSCs) Inhibit In Vitro Proliferation of Oral Squamous Cell Carcinoma. Sci Rep 2017; 7:9376. [PMID: 28839168 PMCID: PMC5571047 DOI: 10.1038/s41598-017-09175-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 07/20/2017] [Indexed: 12/29/2022] Open
Abstract
Human mesenchymal stromal cells (MSCs) have been widely investigated both for regenerative medicine and their antinflammatory/immunomodulatory capacity. However, their ability to home pathological tissues suggested the development of strategies for using MSCs as carrier to deliver drug into tumor microenvironment. MSCs obtained from different tissues can be loaded in vitro with anti-cancer drugs by a simple procedures. In this report, we studied MSCs isolated and expanded from gingival papilla (GinPa-MSCs), by testing their ability to uptake and release three important anti-neoplastic drugs: Paclitaxel (PTX), Doxorubicin (DXR) and Gemcitabine (GCB). The efficacy of drugs releasing GinPa-MSCs was studied on a pancreatic cancer cell line and confirmed in vitro against a line of tongue squamous cell carcinoma (SCC154). Our results demonstrated that GinPa-MSCs efficiently incorporate the drugs and then released them in active form and in sufficient amount to produce a dramatic inhibition of squamous cell carcinoma growth in vitro. If compared with other MSCs sources, the collection of GinPa-MSCs is poorly invasive and cells can be easily expanded and efficiently loaded with anti cancer drugs. In particular, gemcitabine loaded GinPa-MSCs provide a good "cell-mediated drug delivery system" for a future potential application in the context of the oral oncology.
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Crivelli B, Chlapanidas T, Perteghella S, Lucarelli E, Pascucci L, Brini AT, Ferrero I, Marazzi M, Pessina A, Torre ML. Mesenchymal stem/stromal cell extracellular vesicles: From active principle to next generation drug delivery system. J Control Release 2017; 262:104-117. [PMID: 28736264 DOI: 10.1016/j.jconrel.2017.07.023] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 07/12/2017] [Accepted: 07/15/2017] [Indexed: 02/06/2023]
Abstract
It has been demonstrated that the biological effector of mesenchymal stem/stromal cells (MSCs) is their secretome, which is composed of a heterogeneous pool of bioactive molecules, partially enclosed in extracellular vesicles (EVs). Therefore, the MSC secretome (including EVs) has been recently proposed as possible alternative to MSC therapy. The secretome can be considered as a protein-based biotechnological product, it is probably safer compared with living/cycling cells, it presents virtually lower tumorigenic risk, and it can be handled, stored and sterilized as an Active Pharmaceutical/Principle Ingredient (API). EVs retain some structural and technological analogies with synthetic drug delivery systems (DDS), even if their potential clinical application is also limited by the absence of reproducible/scalable isolation methods and Good Manufacturing Practice (GMP)-compliant procedures. Notably, EVs secreted by MSCs preserve some of their parental cell features such as homing, immunomodulatory and regenerative potential. This review focuses on MSCs and their EVs as APIs, as well as DDS, considering their ability to reach inflamed and damaged tissues and to prolong the release of encapsulated drugs. Special attention is devoted to the illustration of innovative therapeutic approaches in which nanomedicine is successfully combined with stem cell therapy, thus creating a novel class of "next generation drug delivery systems."
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Affiliation(s)
- Barbara Crivelli
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
| | - Theodora Chlapanidas
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
| | - Sara Perteghella
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
| | - Enrico Lucarelli
- Osteoarticular Regeneration Laboratory, 3rd Orthopaedic and Traumatologic Clinic, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, 40136 Bologna, Italy.
| | - Luisa Pascucci
- Veterinary Medicine Department, University of Perugia, Via San Costanzo 4, 06126 Perugia, Italy.
| | - Anna Teresa Brini
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, 20100 Milan, Italy; I.R.C.C.S. Galeazzi Orthopedic Institute, Via Riccardo Galeazzi 4, 20161 Milan, Italy.
| | - Ivana Ferrero
- Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, City of Science and Health of Turin, Regina Margherita Children's Hospital, Piazza Polonia 94, 10126 Turin, Italy; Department of Public Health and Paediatrics, University of Turin, Piazza Polonia 94, 10126 Turin, Italy.
| | - Mario Marazzi
- Tissue Therapy Unit, ASST Niguarda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy.
| | - Augusto Pessina
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, 20100 Milan, Italy.
| | - Maria Luisa Torre
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
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Pacioni S, D'Alessandris QG, Giannetti S, Morgante L, Coccè V, Bonomi A, Buccarelli M, Pascucci L, Alessandri G, Pessina A, Ricci-Vitiani L, Falchetti ML, Pallini R. Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts. Stem Cell Res Ther 2017; 8:53. [PMID: 28279193 PMCID: PMC5345323 DOI: 10.1186/s13287-017-0516-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 01/27/2017] [Accepted: 02/21/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) represent an attractive tool for cell-based cancer therapy mainly because of their ability to migrate to tumors and to release bioactive molecules. However, the impact of MSCs on tumor growth has not been fully established. We previously demonstrated that murine MSCs show a strong tropism towards glioblastoma (GBM) brain xenografts and that these cells are able to uptake and release the chemotherapeutic drug paclitaxel (PTX), maintaining their tropism towards the tumor. Here, we address the therapy-relevant issue of using MSCs from human donors (hMSCs) for local or systemic administration in orthotopic GBM models, including xenografts of patient-derived glioma stem cells (GSCs). METHODS U87MG or GSC1 cells expressing the green fluorescent protein (GFP) were grafted onto the striatum of immunosuppressed rats. Adipose hMSCs (Ad-hMSCs), fluorescently labeled with the mCherry protein, were inoculated adjacent to or into the tumor. In rats bearing U87MG xenografts, systemic injections of Ad-hMSCs or bone marrow (BM)-hMSCs were done via the femoral vein or carotid artery. In each experiment, either PTX-loaded or unloaded hMSCs were used. To characterize the effects of hMSCs on tumor growth, we analyzed survival, tumor volume, tumor cell proliferation, and microvascular density. RESULTS Overall, the AD-hMSCs showed remarkable tropism towards the tumor. Intracerebral injection of Ad-hMSCs significantly improved the survival of rats with U87MG xenografts. This effect was associated with a reduction in tumor growth, tumor cell proliferation, and microvascular density. In GSC1 xenografts, intratumoral injection of Ad-hMSCs depleted the tumor cell population and induced migration of resident microglial cells. Overall, PTX loading did not significantly enhance the antitumor potential of hMSCs. Systemically injected Ad- and BM-hMSCs homed to tumor xenografts. The efficiency of hMSC homing ranged between 0.02 and 0.5% of the injected cells, depending both on the route of cell injection and on the source from which the hMSCs were derived. Importantly, systemically injected PTX-loaded hMSCs that homed to the xenograft induced cytotoxic damage to the surrounding tumor cells. CONCLUSIONS hMSCs have a therapeutic potential in GBM brain xenografts which is also expressed against the GSC population. In this context, PTX loading of hMSCs seems to play a minor role.
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Affiliation(s)
- Simone Pacioni
- Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy.,CNR-Institute of Cell Biology and Neurobiology (IBCN), Rome, Italy
| | | | - Stefano Giannetti
- Institute of Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Liliana Morgante
- Institute of Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Valentina Coccè
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Arianna Bonomi
- Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute Carlo Besta, Milan, Italy
| | - Mariachiara Buccarelli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Luisa Pascucci
- Department of Veterinary Medicine, University of Perugia, Perugia, Italy
| | - Giulio Alessandri
- Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute Carlo Besta, Milan, Italy
| | - Augusto Pessina
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Lucia Ricci-Vitiani
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | | | - Roberto Pallini
- Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy
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