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Jiang M, Bu W, Wang X, Ruan J, Shi W, Yu S, Huang L, Xue P, Tang J, Zhao X, Su L, Cheng D. Pulmonary fibrosis: from mechanisms to therapies. J Transl Med 2025; 23:515. [PMID: 40340941 PMCID: PMC12063347 DOI: 10.1186/s12967-025-06514-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/18/2025] [Indexed: 05/10/2025] Open
Abstract
Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by excessive deposition of extracellular matrix (ECM) and abnormal fibroblast proliferation, which is mainly caused by air pollution, smoking, aging, occupational exposure, environmental pollutants exposure, and microbial infections. Although antifibrotic agents such as pirfenidone and nintedanib, approved by the United States (US) Food and Drug Administration (FDA), can slow the decline in lung function and disease progression, their side effects and delivery inefficiency limit the overall prognosis of PF. Therefore, there is an urgent need to develop effective therapeutic targets and delivery approaches for PF in clinical settings. This review provides an overview of the pathogenic mechanisms, therapeutic drug targeting signaling pathways, and promising drug delivery strategies for treating PF.
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Affiliation(s)
- Mengna Jiang
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China
| | - Wenxia Bu
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China
| | - Xuehai Wang
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China
| | - Jialing Ruan
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China
| | - Weijian Shi
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China
| | - Siqi Yu
- Department of Clinical Medicine, Jiangxi Medical College, Shangrao, 334000, China
| | - Lizhen Huang
- Department of Clinical Medicine, Jiangxi Medical College, Shangrao, 334000, China
| | - Peng Xue
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China
| | - Juan Tang
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China
| | - Xinyuan Zhao
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China.
| | - Liling Su
- Department of Clinical Medicine, Jiangxi Medical College, Shangrao, 334000, China.
| | - Demin Cheng
- Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China.
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Lee D, Oh S, Lawler S, Kim Y. Bistable dynamics of TAN-NK cells in tumor growth and control of radiotherapy-induced neutropenia in lung cancer treatment. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2025; 22:744-809. [PMID: 40296792 DOI: 10.3934/mbe.2025028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Neutrophils play a crucial role in the innate immune response as a first line of defense in many diseases, including cancer. Tumor-associated neutrophils (TANs) can either promote or inhibit tumor growth in various steps of cancer progression via mutual interactions with cancer cells in a complex tumor microenvironment (TME). In this study, we developed and analyzed mathematical models to investigate the role of natural killer cells (NK cells) and the dynamic transition between N1 and N2 TAN phenotypes in killing cancer cells through key signaling networks and how adjuvant therapy with radiation can be used in combination to increase anti-tumor efficacy. We examined the complex immune-tumor dynamics among N1/N2 TANs, NK cells, and tumor cells, communicating through key extracellular mediators (Transforming growth factor (TGF-$ \beta $), Interferon gamma (IFN-$ \gamma $)) and intracellular regulation in the apoptosis signaling network. We developed several tumor prevention strategies to eradicate tumors, including combination (IFN-$ \gamma $, exogenous NK, TGF-$ \beta $ inhibitor) therapy and optimally-controlled ionizing radiation in a complex TME. Using this model, we investigated the fundamental mechanism of radiation-induced changes in the TME and the impact of internal and external immune composition on the tumor cell fate and their response to different treatment schedules.
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Affiliation(s)
- Donggu Lee
- Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea
| | - Sunju Oh
- Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea
| | - Sean Lawler
- Department of Pathology and Laboratory Medicine, Legorreta Brown Cancer Center, Brown University, Providence, RI 02912, USA
| | - Yangjin Kim
- Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea
- Department of Pathology and Laboratory Medicine, Legorreta Brown Cancer Center, Brown University, Providence, RI 02912, USA
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Baran Z, Çetinkaya M, Baran Y. Mesenchymal Stem Cells in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:149-177. [PMID: 39470980 DOI: 10.1007/5584_2024_824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/01/2024]
Abstract
The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies.
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Affiliation(s)
- Züleyha Baran
- Laboratory of Molecular Pharmacology, Department of Pharmacology, Anadolu University, Eskişehir, Turkey
| | - Melisa Çetinkaya
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey
| | - Yusuf Baran
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
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Rehman A, Panda SK, Torsiello M, Marigliano M, Tufano CC, Nigam A, Parveen Z, Papaccio G, La Noce M. The crosstalk between primary MSCs and cancer cells in 2D and 3D cultures: potential therapeutic strategies and impact on drug resistance. Stem Cells Transl Med 2024; 13:1178-1185. [PMID: 39418131 PMCID: PMC11631265 DOI: 10.1093/stcltm/szae077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/23/2024] [Indexed: 10/19/2024] Open
Abstract
The tumor microenvironment (TME) significantly influences cancer progression, and mesenchymal stem cells (MSCs) play a crucial role in interacting with tumor cells via paracrine signaling, affecting behaviors such as proliferation, migration, and epithelial-mesenchymal transition. While conventional 2D culture models have provided valuable insights, they cannot fully replicate the complexity and diversity of the TME. Therefore, developing 3D culture systems that better mimic in vivo conditions is essential. This review delves into the heterogeneous nature of the TME, spotlighting MSC-tumor cellular signaling and advancements in 3D culture technologies. Utilizing MSCs in cancer therapy presents opportunities to enhance treatment effectiveness and overcome resistance mechanisms. Understanding MSC interactions within the TME and leveraging 3D culture models can advance novel cancer therapies and improve clinical outcomes. Additionally, this review underscores the therapeutic potential of engineered MSCs, emphasizing their role in targeted anti-cancer treatments.
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Affiliation(s)
- Ayesha Rehman
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Sameer Kumar Panda
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Martina Torsiello
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Martina Marigliano
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana,”Via Salvador Allende, 43, Baronissi, Salerno, Italy
| | - Camilla Carmela Tufano
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Aditya Nigam
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Zahida Parveen
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Gianpaolo Papaccio
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
| | - Marcella La Noce
- Department of Experimental Medicine, University of Campania “L. Vanvitelli” via L. Armanni, 5-80138 Naples, Italy
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Panda SK, Robinson N, Desiderio V. Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance. Biochim Biophys Acta Rev Cancer 2024; 1879:189205. [PMID: 39481663 DOI: 10.1016/j.bbcan.2024.189205] [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: 06/25/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024]
Abstract
Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance. However, even with the third-generation inhibitors available, we are still far from effectively inhibiting the efflux transporters. Additionally, Cancer stem cells (CSCs) pose another significant challenge, contributing to cancer recurrence even after successful treatment. The ability of CSCs to enter dormancy and evade detection makes them almost invulnerable to chemotherapeutic drug treatment. In this review, we discuss how Mesenchymal stem cells (MSCs), one of the key components of the Tumor Microenvironment (TME), regulate both the CSCs and efflux transporters. We propose a new approach focusing on MSCs, which can be crucial to successfully address CSCs and efflux transporters.
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Affiliation(s)
- Sameer Kumar Panda
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy; Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Nirmal Robinson
- Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
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Wu J, Chen Y. Unraveling the Connection: Extracellular Vesicles and Non-Small Cell Lung Cancer. Int J Nanomedicine 2024; 19:8139-8157. [PMID: 39139506 PMCID: PMC11321355 DOI: 10.2147/ijn.s477851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 08/04/2024] [Indexed: 08/15/2024] Open
Abstract
Extracellular vesicles (EVs) are nanoscale lipid bilayer vesicles released during cell activation, cellular damage, or apoptosis. They carry nucleic acids, proteins, and lipids facilitating intercellular communication and activate signaling pathways in target cells. In non-small cell lung cancer (NSCLC), EVs may contribute to tumor growth and metastasis by modulating immune responses, facilitating epithelial-mesenchymal transition, and promoting angiogenesis, while potentially contributing to resistance to chemotherapy drugs. EVs in liquid biopsies serve as non-invasive biomarkers for early cancer detection and diagnosis. Due to their small size, inherent molecular transport properties, and excellent biocompatibility, EVs also act as natural drug delivery vehicles in NSCLC therapy.
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Affiliation(s)
- Jiankang Wu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, People’s Republic of China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine, Changsha, Hunan, People’s Republic of China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, People’s Republic of China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, People’s Republic of China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine, Changsha, Hunan, People’s Republic of China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, People’s Republic of China
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Garza Treviño EN, Quiroz Reyes AG, Delgado Gonzalez P, Rojas Murillo JA, Islas JF, Alonso SS, Gonzalez Villarreal CA. Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells. Int J Mol Sci 2024; 25:7791. [PMID: 39063032 PMCID: PMC11276748 DOI: 10.3390/ijms25147791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/22/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
Combined gene and cell therapy are promising strategies for cancer treatment. Given the complexity of cancer, several approaches are actively studied to fight this disease. Using mesenchymal stem cells (MSCs) has demonstrated dual antitumor and protumor effects as they exert massive immune/regulatory effects on the tissue microenvironment. MSCs have been widely investigated to exploit their antitumor target delivery system. They can be genetically modified to overexpress genes and selectively or more efficiently eliminate tumor cells. Current approaches tend to produce more effective and safer therapies using MSCs or derivatives; however, the effect achieved by engineered MSCs in solid tumors is still limited and depends on several factors such as the cell source, transgene, and tumor target. This review describes the progress of gene and cell therapy focused on MSCs as a cornerstone against solid tumors, addressing the different MSC-engineering methods that have been approached over decades of research. Furthermore, we summarize the main objectives of engineered MSCs against the most common cancers and discuss the challenges, limitations, risks, and advantages of targeted treatments combined with conventional ones.
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Affiliation(s)
- Elsa N. Garza Treviño
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Adriana G. Quiroz Reyes
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Paulina Delgado Gonzalez
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Juan Antonio Rojas Murillo
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Jose Francisco Islas
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Santiago Saavedra Alonso
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500, Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
| | - Carlos A. Gonzalez Villarreal
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500, Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
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Cantero MJ, Bueloni B, Gonzalez Llamazares L, Fiore E, Lameroli L, Atorrasagasti C, Mazzolini G, Malvicini M, Bayo J, García MG. Modified mesenchymal stromal cells by in vitro transcribed mRNA: a therapeutic strategy for hepatocellular carcinoma. Stem Cell Res Ther 2024; 15:208. [PMID: 38992782 PMCID: PMC11241816 DOI: 10.1186/s13287-024-03806-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 06/18/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) tropism for tumours allows their use as carriers of antitumoural factors and in vitro transcribed mRNA (IVT mRNA) is a promising tool for effective transient expression without insertional mutagenesis risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with antitumor properties by stimulating the specific immune response. The aim of this work was to generate modified MSCs by IVT mRNA transfection to overexpress GM-CSF and determine their therapeutic effect alone or in combination with doxorubicin (Dox) in a murine model of hepatocellular carcinoma (HCC). METHODS DsRed or GM-CSF IVT mRNAs were generated from a cDNA template designed with specific primers followed by reverse transcription. Lipofectamine was used to transfect MSCs with DsRed (MSC/DsRed) or GM-CSF IVT mRNA (MSC/GM-CSF). Gene expression and cell surface markers were determined by flow cytometry. GM-CSF secretion was determined by ELISA. For in vitro experiments, the J774 macrophage line and bone marrow monocytes from mice were used to test GM-CSF function. An HCC model was developed by subcutaneous inoculation (s.c.) of Hepa129 cells into C3H/HeN mice. After s.c. injection of MSC/GM-CSF, Dox, or their combination, tumour size and mouse survival were evaluated. Tumour samples were collected for mRNA analysis and flow cytometry. RESULTS DsRed expression by MSCs was observed from 2 h to 15 days after IVT mRNA transfection. Tumour growth remained unaltered after the administration of DsRed-expressing MSCs in a murine model of HCC and MSCs expressing GM-CSF maintained their phenotypic characteristic and migration capability. GM-CSF secreted by modified MSCs induced the differentiation of murine monocytes to dendritic cells and promoted a proinflammatory phenotype in the J774 macrophage cell line. In vivo, MSC/GM-CSF in combination with Dox strongly reduced HCC tumour growth in C3H/HeN mice and extended mouse survival in comparison with individual treatments. In addition, the tumours in the MSC/GM-CSF + Dox treated group exhibited elevated expression of proinflammatory genes and increased infiltration of CD8 + T cells and macrophages. CONCLUSIONS Our results showed that IVT mRNA transfection is a suitable strategy for obtaining modified MSCs for therapeutic purposes. MSC/GM-CSF in combination with low doses of Dox led to a synergistic effect by increasing the proinflammatory tumour microenvironment, enhancing the antitumoural response in HCC.
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Affiliation(s)
- María José Cantero
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Barbara Bueloni
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Lucrecia Gonzalez Llamazares
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Esteban Fiore
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Lucia Lameroli
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Catalina Atorrasagasti
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Mariana Malvicini
- Cancer Immunobiology Laboratory, IIMT, Universidad Austral - CONICET, Buenos Aires, Argentina
| | - Juan Bayo
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Mariana G García
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
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Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, Ramezani M. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med Res Rev 2024; 44:1596-1661. [PMID: 38299924 DOI: 10.1002/med.22023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 11/28/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Lei T, Li C, Liu Y, Cui Z, Deng S, Cao J, Yang H, Chen P. Microfluidics-enabled mesenchymal stem cell derived Neuron like cell membrane coated nanoparticles inhibit inflammation and apoptosis for Parkinson's Disease. J Nanobiotechnology 2024; 22:370. [PMID: 38918856 PMCID: PMC11197265 DOI: 10.1186/s12951-024-02587-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 05/26/2024] [Indexed: 06/27/2024] Open
Abstract
Parkinson's disease (PD) is the second largest group of neurodegenerative diseases, and its existing drug treatments are not satisfactory. Natural cell membrane drugs are used for homologous targeting to enhance efficacy. In this study, microfluidic electroporation chip prepared mesenchymal stem cell-derived neuron-like cell membrane-coated curcumin PLGA nanoparticles (MM-Cur-NPs) was synthesized and explored therapeutic effect and mechanism in PD. MM-Cur-NPs can protect neuron from damage, restore mitochondrial membrane potential and reduce oxidative stress in vitro. In PD mice, it also can improve movement disorders and restore damaged TH neurons. MM-Cur-NPs was found to be distributed in the brain and metabolized with a delay within 24 h. After 1 h administration, MM-Cur-NPs were distributed in brain with a variety of neurotransmitters were significantly upregulated, such as dopamine. Differentially expressed genes of RNA-seq were enriched in the inflammation regulation, and it was found the up-expression of anti-inflammatory factors and inhibited pro-inflammatory factors in PD. Mechanically, MM-Cur-NPs can not only reduce neuronal apoptosis, inhibit the microglial marker IBA-1 and inflammation, but also upregulate expression of neuronal mitochondrial protein VDAC1 and restore mitochondrial membrane potential. This study proposes a therapeutic strategy provide neuroprotective effects through MM-Cur-NPs therapy for PD.
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Affiliation(s)
- Tong Lei
- Department of Disease and Syndromes Research, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China.
| | - Caifeng Li
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China
| | - Yang Liu
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China
| | - Zhao Cui
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China
| | - Shiwen Deng
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China
| | - Junxian Cao
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China
| | - Hongjun Yang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China.
- Hunan Provincial Key Laboratory of Complex Effects Analysis for Chinese Patent Medicine, Yongzhou, Hunan Province, 425199, China.
| | - Peng Chen
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, Dongcheng District, 100700, China.
- Hunan Provincial Key Laboratory of Complex Effects Analysis for Chinese Patent Medicine, Yongzhou, Hunan Province, 425199, China.
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11
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Švajger U, Kamenšek U. Interleukins and interferons in mesenchymal stromal stem cell-based gene therapy of cancer. Cytokine Growth Factor Rev 2024; 77:76-90. [PMID: 38508954 DOI: 10.1016/j.cytogfr.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
The tumor microenvironment is importantly shaped by various cytokines, where interleukins (ILs) and interferons (IFNs) shape the balance of immune activity within tumor niche and associated lymphoid organs. Their importance in activation and tuning of both innate and adaptive immune responses prompted their use in several clinical trials, albeit with limited therapeutic efficacy and risk of toxicity due to systemic administration. Increasing preclinical evidence suggests that local delivery of ILs and IFNs could significantly increase their effectiveness, while simultaneously attenuate the known side effects and issues related to their biological activity. A prominent way to achieve this is to use cell-based delivery vehicles. For this purpose, mesenchymal stromal stem cells (MSCs) are considered an almost ideal candidate. Namely, MSCs can be obtained in large quantities and from obtainable sources (e.g. umbilical cord or adipose tissue), their ex vivo expansion is relatively straightforward compared to other cell types and they possess very low immunogenicity making them suitable for allogeneic use. Importantly, MSCs have shown an intrinsic capacity to respond to tumor-directed chemotaxis. This review provides a focused and detailed discussion on MSC-based gene therapy using ILs and IFNs, engineering techniques and insights on potential future advancements.
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Affiliation(s)
- Urban Švajger
- Slovenian Institute for Transfusion Medicine, Department for Therapeutic Services, Šlajmerjeva Ulica 6, Ljubljana SI-1000, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, Ljubljana SI-1000, Slovenia.
| | - Urška Kamenšek
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška Cesta 2, Ljubljana SI-1000, Slovenia; Biotechnical Faculty, University of Ljubljana, Jamnikarjeva Ulica 101, Ljubljana SI-1000, Slovenia
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12
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Kim JH, Yang HJ, Lee SH, Song YS. Cytosine Deaminase-Overexpressing hTERT-Immortalized Human Adipose Stem Cells Enhance the Inhibitory Effects of Fluorocytosine on Tumor Growth in Castration Resistant Prostate Cancer. Int J Mol Sci 2024; 25:5519. [PMID: 38791557 PMCID: PMC11121865 DOI: 10.3390/ijms25105519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/06/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
A promising de novo approach for the treatment of Castration-resistant prostate cancer (CRPC) exploits cell-mediated enzyme prodrug therapy comprising cytosine deaminase (CD) and fluorouracil (5-FC). The aim of this study was to determine the potential of bacterial CD-overexpressing hTERT-immortalized human adipose stem cells (hTERT-ADSC.CD) to suppress CRPC. A lentiviral vector encoding a bacterial CD gene was used to transfect and to generate the hTERT-ADSC.CD line. The ability of the cells to migrate selectively towards malignant cells was investigated in vitro. PC3 and hTERT-ADSC.CD cells were co-cultured. hTERT-ADSC.CD and 1 × 106 PC3 cells were administered to nude mice via intracardiac and subcutaneous injections, respectively, and 5-FC was given for 14 days. hTERT-ADSC.CD were successfully engineered. Enhanced in vitro hTERT-ADSC.CD cytotoxicity and suicide effect were evident following administration of 5 μM 5-FC. hTERT-ADSC.CD, together with 5-FC, augmented the numbers of PC3 cells undergoing apoptosis. In comparison to controls administered hTERT-ADSC.CD monotherapy, hTERT-ADSC.CD in combination with 5-FC demonstrated a greater suppressive effect on tumor. In CPRC-bearing mice, tumor suppression was enhanced by the combination of CD-overexpressing ADSC and the prodrug 5-FC. Stem cells exhibiting CD gene expression are a potential novel approach to treatment for CRPC.
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Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang University School of Medicine, Seoul 04401, Republic of Korea
| | - Hee Jo Yang
- Department of Urology, Soonchunhyang University School of Medicine, Cheonan 31151, Republic of Korea
| | - Sang Hun Lee
- Program in Biomedical Sciences & Engineering, Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang University School of Medicine, Seoul 04401, Republic of Korea
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13
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Gao X, Ren H, Zhang Z, Cao S, Zhang B, Sun Q, Melino G, Huang H. Human lung cancer-derived mesenchymal stem cells promote tumor growth and immunosuppression. Biol Direct 2024; 19:39. [PMID: 38755705 PMCID: PMC11097554 DOI: 10.1186/s13062-024-00479-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 04/30/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND The presence of mesenchymal stem cells has been confirmed in some solid tumors where they serve as important components of the tumor microenvironment; however, their role in cancer has not been fully elucidated. The aim of this study was to investigate the functions of mesenchymal stem cells isolated from tumor tissues of patients with non-small cell lung cancer. RESULTS Human lung cancer-derived mesenchymal stem cells displayed the typical morphology and immunophenotype of mesenchymal stem cells; they were nontumorigenic and capable of undergoing multipotent differentiation. These isolated cells remarkably enhanced tumor growth when incorporated into systems alongside tumor cells in vivo. Importantly, in the presence of mesenchymal stem cells, the ability of peripheral blood mononuclear cell-derived natural killer and activated T cells to mediate tumor cell destruction was significantly compromised. CONCLUSION Collectively, these data support the notion that human lung cancer-derived mesenchymal stem cells protect tumor cells from immune-mediated destruction by inhibiting the antitumor activities of natural killer and T cells.
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Affiliation(s)
- Xiaoyan Gao
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 Tieyi Road, Beijing, 100038, China
| | - He Ren
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 Tieyi Road, Beijing, 100038, China
| | - Zhengrong Zhang
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 Tieyi Road, Beijing, 100038, China
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy
| | - Shuai Cao
- Department of Orthopedics, Civil Aviation General Hospital, No.1 Gaojing Street, Chaoyang District, Beijing, 100123, China
| | - Bo Zhang
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 Tieyi Road, Beijing, 100038, China
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
| | - Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy
- DZNE German Center for Neurodegenerative Diseases, Bonn, Germany
| | - Hongyan Huang
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 Tieyi Road, Beijing, 100038, China.
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14
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Ou S, Kim TY, Jung E, Shin SY. p38 mitogen-activated protein kinase contributes to TNFα-induced endothelial tube formation of bone-marrow-derived mesenchymal stem cells by activating the JAK/STAT/TIE2 signaling axis. BMB Rep 2024; 57:238-243. [PMID: 37915133 PMCID: PMC11139678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/04/2023] [Accepted: 10/28/2023] [Indexed: 11/03/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) can differentiate into endothelial cells in an inflammatory microenvironment. However, the regulatory mechanisms underlying this process are not entirely understood. Here, we found that TIE2 in BM-MSCs was upregulated at the transcriptional level after stimulation with tumor necrosis factor-alpha (TNFα), a major pro-inflammatory cytokine. Additionally, the STAT-binding sequence within the proximal region of TIE2 was necessary for TNFα-induced TIE2 promoter activation. TIE2 and STAT3 knockdown reduced TNFα-induced endothelial tube formation in BMMSCs. Among the major TNFα-activated MAP kinases (ERK1/2, JNK1/2, and p38 MAPK) in BM-MSCs, only inhibition of the p38 kinase abrogated TNFα-induced TIE2 upregulation by inhibiting the JAK-STAT signaling pathway. These findings suggest that p38 MAP contributes to the endothelial differentiation of BM-MSCs by activating the JAK-STAT-TIE2 signaling axis in the inflammatory microenvironment. [BMB Reports 2024; 57(5): 238-243].
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Affiliation(s)
- Sukjin Ou
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
| | - Tae Yoon Kim
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
| | - Euitaek Jung
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
| | - Soon Young Shin
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
- Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Korea
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15
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Abalymov A, Kurochkin MA, German S, Komlev A, Vavaev ES, Lyubin EV, Fedyanin AA, Gorin D, Novoselova M. Functionalization and magnetonavigation of T-lymphocytes functionalized via nanocomposite capsules targeting with electromagnetic tweezers. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 57:102742. [PMID: 38460654 DOI: 10.1016/j.nano.2024.102742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 02/07/2024] [Accepted: 02/23/2024] [Indexed: 03/11/2024]
Abstract
Modification of T-lymphocytes, which are capable of paracellular transmigration is a promising trend in modern personalized medicine. However, the delivery of required concentrations of functionalized T-cells to the target tissues remains a problem. We describe a novel method to functionalize T-cells with magnetic nanocapsules and target them with electromagnetic tweezers. T-cells were modified with the following magnetic capsules: Parg/DEX (150 nm), BSA/TA (300 nm), and BSA/TA (500 nm). T-cells were magnetonavigated in a phantom blood vessel capillary in cultural medium and in whole blood. The permeability of tumor tissues to captured T-cells was analyzed by magnetic delivery of modified T-cells to spheroids formed from 4T1 breast cancer cells. The dynamics of T-cell motion under a magnetic field gradient in model environments were analyzed by particle image velocimetry. The magnetic properties of the nanocomposite capsules and magnetic T-cells were measured. The obtained results are promising for biomedical applications in cancer immunotherapy.
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Affiliation(s)
- Anatolii Abalymov
- Skolkovo Institute of Science and Technology, Moscow 121205, Russia; Science Medical Center, Saratov State University, 410012 Saratov, Russia.
| | | | - Sergei German
- Skolkovo Institute of Science and Technology, Moscow 121205, Russia
| | - Aleksei Komlev
- Lomonosov Moscow State University, Moscow 119991, Russia
| | | | | | | | - Dmitry Gorin
- Skolkovo Institute of Science and Technology, Moscow 121205, Russia
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16
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Stepanov YV, Golovynska I, Ostrovska G, Pylyp L, Dovbynchuk T, Stepanova LI, Gorbach O, Shablii V, Xu H, Garmanchuk LV, Ohulchanskyy TY, Qu J, Solyanik GI. Human mesenchymal stem cells increase LLC metastasis and stimulate or decelerate tumor development depending on injection method and cell amount. Cytometry A 2024; 105:252-265. [PMID: 38038631 DOI: 10.1002/cyto.a.24814] [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: 05/11/2023] [Revised: 09/20/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
Mesenchymal stem cells (MSCs) being injected into the body can stimulate or decelerate carcinogenesis. Here, the direction of influence of human placenta-derived MSCs (P-MSCs) on the Lewis lung carcinoma (LLC) tumor development and metastatic potential is investigated in C57BL/6 mice depending on the injection method. After intramuscular co-inoculation of LLC and P-MSCs (LLC + P-MSCs), the growth of primary tumor and angiogenesis are slowed down compared to the control LLC on the 15th day. This is explained by the fact of a decrease in the secretion of proangiogenic factors during in vitro co-cultivation of an equal amount of LLC and P-MSCs. When P-MSCs are intravenously (i.v.) injected in the mice with developing LLC (LLC + P-MSCs(i.v.)), the tumor growth and angiogenesis are stimulated on the 15th day. A highly activated secretion of proangiogenic factors by P-MSCs in a similar in vitro model can explain this. In both the models compared to the control on the 23rd day, there is no significant difference in the tumor growth, while angiogenesis remains correspondingly decelerated or stimulated. However, in both the models, the total volume and number of lung metastases constantly increase compared to the control: it is mainly due to small-size metastases for LLC + P-MSCs(i.v.) and larger ones for LLC + P-MSCs. The increase in the rate of LLC cell dissemination after the injection of P-MSCs is explained by the disordered polyploidy and chromosomal instability, leading to an increase in migration and invasion of cancer cells. After LLC + P-MSCs co-inoculation, the tumor cell karyotype has the most complex and heterogeneous chromosomal structure. These findings indicate a bidirectional effect of P-MSCs on the growth of LLC in the early periods after injection, depending on the injection method, and, correspondingly, the number of contacting cells. However, regardless of the injection method, P-MSCs are shown to increase LLC aggressiveness related to cancer-associated angiogenesis and metastasis activation in the long term.
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Affiliation(s)
- Yurii V Stepanov
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
- Laboratory of Molecular and Cellular Mechanisms of Metastasis, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
| | - Iuliia Golovynska
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Galyna Ostrovska
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Larysa Pylyp
- Clinic of Reproductive Medicine "Nadiya", Kyiv, Ukraine
| | - Taisa Dovbynchuk
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Liudmyla I Stepanova
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Oleksandr Gorbach
- Laboratory of Experimental Oncology, National Cancer Institute of Ukraine, Kyiv, Ukraine
| | - Volodymyr Shablii
- Institute of Molecular Biology and Genetics, NAS of Ukraine, Kyiv, Ukraine
- Institute of Cell Therapy, Kyiv, Ukraine
| | - Hao Xu
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Liudmyla V Garmanchuk
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Tymish Y Ohulchanskyy
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Junle Qu
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Galina I Solyanik
- Laboratory of Molecular and Cellular Mechanisms of Metastasis, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
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17
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Zeng M, Zhang W, Li Y, Yu L. Harnessing adenovirus in cancer immunotherapy: evoking cellular immunity and targeting delivery in cell-specific manner. Biomark Res 2024; 12:36. [PMID: 38528632 DOI: 10.1186/s40364-024-00581-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 03/09/2024] [Indexed: 03/27/2024] Open
Abstract
Recombinant adenovirus (rAd) regimens, including replication-competent oncolytic adenovirus (OAV) and replication-deficient adenovirus, have been identified as potential cancer therapeutics. OAV presents advantages such as selective replication, oncolytic efficacy, and tumor microenvironment (TME) remodeling. In this perspective, the principles and advancements in developing OAV toolkits are reviewed. The burgeoning rAd may dictate efficacy of conventional cancer therapies as well as cancer immunotherapies, including cancer vaccines, synergy with adoptive cell therapy (ACT), and TME reshaping. Concurrently, we explored the potential of rAd hitchhiking to adoptive immune cells or stem cells, highlighting how this approach facilitates synergistic interactions between rAd and cellular therapeutics at tumor sites. Results from preclinical and clinical trials in which immune and stem cells were infected with rAd have been used to address significant oncological challenges, such as postsurgical residual tumor tissue and metastatic tissue. Briefly, rAd can eradicate tumors through various mechanisms, resulting from tumor immunogenicity, reprogramming of the TME, enhancement of cellular immunity, and effective tumor targeting. In this context, we argue that rAd holds immense potential for enhancing cellular immunity and synergistically improving antitumor effects in combination with novel cancer immunotherapies.
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Affiliation(s)
- Miao Zeng
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Wei Zhang
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Yisheng Li
- Shenzhen Haoshi Biotechnology Co., Ltd. No, 155 Hongtian Road, Xinqiao Street, Bao'an District, Shenzhen, Guangdong, 518125, China.
| | - Li Yu
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China.
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18
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Wu CH, Weng TF, Li JP, Wu KH. Biology and Therapeutic Properties of Mesenchymal Stem Cells in Leukemia. Int J Mol Sci 2024; 25:2527. [PMID: 38473775 DOI: 10.3390/ijms25052527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 03/14/2024] Open
Abstract
This comprehensive review delves into the multifaceted roles of mesenchymal stem cells (MSCs) in leukemia, focusing on their interactions within the bone marrow microenvironment and their impact on leukemia pathogenesis, progression, and treatment resistance. MSCs, characterized by their ability to differentiate into various cell types and modulate the immune system, are integral to the BM niche, influencing hematopoietic stem cell maintenance and functionality. This review extensively explores the intricate relationship between MSCs and leukemic cells in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. This review also addresses the potential clinical applications of MSCs in leukemia treatment. MSCs' role in hematopoietic stem cell transplantation, their antitumor effects, and strategies to disrupt chemo-resistance are discussed. Despite their therapeutic potential, the dual nature of MSCs in promoting and inhibiting tumor growth poses significant challenges. Further research is needed to understand MSCs' biological mechanisms in hematologic malignancies and develop targeted therapeutic strategies. This in-depth exploration of MSCs in leukemia provides crucial insights for advancing treatment modalities and improving patient outcomes in hematologic malignancies.
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Affiliation(s)
- Cheng-Hsien Wu
- School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
| | - Te-Fu Weng
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Ju-Pi Li
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Kang-Hsi Wu
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
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19
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Wang J, Deng G, Wang S, Li S, Song P, Lin K, Xu X, He Z. Enhancing regenerative medicine: the crucial role of stem cell therapy. Front Neurosci 2024; 18:1269577. [PMID: 38389789 PMCID: PMC10881826 DOI: 10.3389/fnins.2024.1269577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 01/23/2024] [Indexed: 02/24/2024] Open
Abstract
Stem cells offer new therapeutic avenues for the repair and replacement of damaged tissues and organs owing to their self-renewal and multipotent differentiation capabilities. In this paper, we conduct a systematic review of the characteristics of various types of stem cells and offer insights into their potential applications in both cellular and cell-free therapies. In addition, we provide a comprehensive summary of the technical routes of stem cell therapy and discuss in detail current challenges, including safety issues and differentiation control. Although some issues remain, stem cell therapy demonstrates excellent potential in the field of regenerative medicine and provides novel tactics and methodologies for managing a wider spectrum of illnesses and traumas.
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Affiliation(s)
- Jipeng Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Gang Deng
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shuang Li
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Peng Song
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Kun Lin
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiaoxiang Xu
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zuhong He
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
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20
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Song Y, Song Q, Hu D, Sun B, Gao M, Liang X, Qu B, Suo L, Yin Z, Wang L. The potential applications of artificially modified exosomes derived from mesenchymal stem cells in tumor therapy. Front Oncol 2024; 13:1299384. [PMID: 38250549 PMCID: PMC10798044 DOI: 10.3389/fonc.2023.1299384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/15/2023] [Indexed: 01/23/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have tumor-homing ability and play critical roles in tumor treatment, but their dual influences on tumor progression limit their therapeutic applications. Exosomes derived from MSCs (MSC-exosomes) exhibit great potential in targeted tumor treatment due to their advantages of high stability, low immunogenicity, good biocompatibility, long circulation time and homing characteristics. Furthermore, the artificial modification of MSC-exosomes could amplify their advantages and their inhibitory effect on tumors and could overcome the limit of tumor-promoting effect. In this review, we summarize the latest therapeutic strategies involving artificially modified MSC-exosomes in tumor treatment, including employing these exosomes as nanomaterials to carry noncoding RNAs or their inhibitors and anticancer drugs, and genetic engineering modification of MSC-exosomes. We also discuss the feasibility of utilizing artificially modified MSC-exosomes as an emerging cell-free method for tumor treatment and related challenges.
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Affiliation(s)
- Yilin Song
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Quanlin Song
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Daosheng Hu
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Binwen Sun
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Mingwei Gao
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiangnan Liang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Boxin Qu
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lida Suo
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zeli Yin
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Liming Wang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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21
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Borzone FR, Giorello MB, Sanmartin MC, Yannarelli G, Martinez LM, Chasseing NA. Mesenchymal stem cells and cancer-associated fibroblasts as a therapeutic strategy for breast cancer. Br J Pharmacol 2024; 181:238-256. [PMID: 35485850 DOI: 10.1111/bph.15861] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/21/2022] [Accepted: 04/22/2022] [Indexed: 11/26/2022] Open
Abstract
Breast cancer is the most common type of cancer and the leading cause of death among women. Recent evidence suggests that mesenchymal stromal/stem cells and cancer-associated fibroblasts (CAFs) have an essential role in cancer progression, invasion and therapy resistance. Therefore, they are considered as highly promising future therapeutic targets against breast cancer. The intrinsic tumour tropism and immunomodulatory capacities of mesenchymal stromal/stem cells are of special relevance for developing mesenchymal stromal/stem cells-based anti-tumour therapies that suppress primary tumour growth and metastasis. In addition, the utilization of therapies that target the stromal components of the tumour microenvironment in combination with standard drugs is an innovative tool that could improve patients' response to therapies and their survival. In this review, we discuss the currently available information regarding the possible use of mesenchymal stromal/stem cells-derived anti-tumour therapies, as well as the utilization of therapies that target CAFs in breast cancer microenvironment. Finally, these data can serve as a guide map for future research in this field, ultimately aiding the effective transition of these results into the clinic. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.
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Affiliation(s)
- Francisco Raúl Borzone
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Belén Giorello
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Cecilia Sanmartin
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - Gustavo Yannarelli
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - Leandro Marcelo Martinez
- Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Norma Alejandra Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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22
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Lyu ZZ, Li M, Yang MY, Han MH, Yang Z. Exosome-mediated transfer of circRNA563 promoting hepatocellular carcinoma by targeting the microRNA148a-3p/metal-regulatory transcription factor-1 pathway. World J Gastroenterol 2023; 29:6060-6075. [PMID: 38130740 PMCID: PMC10731156 DOI: 10.3748/wjg.v29.i46.6060] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/24/2023] [Accepted: 11/17/2023] [Indexed: 12/13/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) exert anti-oncogenic effects via exosomes containing non-coding RNA (ncRNA), which play important roles in tumor biology. Our preliminary study identified the interaction of the ncRNA hsa_circ_0000563 (circ563) and the circ563-associated miR-148a-3p in exosomes, as miR-148a-3p and its target metal-regulatory transcription factor-1 (MTF-1) are implicated in hepatocellular carcinoma (HCC) progression. AIM To identify the clinical significance, functional implications, and mechanisms of circ563 in HCC. METHODS The expression levels of miR-148a-3p and MTF-1 in exosomes derived from MSC and HCC cells were compared, and their effects on HCC cells were assessed. Using a dual-luciferase reporter assay, miR-148a-3p was identified as an associated microRNA of circ563, whose role in HCC regulation was assessed in vitro and in vivo. RESULTS The silencing of circ563 blocked the HCC cell proliferation and invasion and induced apoptosis. Co-culturing of HCC cells with MSC-derived exosomes following circ563 overexpression promoted cell proliferation and metastasis and elicited changes in miR-148a-3p and MTF-1 expression. The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or MTF-1 depletion. Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth by upregulating the expression of MTF-1. In HCC tissues, circ563 expression was negatively correlated with miR-148a-3p expression but positively correlated with MTF-1 levels. CONCLUSION MSCs may exhibit anti-HCC activity through the exosomal circ563/miR-148a-3p/MTF-1 pathway, while exosomes can transmit circ563 to promote oncogenic behavior by competitively binding to miR-148a-3p to activate MTF-1.
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Affiliation(s)
- Zhuo-Zhen Lyu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Meng Li
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Ming-Yu Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Mei-Hong Han
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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23
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Ramírez Idarraga JA, Restrepo Múnera LM. Mesenchymal Stem Cells: Their Role in the Tumor Microenvironment. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:681-691. [PMID: 37276173 DOI: 10.1089/ten.teb.2023.0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Mesenchymal stem cells (MSCs) have been seen for years as great candidates for treating different diseases and an alternative to embryonic stem cells due to their differentiation capacity in vitro. More recent research has focused on their ability to modulate the immune response and regeneration at sites associated with inflammation, activities attributable to the release of trophic factors into the extracellular medium, a set of components known as the secretome. It has been possible to demonstrate the presence of these cells within the tumor microenvironment, which is associated with their tropism for sites of inflammation; however, their role here needs to be clarified. In different investigations, the feasibility of using MSCs or their secretome to treat cancer has been sought, with these results being ambiguous. It has been described that MSCs can be activated and present various phenotypes, which could explain the divergence in their action; however, these activation mechanisms and the different phenotypes still need to be well known. This review explores MSCs and their use in regenerative medicine with a targeted approach to cancer. Impact Statement This text addresses the diverging findings on the role of mesenchymal stem cells in the tumor microenvironment and discrepancies on the use of these cells as cancer treatment, separating the direct use of the cells from the use of the secretome. Multiple authors refer equally to the cells and their secretome to conclude on the positive or negative outcome, without taking into consideration how the cells are affected by their surroundings.
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Affiliation(s)
- Jhon Alexander Ramírez Idarraga
- Corporación Académica Ciencias Básicas Biomédicas, Universidad de Antioquía, Medellín, Colombia
- Grupo Ingeniería de Tejidos y Terapias Celulares, Instituto de Investigaciones Médicas, Universidad de Antioquía, Medellín, Colombia
| | - Luz Marina Restrepo Múnera
- Grupo Ingeniería de Tejidos y Terapias Celulares, Instituto de Investigaciones Médicas, Universidad de Antioquía, Medellín, Colombia
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24
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Nishida Y, Ishizawa J, Ayoub E, Montoya RH, Ostermann LB, Muftuoglu M, Ruvolo VR, Patsilevas T, Scruggs DA, Khazaei S, Mak PY, Tao W, Carter BZ, Boettcher S, Ebert BL, Daver NG, Konopleva M, Seki T, Kojima K, Andreeff M. Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias. SCIENCE ADVANCES 2023; 9:eadh1436. [PMID: 38019903 PMCID: PMC10686564 DOI: 10.1126/sciadv.adh1436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023]
Abstract
The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.
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Affiliation(s)
- Yuki Nishida
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jo Ishizawa
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Edward Ayoub
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rafael Heinz Montoya
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lauren B. Ostermann
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Muharrem Muftuoglu
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vivian R Ruvolo
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Tallie Patsilevas
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Darah A. Scruggs
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shayaun Khazaei
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Po Yee Mak
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wenjing Tao
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bing Z. Carter
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Steffen Boettcher
- Department of Medical Oncology and Haematology, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland
- Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, The Broad Institute, Boston, MA 02115, USA
| | - Benjamin L. Ebert
- Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, The Broad Institute, Boston, MA 02115, USA
| | - Naval G. Daver
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Marina Konopleva
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Section of Leukemia Biology Research, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | | | - Kensuke Kojima
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Hematology, Kochi University, Nankoku, Kochi 783-8505, Japan
| | - Michael Andreeff
- Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Merino JJ, Cabaña-Muñoz ME. Nanoparticles and Mesenchymal Stem Cell (MSC) Therapy for Cancer Treatment: Focus on Nanocarriers and a si-RNA CXCR4 Chemokine Blocker as Strategies for Tumor Eradication In Vitro and In Vivo. MICROMACHINES 2023; 14:2068. [PMID: 38004925 PMCID: PMC10673568 DOI: 10.3390/mi14112068] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/07/2023] [Accepted: 10/13/2023] [Indexed: 11/26/2023]
Abstract
Mesenchymal stem cells (MSCs) have a high tropism for the hypoxic microenvironment of tumors. The combination of nanoparticles in MSCs decreases tumor growth in vitro as well as in rodent models of cancers in vivo. Covalent conjugation of nanoparticles with the surface of MSCs can significantly increase the drug load delivery in tumor sites. Nanoparticle-based anti-angiogenic systems (gold, silica and silicates, diamond, silver, and copper) prevented tumor growth in vitro. For example, glycolic acid polyconjugates enhance nanoparticle drug delivery and have been reported in human MSCs. Labeling with fluorescent particles (coumarin-6 dye) identified tumor cells using fluorescence emission in tissues; the conjugation of different types of nanoparticles in MSCs ensured success and feasibility by tracking the migration and its intratumor detection using non-invasive imaging techniques. However, the biosafety and efficacy; long-term stability of nanoparticles, and the capacity for drug release must be improved for clinical implementation. In fact, MSCs are vehicles for drug delivery with nanoparticles and also show low toxicity but inefficient accumulation in tumor sites by clearance of reticuloendothelial organs. To solve these problems, the internalization or conjugation of drug-loaded nanoparticles should be improved in MSCs. Finally, CXCR4 may prove to be a promising target for immunotherapy and cancer treatment since the delivery of siRNA to knock down this alpha chemokine receptor or CXCR4 antagonism has been shown to disrupt tumor-stromal interactions.
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Affiliation(s)
- José Joaquín Merino
- Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M.), 28040 Madrid, Spain
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Shams F, Pourjabbar B, Hashemi N, Farahmandian N, Golchin A, Nuoroozi G, Rahimpour A. Current progress in engineered and nano-engineered mesenchymal stem cells for cancer: From mechanisms to therapy. Biomed Pharmacother 2023; 167:115505. [PMID: 37716113 DOI: 10.1016/j.biopha.2023.115505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
Mesenchymal stem cells (MSCs), as self-renewing multipotent stromal cells, have been considered promising agents for cancer treatment. A large number of studies have demonstrated the valuable properties of MSC-based treatment, such as low immunogenicity and intrinsic tumor-trophic migratory properties. To enhance the potency of MSCs for therapeutic purposes, equipping MSCs with targeted delivery functions using genetic engineering is highly beneficial. Genetically engineered MSCs can express tumor suppressor agents such as pro-apoptotic, anti-proliferative, anti-angiogenic factors and act as ideal delivery vehicles. MSCs can also be loaded with nanoparticle drugs for increased efficacy and externally moderated targeting. Moreover, exosomes secreted by MSCs have important physiological properties, so they can contribute to intercellular communication and transfer cargo into targeted tumor cells. The precise role of genetically modified MSCs in tumor environments is still up for debate, but the beginning of clinical trials has been confirmed by promising results from preclinical investigations of MSC-based gene therapy for a wide range of malignancies. This review highlights the advanced techniques of engineering/nano-engineering and MSC-derived exosomes in tumor-targeted therapy.
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Affiliation(s)
- Forough Shams
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Navid Farahmandian
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Golchin
- Cellular & Molecular Research Center, Cellular & Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia 57157993313, Iran; Department of Clinical Biochemistry & Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia 57157993313, Islamic Republic of Iran
| | - Ghader Nuoroozi
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azam Rahimpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Lv T, Li Z, Wang D, Guo X, Zhang X, Cao J, Wang Z. Role of exosomes in prostate cancer bone metastasis. Arch Biochem Biophys 2023; 748:109784. [PMID: 37816420 DOI: 10.1016/j.abb.2023.109784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/05/2023] [Accepted: 10/07/2023] [Indexed: 10/12/2023]
Abstract
Bone is a preferred metastatic site of prostate cancer (PCa), and most patients with PCa metastases develop osteogenic bone metastasis, which manifests as disturbed bone structure and poor bone quality. However, the underlying mechanisms of PCa bone metastasis remain unclear. In recent years, increasing evidence has implicated extracellular vesicles, especially exosomes, in PCa bone metastasis. Exosomes are 30-150 nm in diameter, enclosing a cargo of biomolecules, such as DNA, RNA, and proteins. Exosomes play a functional role in intercellular communication, modulate the functions of recipient cells, and potentially modulate bone microenvironment changes, thereby influencing the development of PCa bone metastasis. This review summarizes the involvement of exosomes in the imbalance between bone resorption and formation, and establishing a pre-metastatic niche in bone marrow, as well as potential clinical applications of exosomes in therapeutic strategies for treating patients with advanced PCa with bone metastasis.
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Affiliation(s)
- Tingting Lv
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, PR China
| | - Zijie Li
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, PR China
| | - Dehua Wang
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, PR China
| | - Xiaojin Guo
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, PR China
| | - Xiaokuan Zhang
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, PR China
| | - Jing Cao
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, PR China
| | - Zhiyu Wang
- Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, PR China.
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Slama Y, Ah-Pine F, Khettab M, Arcambal A, Begue M, Dutheil F, Gasque P. The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential. Int J Mol Sci 2023; 24:13511. [PMID: 37686315 PMCID: PMC10488262 DOI: 10.3390/ijms241713511] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.
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Affiliation(s)
- Youssef Slama
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Franck Ah-Pine
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Mohamed Khettab
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Angelique Arcambal
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Mickael Begue
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Fabien Dutheil
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Philippe Gasque
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
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Gundersen RA, Chu T, Abolfathi K, Dogan SG, Blair PE, Nago N, Hamblin M, Brooke GN, Zwacka RM, Hoshiar AK, Mohr A. Generation of magnetic biohybrid microrobots based on MSC.sTRAIL for targeted stem cell delivery and treatment of cancer. Cancer Nanotechnol 2023; 14:54. [PMID: 37869575 PMCID: PMC7615227 DOI: 10.1186/s12645-023-00203-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/25/2023] [Indexed: 10/24/2023] Open
Abstract
Background Combining the power of magnetic guidance and the biological activities of stem cells transformed into biohybrid microrobots holds great promise for the treatment of several diseases including cancer. Results We found that human MSCs can be readily loaded with magnetic particles and that the resulting biohybrid microrobots could be guided by a rotating magnetic field. Rotating magnetic fields have the potential to be applied in the human setting and steer therapeutic stem cells to the desired sites of action in the body. We could demonstrate that the required loading of magnetic particles into stem cells is compatible with their biological activities. We examined this issue with a particular focus on the expression and functionality of therapeutic genes inside of human MSC-based biohybrid microrobots. The loading with magnetic particles did not cause a loss of viability or apoptosis in the human MSCs nor did it impact on the therapeutic gene expression from the cells. Furthermore, the therapeutic effect of the gene products was not affected, and the cells also did not lose their migration potential. Conclusion These results demonstrate that the fabrication of guidable MSC-based biohybrid microrobots is compatible with their biological and therapeutic functions. Thus, MSC-based biohybrid microrobots represent a novel way of delivering gene therapies to tumours as well as in the context of other diseases.
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Affiliation(s)
- Rebekah Anamarie Gundersen
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester CO4 3SQ, UK
| | - Tianyuan Chu
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester CO4 3SQ, UK
| | - Kiana Abolfathi
- School of Computer Science and Electronic Engineering, University of Essex, Colchester CO4 3SQ, UK
| | - Serap Gokcen Dogan
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester CO4 3SQ, UK
| | - Phoebe Elizabeth Blair
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester CO4 3SQ, UK
| | - Nyasha Nago
- Haematology Unit, East Suffolk and North Essex NHS Foundation Trust, Colchester CO4 5JL, UK
| | - Michael Hamblin
- Haematology Unit, East Suffolk and North Essex NHS Foundation Trust, Colchester CO4 5JL, UK
| | - Greg Nicholas Brooke
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Molecular Oncology Laboratory, University of Essex, Colchester CO4 3SQ, UK
| | - Ralf Michael Zwacka
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester CO4 3SQ, UK
| | - Ali Kafash Hoshiar
- School of Computer Science and Electronic Engineering, University of Essex, Colchester CO4 3SQ, UK
| | - Andrea Mohr
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester CO4 3SQ, UK
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Dzobo K, Dandara C. The Extracellular Matrix: Its Composition, Function, Remodeling, and Role in Tumorigenesis. Biomimetics (Basel) 2023; 8:146. [PMID: 37092398 PMCID: PMC10123695 DOI: 10.3390/biomimetics8020146] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/25/2023] Open
Abstract
The extracellular matrix (ECM) is a ubiquitous member of the body and is key to the maintenance of tissue and organ integrity. Initially thought to be a bystander in many cellular processes, the extracellular matrix has been shown to have diverse components that regulate and activate many cellular processes and ultimately influence cell phenotype. Importantly, the ECM's composition, architecture, and stiffness/elasticity influence cellular phenotypes. Under normal conditions and during development, the synthesized ECM constantly undergoes degradation and remodeling processes via the action of matrix proteases that maintain tissue homeostasis. In many pathological conditions including fibrosis and cancer, ECM synthesis, remodeling, and degradation is dysregulated, causing its integrity to be altered. Both physical and chemical cues from the ECM are sensed via receptors including integrins and play key roles in driving cellular proliferation and differentiation and in the progression of various diseases such as cancers. Advances in 'omics' technologies have seen an increase in studies focusing on bidirectional cell-matrix interactions, and here, we highlight the emerging knowledge on the role played by the ECM during normal development and in pathological conditions. This review summarizes current ECM-targeted therapies that can modify ECM tumors to overcome drug resistance and better cancer treatment.
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Affiliation(s)
- Kevin Dzobo
- Medical Research Council, SA Wound Healing Unit, Hair and Skin Research Laboratory, Division of Dermatology, Department of Medicine, Groote Schuur Hospital, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
| | - Collet Dandara
- Division of Human Genetics and Institute of Infectious Disease and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
- The South African Medical Research Council-UCT Platform for Pharmacogenomics Research and Translation, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
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Quiroz-Reyes AG, Gonzalez-Villarreal CA, Limon-Flores AY, Delgado-Gonzalez P, Martinez-Rodriguez HG, Said-Fernandez SL, Soto-Dominguez A, Rivas-Estilla AM, Islas JF, Molina-De la Garza JF, Garza-Treviño EN. Mesenchymal Stem Cells Genetically Modified by Lentivirus-Express Soluble TRAIL and Interleukin-12 Inhibit Growth and Reduced Metastasis-Relate Changes in Lymphoma Mice Model. Biomedicines 2023; 11:biomedicines11020595. [PMID: 36831131 PMCID: PMC9953195 DOI: 10.3390/biomedicines11020595] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND Cancer treatment has many side effects; therefore, more efficient treatments are needed. Mesenchymal stem cells (MSC) have immunoregulatory properties, tumor site migration and can be genetically modified. Some proteins, such as soluble TRAIL (sTRAIL) and interleukin-12 (IL-12), have shown antitumoral potential, thus its combination in solid tumors could increase their activity. MATERIALS AND METHODS Lentiviral transduction of bone marrow MSC with green fluorescent protein (GFP) and transgenes (sTRAIL and IL-12) was confirmed by fluorescence microscopy and Western blot. Soluble TRAIL levels were quantified by ELISA. Lymphoma L5178Y cells express a reporter gene (GFP/mCherry), and TRAIL receptor (DR5). RESULTS An in vivo model showed that combined treatment with MSC expressing sTRAIL+IL-12 or IL-12 alone significantly reduced tumor volume and increased survival in BALB/c mice (p < 0.05) with only one application. However, at the histological level, only MSC expressing IL-12 reduced tumor cell infiltration significantly in the right gastrocnemius compared with the control group (p < 0.05). It presented less tissue dysplasia confirmed by fluorescence and hematoxylin-eosin dye; nevertheless, treatment not inhibited hepatic metastasis. CONCLUSIONS MSC expressing IL-12, is or combination with BM-MSC expressing sTRAIL represents an antitumor strategy for lymphoma tumors since they increase survival and reduce tumor development. However, the combination did not show significative additive effect. The localized application did not inhibit metastasis but reduced morphological alterations of tissue associated with liver metastasis.
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Affiliation(s)
- Adriana G. Quiroz-Reyes
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Carlos A. Gonzalez-Villarreal
- Department of Basic Sciences, Laboratory of Molecular Genetics, University of Monterrey (UDEM), Monterrey 66238, Mexico
| | - Alberto Y. Limon-Flores
- Department and Service of Immunology, School of Medicine, Autonomous University of Nuevo Leon (UANL), San Nicolás de los Garza 64460, Mexico
| | - Paulina Delgado-Gonzalez
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Herminia G. Martinez-Rodriguez
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Salvador L. Said-Fernandez
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Adolfo Soto-Dominguez
- Department of Histology, School of Medicine, Autonomous University of Nuevo Leon (UANL), San Nicolás de los Garza 64460, Mexico
| | - Ana M. Rivas-Estilla
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Jose F. Islas
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Juan F. Molina-De la Garza
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Elsa N. Garza-Treviño
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon (UANL), Monterrey 64460, Mexico
- Correspondence: ; Tel.: +52-818-3294-173
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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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Ma R, Li Z, Chiocca EA, Caligiuri MA, Yu J. The emerging field of oncolytic virus-based cancer immunotherapy. Trends Cancer 2023; 9:122-139. [PMID: 36402738 PMCID: PMC9877109 DOI: 10.1016/j.trecan.2022.10.003] [Citation(s) in RCA: 128] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/18/2022]
Abstract
Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs are multifaceted tumor killers. They directly lyse tumor cells while sparing normal cells, and indirectly potentiate antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment. However, some limitations, such as limited penetration of OVs into tumors, short persistence, and the host antiviral immune response, are impeding the broad translation of oncolytic virotherapy into the clinic. If these challenges can be overcome, combination therapies, such as OVs plus immune checkpoint blockade (ICB), chimeric antigen receptor (CAR) T cells, or CAR natural killer (NK) cells, may provide powerful therapeutic platforms in the clinic.
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Affiliation(s)
- Rui Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Zhenlong Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
| | - E Antonio Chiocca
- Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA; Comprehensive Cancer Center, City of Hope, Los Angeles, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute, Los Angeles, CA 91010, USA.
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Li X, Sun X, Wang B, Li Y, Tong J. Oncolytic virus-based hepatocellular carcinoma treatment: Current status, intravenous delivery strategies, and emerging combination therapeutic solutions. Asian J Pharm Sci 2023; 18:100771. [PMID: 36896445 PMCID: PMC9989663 DOI: 10.1016/j.ajps.2022.100771] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/24/2022] [Accepted: 12/04/2022] [Indexed: 12/30/2022] Open
Abstract
Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients.
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Affiliation(s)
- Xinguo Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiaonan Sun
- The 4th People's Hospital of Shenyang, Shenyang 110031, China
| | - Bingyuan Wang
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Yiling Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Jing Tong
- The First Hospital of China Medical University, Shenyang 110001, China
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Liu R, Xie Y, Xu JR, Luo Q, Ren YX, Chen M, Duan JL, Bao CJ, Liu YX, Li PS, Li JW, Wang GL, Lu WL. Engineered stem cell biomimetic liposomes carrying levamisole for macrophage immunity reconstruction in leukemia therapy. CHEMICAL ENGINEERING JOURNAL 2022; 447:137582. [DOI: 10.1016/j.cej.2022.137582] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Tu Z, Karnoub AE. Mesenchymal stem/stromal cells in breast cancer development and management. Semin Cancer Biol 2022; 86:81-92. [PMID: 36087857 DOI: 10.1016/j.semcancer.2022.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/02/2022] [Accepted: 09/03/2022] [Indexed: 11/17/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) encompass a heterogeneous population of fibroblastic progenitor cells that reside in multiple tissues around the body. They are endowed with capacities to differentiate into multiple connective tissue lineages, including chondrocytes, adipocytes, and osteoblasts, and are thought to function as trophic cells recruited to sites of injury and inflammation where they contribute to tissue regeneration. In keeping with these roles, MSCs also to home to sites of breast tumorigenesis, akin to their migration to wounds, and participate in tumor stroma formation. Mounting evidence over the past two decades has described the critical regulatory roles for tumor-associated MSCs in various aspects of breast tumor pathogenesis, be it tumor initiation, growth, angiogenesis, tumor microenvironment formation, immune evasion, cancer cell migration, invasion, survival, therapeutic resistance, dissemination, and metastatic colonization. In this review, we present a brief summary of the role of MSCs in breast tumor development and progression, highlight some of the molecular frameworks underlying their pro-malignant contributions, and present evidence of their promising utility in breast cancer therapy.
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Affiliation(s)
- Zhenbo Tu
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Antoine E Karnoub
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Boston Veterans Affairs Research Institute, West Roxbury, MA 02132, USA.
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Bunnell BA, Martin EC, Matossian MD, Brock CK, Nguyen K, Collins-Burow B, Burow ME. The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer. Cancer Metastasis Rev 2022; 41:549-573. [PMID: 35999486 DOI: 10.1007/s10555-022-10063-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022]
Abstract
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
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Affiliation(s)
- Bruce A Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
| | - Elizabeth C Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Margarite D Matossian
- Department of Microbiology, Immunology and Genetics, University of Chicago, IL, Chicago, USA
| | - Courtney K Brock
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Khoa Nguyen
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bridgette Collins-Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Matthew E Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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Huang R, Zhou X, Chen G, Su L, Liu Z, Zhou P, Weng J, Min Y. Advances of functional nanomaterials for magnetic resonance imaging and biomedical engineering applications. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1800. [PMID: 35445588 DOI: 10.1002/wnan.1800] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/21/2022] [Accepted: 03/25/2022] [Indexed: 11/12/2022]
Abstract
Functional nanomaterials have been widely used in biomedical fields due to their good biocompatibility, excellent physicochemical properties, easy surface modification, and easy regulation of size and morphology. Functional nanomaterials for magnetic resonance imaging (MRI) can target specific sites in vivo and more easily detect disease-related specific biomarkers at the molecular and cellular levels than traditional contrast agents, achieving a broad application prospect in MRI. This review focuses on the basic principles of MRI, the classification, synthesis and surface modification methods of contrast agents, and their clinical applications to provide guidance for designing novel contrast agents and optimizing the contrast effect. Furthermore, the latest biomedical advances of functional nanomaterials in medical diagnosis and disease detection, disease treatment, the combination of diagnosis and treatment (theranostics), multi-model imaging and nanozyme are also summarized and discussed. Finally, the bright application prospects of functional nanomaterials in biomedicine are emphasized and the urgent need to achieve significant breakthroughs in the industrial transformation and the clinical translation is proposed. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Ruijie Huang
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Xingyu Zhou
- Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Guiyuan Chen
- Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Lanhong Su
- Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Zhaoji Liu
- Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Peijie Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yuanzeng Min
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Department of Chemistry, University of Science and Technology of China, Hefei, China
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Khosravi N, Pishavar E, Baradaran B, Oroojalian F, Mokhtarzadeh A. Stem cell membrane, stem cell-derived exosomes and hybrid stem cell camouflaged nanoparticles: A promising biomimetic nanoplatforms for cancer theranostics. J Control Release 2022; 348:706-722. [PMID: 35732250 DOI: 10.1016/j.jconrel.2022.06.026] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 02/07/2023]
Abstract
Nanomedicine research has advanced dramatically in recent decades. Nonetheless, traditional nanomedicine faces significant obstacles such as the low concentration of the drug at target sites and accelerated removal of the drug from blood circulation. Various techniques of nanotechnology, including cell membrane coating, have been developed to address these challenges and to improve targeted distribution and redcue cell membrane-mediated immunogenicity. Recently, stem cell (SC) membranes, owing to their immunosuppressive and regenerative properties, have grabbed attention as attractive therapeutic carriers for targeting specific tissues or organs. Bioengineering strategies that combine synthetic nanoparticles (NPs) with SC membranes, because of their homing potential and tumor tropism, have recently received a lot of publicity. Several laboratory experiments and clinical trials have indicated that the benefits of SC-based technologies are mostly related to the effects of SC-derived exosomes (SC-Exos). Exosomes are known as nano-sized extracellular vehicles (EVs) that deliver particular bioactive molecules for cell-to-cell communication. In this regard, SC-derived exosome membranes have recently been employed to improve the therapeutic capability of engineered drug delivery vehicles. Most recently, for further enhancing NPs' functionality, a new coating approach has been offered that combines membranes from two separate cells. These hybrid membrane delivery vehicles have paved the way for the development of biocompatible, high-efficiency, biomimetic NPs with varying hybrid capabilities that can overcome the drawbacks of present NP-based treatment techniques. This review explores stem cell membranes, SC-Exos, and hybrid SC-camouflaged NPs preparation methods and their importance in cancer therapy.
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Affiliation(s)
- Neda Khosravi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Pishavar
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Oroojalian
- Department of Advanced Technologies, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran.
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Stem cells therapy for thyroid diseases: progress and challenges. Curr Ther Res Clin Exp 2022; 96:100665. [PMID: 35371349 PMCID: PMC8968462 DOI: 10.1016/j.curtheres.2022.100665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/25/2022] [Indexed: 11/18/2022] Open
Abstract
Background Thyroid hormones are indispensable for organ development and maintaining homeostasis. Thyroid diseases, including thyroiditis and thyroid cancer, affect the normal secretion of hormones and result in thyroid dysfunction. Objective This review focuses on therapeutic applications of stem cells for thyroid diseases. Methods A literature search of Medline and PubMed was conducted (January 2000–July 2021) to identify recent reports on stem cell therapy for thyroid diseases. Results Stem cells are partially developed cell types. They have the capacity to form specialized cells. Besides embryonic stem cells and mesenchymal stem cells, organ resident stem cells and cancer stem cells are recently reported to have important roles in forming organ specific cells and cancers. Stem cells, especially mesenchymal stem cells, have anti-inflammatory and anticancer functions as well. Conclusions This review outlines the therapeutic potency of embryonic stem cells, mesenchymal stem cells, thyroid resident stem cells, and thyroid cancer stem cells in thyroid cells’ regeneration, thyroid function modulation, thyroiditis suppression, and antithyroid cancers. Stem cells represent a promising form of treatment for thyroid disorders.
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de los Reyes AA, Kim Y. Optimal regulation of tumour-associated neutrophils in cancer progression. ROYAL SOCIETY OPEN SCIENCE 2022; 9:210705. [PMID: 35127110 PMCID: PMC8808100 DOI: 10.1098/rsos.210705] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 11/19/2021] [Indexed: 06/14/2023]
Abstract
In a tumour microenvironment, tumour-associated neutrophils could display two opposing differential phenotypes: anti-tumour (N1) and pro-tumour (N2) effector cells. Converting N2 to N1 neutrophils provides innovative therapies for cancer treatment. In this study, a mathematical model for N1-N2 dynamics describing the cancer survival and immune inhibition in response to TGF-β and IFN-β is considered. The effects of exogenous intervention of TGF-β inhibitor and IFN-β are examined in order to enhance N1 recruitment to combat tumour progression. Our approach employs optimal control theory to determine drug infusion protocols that could minimize tumour volume with least administration cost possible. Four optimal control scenarios corresponding to different therapeutic strategies are explored, namely, TGF-β inhibitor control only, IFN-β control only, concomitant TGF-β inhibitor and IFN-β controls, and alternating TGF-β inhibitor and IFN-β controls. For each scheme, different initial conditions are varied to depict different pathophysiological condition of a cancer patient, leading to adaptive treatment schedule. TGF-β inhibitor and IFN-β drug dosages, total drug amount, infusion times and relative cost of drug administrations are obtained under various circumstances. The control strategies achieved could guide in designing individualized therapeutic protocols.
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Affiliation(s)
- Aurelio A. de los Reyes
- Biomedical Mathematics Group, Pioneer Research Center for Mathematical and Computational Sciences, Institute for Basic Science, Daejeon 34126, Republic of Korea
- Institute of Mathematics, University of the Philippines Diliman, Quezon City 1101, Philippines
| | - Yangjin Kim
- Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea
- Mathematical Biosciences Institute, Columbus, OH 43210, USA
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Yeeravalli R, Das A. Mesenchymal Stem Cells. HANDBOOK OF OXIDATIVE STRESS IN CANCER: THERAPEUTIC ASPECTS 2022:2465-2487. [DOI: 10.1007/978-981-16-5422-0_228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kim JH, Oh E, Yun CW, Lee SH, Song YS. Carboxyl Esterase-TRAIL Expressing Human Adipose Stem Cells Inhibit Tumor Growth in Castration-Resistant Prostate Cancer-Bearing Mice with Less Toxicity. Technol Cancer Res Treat 2022; 21:15330338221093146. [PMID: 35491733 PMCID: PMC9069602 DOI: 10.1177/15330338221093146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
It has been proposed that CRPC treatment with reduced systemic toxicity can be achieved by employing genes that express enzymes that activate pharmacological agents. In this paper, we report our study that used human adipose-derived stem cells (ADSC), rabbit CE, and human TRAIL with reduced toxicity to explore how tumor development can be suppressed in CRPC-bearing mouse models. In vitro and in vivo directional migration of ADSC.CE.sTRAIL cells toward PC3 cells was significantly stimulated.ADSC.CE.sTRAIL showed higher suicide effects than did ADSC, ADSC.CE, or ADSC.sTRAIL under CPT-11 treatment. PC3 cells co-cultured with ADSC.CE.TRAIL showed higher cytotoxicity than did CPT-11 monotherapy, ADSC.CE, or ADSC.sTRAIL under CPT-11 treatment. ADSC.CE.sTRAIL showed higher apoptosis than did CPT-11 monotherapy, ADSC.CE, or ADSC.sTRAIL under CPT-11 treatment. In the in vivo study, ADSC.CE.sTRAIL inhibited tumor growth more than did CPT-11 monotherapy, ADSC.CE, or ADSC.sTRAIL under CPT-11 treatment. The evidence suggests that patients' own ADSC could be used in clinical trials for CRPC treatment based on therapeutic stem cells that express CE and TRAIL complex genes.
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Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University Medical College, Seoul, Korea
| | - Eunjeong Oh
- Department of Pharmacology, 37977Ajou University School of Medicine, Suwon, Republic of Korea
| | - Chul Won Yun
- Medical Science Research Institute, 71544Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Sang Hun Lee
- Medical Science Research Institute, 71544Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University Medical College, Seoul, Korea
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Iida Y, Yoshikawa R, Murata A, Kotani H, Kazuki Y, Oshimura M, Matsuzaki Y, Harada M. Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells. J Immunother Cancer 2021; 8:jitc-2020-000582. [PMID: 32675195 PMCID: PMC7368496 DOI: 10.1136/jitc-2020-000582] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2020] [Indexed: 12/12/2022] Open
Abstract
Background Mesenchymal stem/stromal cells (MSC) accumulate and reside in tumor sites. Methods Taking advantage of this feature in anticancer therapy, immortalized murine MSC (iMSC) were genetically altered to produce chemokine (C-C motif) ligand 19 (iMSC/CCL19), which attracts dendritic cells (DC) and T lymphocytes. Thereafter, iMSC/CCL19 were examined for their therapeutic efficacy using a syngeneic CT26 colon carcinoma cell line. Results Co-injection of iMSC/CCL19 into mice significantly suppressed the in vivo growth of CT26 cells compared with that of CCL19-expressing immortalized fibroblasts (iFib/CCL19). This anticancer effect was not observed when injected in CT26-bearing nude mice. Co-injected iMSC/CCL19 survived longer than iFib/CCL19 in the tumor sites. In a therapeutic model, local injection of iMSC/CCL19 suppressed the tumor growth, and increased IFN (interferon)-γ+ CD8+ T cells and CCR7+ DC infiltration in tumor site was observed when treated with iMSC/CCL19, but not with iMSC. This antitumor effect was completely negated by depletion of CD4+ cells and partially negated by depletion of CD8+ cells. Furthermore, the antitumor effects induced by local injection of iMSC/CCL19 were augmented by additional therapy with anti-programmed death (PD)-ligand 1 (PD-L1) antibody, but not with anti-PD-1 antibody. This combination therapy cured most of the tumors in CT26-bearing mice. Conclusion These results suggest that local therapy with iMSC/CCL19 can suppress tumor growth via effective recruitment of CCR7+ DC into tumor sites and increase IFN-γ+ CD8+ T cells, and that combination with anti-PD-L1 antibody therapy can be a powerful anticancer therapy.
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Affiliation(s)
- Yuichi Iida
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
| | - Rintaro Yoshikawa
- Life Science, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Shimane, Japan
| | - Akihiko Murata
- Molecular and Cellular Biology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Hitoshi Kotani
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
| | - Yasuhiro Kazuki
- Biomedical Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Mitsuo Oshimura
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori, Japan
| | - Yumi Matsuzaki
- Life Science, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Shimane, Japan
| | - Mamoru Harada
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
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Hass R, von der Ohe J, Dittmar T. Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP). Cancers (Basel) 2021; 13:4636. [PMID: 34572863 PMCID: PMC8470238 DOI: 10.3390/cancers13184636] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022] Open
Abstract
Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. Based upon new properties of cancer hybrid cells, the arising clinical consequences of the subsequent tumor heterogeneity after cancer-cell fusion represent a major therapeutic challenge. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Thomas Dittmar
- Institute of Immunology, Center of Biomedical Education and Research (ZABF), Witten/Herdecke University, 58448 Witten, Germany
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Sarwar A, Hashim L, Faisal MS, Haider MZ, Ahmed Z, Ahmed TF, Shahzad M, Ansar I, Ali S, Aslam MM, Anwer F. Advances in viral oncolytics for treatment of multiple myeloma - a focused review. Expert Rev Hematol 2021; 14:1071-1083. [PMID: 34428997 DOI: 10.1080/17474086.2021.1972802] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Oncolytic viruses are genetically engineered viruses that target myeloma-affected cells by detecting specific cell surface receptors (CD46, CD138), causing cell death by activating the signaling pathway to induce apoptosis or by immune-mediated cellular destruction. AREAS COVERED This article summarizes oncolytic virotherapy advancements such as the therapeutic use of viruses by targeting cell surface proteins of myeloma cells as well as the carriers to deliver viruses to the target tissues safely. The major classes of viruses that have been studied for this include measles, myxoma, adenovirus, reovirus, vaccinia, vesicular-stomatitis virus, coxsackie, and others. The measles virus acts as oncolytic viral therapy by binding to the CD46 receptors on the myeloma cells to utilize its surface H protein. These H-protein and CD46 interactions lead to cellular syncytia formation resulting in cellular apoptosis. Vesicular-stomatitis virus acts by downregulation of anti-apoptotic factors (Mcl-2, BCL-2). Based upon the published literature searches till December 2020, we have summarized the data supporting the advances in viral oncolytic for the treatment of MM. EXPERT OPINION Oncolytic virotherapy is an experimental approach in multiple myeloma (MM); many issues need to be addressed for safe viral delivery to the target tissue.
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Affiliation(s)
- Ayesha Sarwar
- Department of Internal Medicine, King Edward Medical University, Lahore, Pakistan
| | | | - Muhammad Salman Faisal
- Department of Internal Medicine, Division of Hematology, The Ohio State University Columbus Oh, USA
| | | | - Zahoor Ahmed
- Department of Internal Medicine, King Edward Medical University, Lahore, Pakistan
| | - Tehniat Faraz Ahmed
- Department of Biochemistry, Dow University of Health Sciences, Karachi, Pakistan
| | - Moazzam Shahzad
- Department of Internal Medicine, St Mary's Medical Center, Huntington, WV, USA
| | - Iqraa Ansar
- Department of Internal medicine, Riverside Methodist hospital, Columbus OH
| | - Sundas Ali
- Department of Internal medicine, Rawalpindi Medical University, Rawalpindi, Pakistan
| | | | - Faiz Anwer
- Department of Hematology and Oncology, Taussig Cancer Center, Cleveland Clinic, Ohio, USA
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Weng Z, Zhang B, Wu C, Yu F, Han B, Li B, Li L. Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer. J Hematol Oncol 2021; 14:136. [PMID: 34479611 PMCID: PMC8414028 DOI: 10.1186/s13045-021-01141-y] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/16/2021] [Indexed: 02/08/2023] Open
Abstract
Extracellular vesicles (EVs) are cell-derived membrane structures enclosing proteins, lipids, RNAs, metabolites, growth factors, and cytokines. EVs have emerged as essential intercellular communication regulators in multiple physiological and pathological processes. Previous studies revealed that mesenchymal stem cells (MSCs) could either support or suppress tumor progression in different cancers by paracrine signaling via MSC-derived EVs. Evidence suggested that MSC-derived EVs could mimic their parental cells, possessing pro-tumor and anti-tumor effects, and inherent tumor tropism. Therefore, MSC-derived EVs can be a cell-free cancer treatment alternative. This review discusses different insights regarding MSC-derived EVs' roles in cancer treatment and summarizes bioengineered MSC-derived EVs’ applications as safe and versatile anti-tumor agent delivery platforms. Meanwhile, current hurdles of moving MSC-derived EVs from bench to bedside are also discussed.
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Affiliation(s)
- Zhijie Weng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bowen Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Comfort Care Dental Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fanyuan Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Han
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Comfort Care Dental Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Lee J, Lee D, Kim Y. Mathematical model of STAT signalling pathways in cancer development and optimal control approaches. ROYAL SOCIETY OPEN SCIENCE 2021; 8:210594. [PMID: 34631119 PMCID: PMC8479343 DOI: 10.1098/rsos.210594] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 09/03/2021] [Indexed: 06/10/2023]
Abstract
In various diseases, the STAT family display various cellular controls over various challenges faced by the immune system and cell death programs. In this study, we investigate how an intracellular signalling network (STAT1, STAT3, Bcl-2 and BAX) regulates important cellular states, either anti-apoptosis or apoptosis of cancer cells. We adapt a mathematical framework to illustrate how the signalling network can generate a bi-stability condition so that it will induce either apoptosis or anti-apoptosis status of tumour cells. Then, we use this model to develop several anti-tumour strategies including IFN-β infusion. The roles of JAK-STATs signalling in regulation of the cell death program in cancer cells and tumour growth are poorly understood. The mathematical model unveils the structure and functions of the intracellular signalling and cellular outcomes of the anti-tumour drugs in the presence of IFN-β and JAK stimuli. We identify the best injection order of IFN-β and DDP among many possible combinations, which may suggest better infusion strategies of multiple anti-cancer agents at clinics. We finally use an optimal control theory in order to maximize anti-tumour efficacy and minimize administrative costs. In particular, we minimize tumour volume and maximize the apoptotic potential by minimizing the Bcl-2 concentration and maximizing the BAX level while minimizing total injection amount of both IFN-β and JAK2 inhibitors (DDP).
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Affiliation(s)
- Jonggul Lee
- Pierre Louis Institute of Epidemiology and Public Health, Paris 75012, France
| | - Donggu Lee
- Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea
| | - Yangjin Kim
- Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea
- Mathematical Biosciences Institute, Columbus, OH 43210, USA
- Department of Neurosurgery, Harvard Medical School & Brigham and Women’s Hospital, Boston MA 02115, USA
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Abdelgawad M, Bakry NS, Farghali AA, Abdel-Latif A, Lotfy A. Mesenchymal stem cell-based therapy and exosomes in COVID-19: current trends and prospects. Stem Cell Res Ther 2021; 12:469. [PMID: 34419143 PMCID: PMC8379570 DOI: 10.1186/s13287-021-02542-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/03/2021] [Indexed: 02/08/2023] Open
Abstract
Novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. The virus causes an exaggerated immune response, resulting in a cytokine storm and acute respiratory distress syndrome, the leading cause of COVID-19-related mortality and morbidity. So far, no therapies have succeeded in circumventing the exacerbated immune response or cytokine storm associated with COVID-19. Mesenchymal stem cells (MSCs), through their immunomodulatory and regenerative activities, mostly mediated by their paracrine effect and extracellular vesicle production, have therapeutic potential in many autoimmune, inflammatory, and degenerative diseases. In this paper, we review clinical studies on the use of MSCs for COVID-19 treatment, including the salutary effects of MSCs on the pathophysiology of COVID-19 and the immunomodulation of the cytokine storm. Ongoing clinical trial designs, cell sources, dose and administration, and populations are summarized, and the paracrine mode of benefit is discussed. We also offer suggestions for optimizing MSC-based therapies, including genetic engineering, strategies for cell surface modification, nanotechnology applications, and combination therapies.
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Affiliation(s)
- Mai Abdelgawad
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni Suef, 62511, Egypt
| | - Nourhan Saied Bakry
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni Suef, 62511, Egypt
| | - Ahmed A Farghali
- Materials Science and Nanotechnology Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni Suef, 62511, Egypt
| | - Ahmed Abdel-Latif
- Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky and the Lexington VA Medical Center, Lexington, KY, USA. .,College of Medicine, University of Kentucky, Lexington, KY, 40506-0046, USA.
| | - Ahmed Lotfy
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni Suef, 62511, Egypt.
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Kostadinova M, Mourdjeva M. Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies. Curr Stem Cell Res Ther 2021; 15:482-491. [PMID: 32148199 DOI: 10.2174/1574888x15666200310171547] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/27/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.
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Affiliation(s)
- Milena Kostadinova
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Bulgarian Academy of Sciences, 73 Tsarigradsko Shose, 1113 Sofia, Bulgaria
| | - Milena Mourdjeva
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Bulgarian Academy of Sciences, 73 Tsarigradsko Shose, 1113 Sofia, Bulgaria
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