|
1
|
Wen Z, Li S, Liu Y, Liu X, Qiu H, Che Y, Bian L, Zhou M. An engineered M2 macrophage-derived exosomes-loaded electrospun biomimetic periosteum promotes cell recruitment, immunoregulation, and angiogenesis in bone regeneration. Bioact Mater 2025; 50:95-115. [PMID: 40242509 PMCID: PMC12002949 DOI: 10.1016/j.bioactmat.2025.03.027] [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: 12/06/2024] [Revised: 02/04/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
The periosteum, a fibrous tissue membrane covering bone surfaces, is critical to osteogenesis and angiogenesis in bone reconstruction. Artificial periostea have been widely developed for bone defect repair, but most of these are lacking of periosteal bioactivity. Herein, a biomimetic periosteum (termed PEC-Apt-NP-Exo) is prepared based on an electrospun membrane combined with engineered exosomes (Exos). The electrospun membrane is fabricated using poly(ε-caprolactone) (core)-periosteal decellularized extracellular matrix (shell) fibers via coaxial electrospinning, to mimic the fibrous structure, mechanical property, and tissue microenvironment of natural periosteum. The engineered Exos derived from M2 macrophages are functionalized by surface modification of bone marrow mesenchymal stem cell (BMSC)-specific aptamers to further enhance cell recruitment, immunoregulation, and angiogenesis in bone healing. The engineered Exos are covalently bonded to the electrospun membrane, to achieve rich loading and long-term effects of Exos. In vitro experiments demonstrate that the biomimetic periosteum promotes BMSC migration and osteogenic differentiation via Rap1/PI3K/AKT signaling pathway, and enhances vascular endothelial growth factor secretion from BMSCs to facilitate angiogenesis. In vivo studies reveal that the biomimetic periosteum promotes new bone formation in large bone defect repair by inducing M2 macrophage polarization, endogenous BMSC recruitment, osteogenic differentiation, and vascularization. This research provides valuable insights into the development of a multifunctional biomimetic periosteum for bone regeneration.
Collapse
Affiliation(s)
- Zhuohao Wen
- Department of Stomatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Shuyi Li
- Department of Stomatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Yi Liu
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Xueyan Liu
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, China
| | - Huiguo Qiu
- Zhuhai Stomatological Hospital, Zhuhai, 519000, China
| | - Yuejuan Che
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, China
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Liming Bian
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, 510006, China
| | - Miao Zhou
- Department of Stomatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| |
Collapse
|
|
2
|
Rahimian S, Mirkazemi K, Kamalinejad A, Doroudian M. Exosome-based advances in pancreatic cancer: The potential of mesenchymal stem cells. Crit Rev Oncol Hematol 2025; 207:104594. [PMID: 39732301 DOI: 10.1016/j.critrevonc.2024.104594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/28/2024] [Accepted: 12/08/2024] [Indexed: 12/30/2024] Open
Abstract
Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), is one of the most challenging clinical conditions due to its late-stage diagnosis and poor survival rates. Mesenchymal stem cells (MSCs), used for targeted therapies, are being explored as a promising treatment because of their tumor-homing properties and potential contributions to the pancreatic cancer microenvironment. Understanding these interactions is crucial for developing effective treatments. In this study, we investigated how MSCs exhibit tropism towards tumors, influence the microenvironment through paracrine effects, and serve as potential drug delivery vehicles. We also examined their role in progression and therapeutic resistance in pancreatic cancer therapy. The cytotoxic effects of certain compounds on tumor cells, the use of genetically modified MSCs as drug carriers, and the potential of exosomal biomarkers like miRNAs and riRNAs for diagnosis and monitoring of pancreatic cancer were analyzed. Overall, MSC-based therapies, coupled with insights into tumor-stromal interactions, offer new avenues for improving outcomes in pancreatic cancer treatment. Additionally, the use of MSC-based therapies in clinical trials is discussed. While MSCs show promising potential for pancreatic cancer monitoring, diagnosis, and treatment, results so far have been limited.
Collapse
Affiliation(s)
- Sana Rahimian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Kimia Mirkazemi
- Faculty of Science, University of Amsterdam, Amsterdam, the Netherlands
| | - Armita Kamalinejad
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
| |
Collapse
|
|
3
|
Lei K, Zhou L, Dan M, Yang F, Jian T, Xin J, Yu Z, Wang Y. Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting. Pharmaceutics 2025; 17:280. [PMID: 40142943 PMCID: PMC11945504 DOI: 10.3390/pharmaceutics17030280] [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: 01/23/2025] [Revised: 02/13/2025] [Accepted: 02/19/2025] [Indexed: 03/28/2025] Open
Abstract
Central nervous system (CNS) diseases, such as brain tumors, Alzheimer's disease, and Parkinson's disease, significantly impact patients' quality of life and impose substantial economic burdens on society. The blood-brain barrier (BBB) limits the effective delivery of most therapeutic drugs, especially natural products, despite their potential therapeutic effects. The Trojan Horse strategy, using nanotechnology to disguise drugs as "cargo", enables them to bypass the BBB, enhancing targeting and therapeutic efficacy. This review explores the applications of natural products in the treatment of CNS diseases, discusses the challenges posed by the BBB, and analyzes the advantages and limitations of the Trojan Horse strategy. Despite the existing technical challenges, future research is expected to enhance the application of natural drugs in CNS treatment by integrating nanotechnology, improving delivery mechanisms, and optimizing targeting characteristics.
Collapse
Affiliation(s)
- Kelu Lei
- Department of Pharmacy, Ya’an People’s Hospital-West China Ya’an Hospital, Sichuan University, Ya’an 625000, China; (K.L.); (M.D.); (F.Y.); (T.J.); (J.X.)
| | - Lanyu Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China;
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Min Dan
- Department of Pharmacy, Ya’an People’s Hospital-West China Ya’an Hospital, Sichuan University, Ya’an 625000, China; (K.L.); (M.D.); (F.Y.); (T.J.); (J.X.)
| | - Fei Yang
- Department of Pharmacy, Ya’an People’s Hospital-West China Ya’an Hospital, Sichuan University, Ya’an 625000, China; (K.L.); (M.D.); (F.Y.); (T.J.); (J.X.)
| | - Tiantian Jian
- Department of Pharmacy, Ya’an People’s Hospital-West China Ya’an Hospital, Sichuan University, Ya’an 625000, China; (K.L.); (M.D.); (F.Y.); (T.J.); (J.X.)
| | - Juan Xin
- Department of Pharmacy, Ya’an People’s Hospital-West China Ya’an Hospital, Sichuan University, Ya’an 625000, China; (K.L.); (M.D.); (F.Y.); (T.J.); (J.X.)
| | - Zhigang Yu
- Department of Pharmacy, Ya’an People’s Hospital-West China Ya’an Hospital, Sichuan University, Ya’an 625000, China; (K.L.); (M.D.); (F.Y.); (T.J.); (J.X.)
| | - Yue Wang
- Department of Pharmacy, Ya’an People’s Hospital-West China Ya’an Hospital, Sichuan University, Ya’an 625000, China; (K.L.); (M.D.); (F.Y.); (T.J.); (J.X.)
| |
Collapse
|
|
4
|
Tong Y, Gao M, Luo Y. Mesenchymal Stem Cell Membrane-Derived Composite System for Enhancing the Tumor Treatment Efficacy of Metal-Organic Framework Nanoparticles. IET Nanobiotechnol 2024; 2024:1069307. [PMID: 39669228 PMCID: PMC11637620 DOI: 10.1049/nbt2/1069307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 11/21/2024] [Indexed: 12/14/2024] Open
Abstract
Mesenchymal stem cell (MSC) membrane-coated metal-organic frameworks (MOFs) represent an innovative approach to enhance the uptake and therapeutic efficacy of copper-based MOFs (Cu-MOFs) in tumor cells. By leveraging the natural homing abilities and biocompatibility of MSC membranes, Cu-MOFs can be effectively targeted to tumor sites, promoting increased cellular uptake. This coating not only facilitates superior internalization by cancer cells but also augments the therapeutic outcomes due to the enhanced delivery of copper ions. In vitro studies demonstrate that MSC membrane-coated Cu-MOFs (MSC-Cu-MOFs) significantly improve the cytotoxic effects on tumor cells compared to uncoated Cu-MOFs. This novel strategy presents a promising avenue for advancing the precision and effectiveness of cancer treatment modalities, showcasing potential for clinical applications in oncology.
Collapse
Affiliation(s)
- Ying Tong
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, Jiangsu, China
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Meng Gao
- Department of Gastroenterology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei 230011, Anhui, China
| | - Yingli Luo
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, Jiangsu, China
| |
Collapse
|
|
5
|
Hang Y, Huang J, Ding M, Shen Y, Zhou Y, Cai W. Extracellular vesicles reshape the tumor microenvironment to improve cancer immunotherapy: Current knowledge and future prospects. Int Immunopharmacol 2024; 140:112820. [PMID: 39096874 DOI: 10.1016/j.intimp.2024.112820] [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: 06/03/2024] [Revised: 07/19/2024] [Accepted: 07/25/2024] [Indexed: 08/05/2024]
Abstract
Tumor immunotherapy has revolutionized cancer treatment, but limitations remain, including low response rates and immune complications. Extracellular vesicles (EVs) are emerging as a new class of therapeutic agents for various diseases. Recent research shows that changes in the amount and composition of EVs can reshape the tumor microenvironment (TME), potentially improving the effectiveness of immunotherapy. This exciting discovery has sparked clinical interest in using EVs to enhance the immune system's response to cancer. In this Review, we delve into the world of EVs, exploring their origins, how they're generated, and their complex interactions within the TME. We also discuss the crucial role EVs play in reshaping the TME during tumor development. Specifically, we examine how their cargo, including molecules like PD-1 and non-coding RNA, influences the behavior of key immune cells within the TME. Additionally, we explore the current applications of EVs in various cancer therapies, the latest advancements in engineering EVs for improved immunotherapy, and the challenges faced in translating this research into clinical practice. By gaining a deeper understanding of how EVs impact the TME, we can potentially uncover new therapeutic vulnerabilities and significantly enhance the effectiveness of existing cancer immunotherapies.
Collapse
Affiliation(s)
- Yu Hang
- Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - JingYi Huang
- Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingming Ding
- Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanhua Shen
- Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - YaoZhong Zhou
- Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China.
| | - Wan Cai
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| |
Collapse
|
|
6
|
Li Y, Fan Y, Xie Y, Li L, Li J, Liu J, Jin Z, Xue H, Wang Z. Genome-wide RNA-Seq identifies TP53-mediated embryonic stem cells inhibiting tumor invasion and metastasis. Stem Cell Res Ther 2024; 15:369. [PMID: 39415294 PMCID: PMC11483973 DOI: 10.1186/s13287-024-04000-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/14/2024] [Indexed: 10/18/2024] Open
Abstract
The discovery of embryonic stem cell (ESC) mediating tumoricidal activity revealed the intimate relationship between ESCs and tumor cells, but the functional role of ESCs in tumor progression is poorly understood. To further investigate tumor cell and ESC interactions, we co-cultured mouse ESCs with mouse pancreatic cancer Pan02 cells or mouse melanoma B16-F10 cells in Transwell, and found that tumor cell invasion was significantly inhibited by ESCs. Application of ESCs to tumor-bearing mice resulted in significant inhibition of tumor metastasis in vivo. RNA-Seq analyses of tumor cell and ESC co-cultures identified TP53 and related signalling as major pathways involved in ESC-mediated inhibition of tumor cell invasion and metastasis, which indicated the potential clinical application of ESCs to treat cancer.
Collapse
Affiliation(s)
- Yatong Li
- Department of Radiology, Peking Union Medical College Hospital, Beijing, 100730, China.
- State Key Laboratory of Medical Molecular Biology, Department of Pathology and Pathophysiology, Institute of Basic Medical Sciences, Center of Molecular Pathology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100005, China.
| | - Yongna Fan
- State Key Laboratory of Medical Molecular Biology, Department of Pathology and Pathophysiology, Institute of Basic Medical Sciences, Center of Molecular Pathology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100005, China
| | - Yunyi Xie
- State Key Laboratory of Medical Molecular Biology, Department of Pathology and Pathophysiology, Institute of Basic Medical Sciences, Center of Molecular Pathology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100005, China
| | - Limin Li
- State Key Laboratory of Medical Molecular Biology, Department of Pathology and Pathophysiology, Institute of Basic Medical Sciences, Center of Molecular Pathology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100005, China
| | - Juan Li
- Department of Radiology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Jingyi Liu
- Department of Radiology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Zhengyu Jin
- Department of Radiology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Huadan Xue
- Department of Radiology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Zhiwei Wang
- Department of Radiology, Peking Union Medical College Hospital, Beijing, 100730, China.
| |
Collapse
|
|
7
|
Stella GM, Lisini D, Pedrazzoli P, Galli G, Bortolotto C, Melloni G, D’Ambrosio G, Klersy C, Grosso A, Paino F, Tomaselli S, Saracino L, Alessandri G, Pessina A, Grignani E, Rosti V, Corsico AG, Comoli P, Agustoni F. Phase I Clinical Trial on Pleural Mesothelioma Using Neoadjuvant Local Administration of Paclitaxel-Loaded Mesenchymal Stromal Cells (PACLIMES Trial): Study Rationale and Design. Cancers (Basel) 2024; 16:3391. [PMID: 39410011 PMCID: PMC11475395 DOI: 10.3390/cancers16193391] [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: 08/14/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Background and rationale. Pleural mesothelioma (PM) is a rare and aggressive neoplasm that originates from the pleural mesothelium and whose onset is mainly linked to exposure to asbestos, which cannot be attacked with truly effective therapies with consequent poor prognosis. The rationale of this study is based on the use of mesenchymal stromal cells (MSCs) as a vehicle for chemotherapy drugs to be injected directly into the pathological site, such as the pleural cavity. Study design. The study involves the use of a conventional chemotherapeutic drug, Paclitaxel (PTX), which is widely used in the treatment of different types of solid tumors, including PM, although some limitations are related to pharmacokinetic aspects. The use of PTX-loaded MSCs to treat PM should provide several potential advantages over the systemically administered drug as reduced toxicity and increased concentration of active drug in the tumor-surrounding context. The PACLIMES trial explores the safety and toxicity of the local administration of Paclimes in chemonaive patients, candidates for pleurectomy. The secondary objective is to find the effective Paclimes dose for subsequent phase II studies and to observe and record the antitumor activity. Future direction. The experimental pre-clinical background and rationale are discussed as well.
Collapse
Affiliation(s)
- Giulia Maria Stella
- Department of Internal Medicine and Medical Therapeutics, University of Pavia Medical School, 27100 Pavia, Italy; (P.P.); (G.G.); (A.G.C.); (F.A.)
- Unit of Respiratory Diseases, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (A.G.); (S.T.); (L.S.)
| | - Daniela Lisini
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy;
| | - Paolo Pedrazzoli
- Department of Internal Medicine and Medical Therapeutics, University of Pavia Medical School, 27100 Pavia, Italy; (P.P.); (G.G.); (A.G.C.); (F.A.)
- Medical Oncology Unit, Oncology and Hematology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Giulia Galli
- Department of Internal Medicine and Medical Therapeutics, University of Pavia Medical School, 27100 Pavia, Italy; (P.P.); (G.G.); (A.G.C.); (F.A.)
- Medical Oncology Unit, Oncology and Hematology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Chandra Bortolotto
- Diagnostic Imaging Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy;
- Radiology Unit-Diagnostic Imaging I, Department of Diagnostic Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Giulio Melloni
- Unit of Thoracic Surgery, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Gioacchino D’Ambrosio
- Pathology Unit, Department of Diagnostical Services and Imaging, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Catherine Klersy
- Biostatistics and Clinical Trial Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy;
| | - Amelia Grosso
- Unit of Respiratory Diseases, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (A.G.); (S.T.); (L.S.)
| | - Francesca Paino
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (F.P.); (G.A.); (A.P.)
| | - Stefano Tomaselli
- Unit of Respiratory Diseases, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (A.G.); (S.T.); (L.S.)
| | - Laura Saracino
- Unit of Respiratory Diseases, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (A.G.); (S.T.); (L.S.)
| | - Giulio Alessandri
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (F.P.); (G.A.); (A.P.)
| | - Augusto Pessina
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (F.P.); (G.A.); (A.P.)
| | - Elena Grignani
- Environmental Research Center, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy;
| | - Vittorio Rosti
- Phase 1 Clinical Trial Unit and Experimental Therapy, IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Angelo Guido Corsico
- Department of Internal Medicine and Medical Therapeutics, University of Pavia Medical School, 27100 Pavia, Italy; (P.P.); (G.G.); (A.G.C.); (F.A.)
- Unit of Respiratory Diseases, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (A.G.); (S.T.); (L.S.)
| | - Patrizia Comoli
- Cell Factory, Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Francesco Agustoni
- Department of Internal Medicine and Medical Therapeutics, University of Pavia Medical School, 27100 Pavia, Italy; (P.P.); (G.G.); (A.G.C.); (F.A.)
- Medical Oncology Unit, Oncology and Hematology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| |
Collapse
|
|
8
|
Shamsul Kamal AA, Fakiruddin KS, Bobbo KA, Ling KH, Vidyadaran S, Abdullah S. Engineered Mesenchymal Stem Cells as Treatment for Cancers: Opportunities, Clinical Applications and Challenges. Malays J Med Sci 2024; 31:56-82. [PMID: 39416732 PMCID: PMC11477465 DOI: 10.21315/mjms2024.31.5.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 06/27/2024] [Indexed: 10/19/2024] Open
Abstract
The insufficient and unspecific target of classical chemotherapies often leads to therapy resistance and cancer recurrence. Over the past decades, discoveries about mesenchymal stem cell (MSC) biology have provided new potential approaches to improve cancer therapy. Researchers have utilised the multipotent, regenerative and immunosuppressive qualities of MSCs and tropisms towards inflammatory, hypoxic and malignant sites in various therapeutic applications. Although MSC-based therapies have generally been demonstrated safe, their effectiveness remains limited when these cells are used alone. However, through genetic engineering, researchers have proven that MSCs can be modified to have specialised delivery roles to increase their therapeutic efficacy in cancer treatment. They can be made to overexpress therapeutic proteins through viral or non-viral genetic modification, which enhances their innate properties. Nevertheless, these engineering strategies must be optimised to increase therapeutic efficacy and targeting effectiveness while minimising any loss of MSC function. This review underscores the cutting-edge methods for engineering MSCs, discusses their promise and the difficulties in translating them into clinical settings, and offers some prospective suggestions for the future on achieving their full therapeutic potential.
Collapse
Affiliation(s)
- Aishah Amirah Shamsul Kamal
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Kamal Shaik Fakiruddin
- Haematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Selangor, Malaysia
| | - Khadijat Abubakar Bobbo
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - King Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Selangor, Malaysia
| | - Sharmili Vidyadaran
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | - Syahril Abdullah
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
- Malaysia Genome and Vaccine Institute, National Institutes of Biotechnology Malaysia, Selangor, Malaysia
| |
Collapse
|
|
9
|
Kangari P, Salahlou R, Vandghanooni S. Harnessing the Therapeutic Potential of Mesenchymal Stem Cells in Cancer Treatment. Adv Pharm Bull 2024; 14:574-590. [PMID: 39494266 PMCID: PMC11530882 DOI: 10.34172/apb.2024.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/12/2024] [Accepted: 06/19/2024] [Indexed: 11/05/2024] Open
Abstract
Cancer, as a complicated disease, is considered to be one of the major leading causes of death globally. Although various cancer therapeutic strategies have been established, however, some issues confine the efficacies of the treatments. In recent decades researchers for finding efficient therapeutic solutions have extensively focused on the abilities of stem cells in cancer inhibition. Mesenchymal stem cells (MSCs) are multipotent stromal cells that can the most widely extracted from various sources such as the bone marrow (BM), placenta, umbilical cord (UC), menses blood, Wharton's jelly (WJ), adipose tissue and dental pulp (DP). These cells are capable of differentiating into the osteoblasts, chondrocytes, and adipocytes. Due to the unique characteristics of MSCs such as paracrine effects, immunomodulation, tumor-tropism, and migration, they are considered promising candidates for cancer therapeutics. Currently, MSCs are an excellent living carrier for delivery of therapeutic genes and chemical agents to target tumor sites. Also, exosomes, the most important extracellular vesicle released from MSCs, act as a strong cell-free tool for cancer therapeutics. MSCs can prevent cancer progression by inhibiting several signaling pathways, such as wnt/β-catenin and PI3K/AKT/mTOR. However, there are several challenges associated with the use of MSCs and their exosomes in the field of therapy that need to be considered. This review explores the significance of MSCs in cell-based therapy, focusing on their homing properties and immunomodulatory characteristics. It also examines the potential of using MSCs as carriers for delivery of anticancer agents and their role in modulating the signal transduction pathways of cancer cells.
Collapse
Affiliation(s)
- Parisa Kangari
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Salahlou
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
10
|
Starska-Kowarska K. Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies. Cells 2024; 13:1270. [PMID: 39120301 PMCID: PMC11311692 DOI: 10.3390/cells13151270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/11/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.
Collapse
Affiliation(s)
- Katarzyna Starska-Kowarska
- Department of Physiology, Pathophysiology and Clinical Immunology, Department of Clinical Physiology, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; ; Tel.: +48-42-2725237
- Department of Otorhinolaryngology, EnelMed Center Expert, Lodz, Drewnowska 58, 91-001 Lodz, Poland
| |
Collapse
|
|
11
|
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.
Collapse
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
| |
Collapse
|
|
12
|
Waqar MA, Zaman M, Khan R, Shafeeq Ur Rahman M, Majeed I. Navigating the tumor microenvironment: mesenchymal stem cell-mediated delivery of anticancer agents. J Drug Target 2024; 32:624-634. [PMID: 38652480 DOI: 10.1080/1061186x.2024.2347356] [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: 02/26/2024] [Accepted: 04/21/2024] [Indexed: 04/25/2024]
Abstract
Scientific knowledge of cancer has advanced greatly throughout the years, with most recent studies findings includes many hallmarks that capture disease's multifaceted character. One of the novel approach utilised for the delivery of anti-cancer agents includes mesenchymal stem cell mediated drug delivery. Mesenchymal stem cells (MSCs) are non-haematopoietic progenitor cells that may be extracted from bone marrow, tooth pulp, adipose tissue and placenta/umbilical cord blood dealing with adult stem cells. MSCs are mostly involved in regeneration of tissue, they have also been shown to preferentially migrate to location of several types of tumour in-vivo. Usage of MSCs ought to improve both effectiveness and safety of anti-cancer drugs by enhancing delivery efficiency of anti-cancer therapies to tumour site. Numerous researches has demonstrated that various drugs, when delivered via mesenchymal stem cell mediated delivery can elicit anti-tumour effect of cells in cancers of breast cells and thyroid cells. MSCs have minimal immunogenicity because to lack of co-stimulatory molecule expression, which means there is no requirement for immunosuppression after allogenic transplantation. This current review elaborates recent advancements of mesenchyma stem cell mediated drug delivery of anti-cancer agents along with its mechanism and previously reported studies of drugs manufactured via this drug delivery system.
Collapse
Affiliation(s)
- Muhammad Ahsan Waqar
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Lahore University of Biological & Applied Sciences, Lahore, Pakistan
| | - Muhammad Zaman
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Pakistan
| | - Rabeel Khan
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Lahore University of Biological & Applied Sciences, Lahore, Pakistan
| | | | - Imtiaz Majeed
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Pakistan
| |
Collapse
|
|
13
|
Gil-Chinchilla JI, Zapata AG, Moraleda JM, García-Bernal D. Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects. Biomolecules 2024; 14:734. [PMID: 39062449 PMCID: PMC11275142 DOI: 10.3390/biom14070734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/11/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.
Collapse
Affiliation(s)
- Jesús I. Gil-Chinchilla
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
| | - Agustín G. Zapata
- Department of Cell Biology, Complutense University, 28040 Madrid, Spain;
| | - Jose M. Moraleda
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Medicine, University of Murcia, 30120 Murcia, Spain
| | - David García-Bernal
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Biochemistry, Molecular Biology and Immunology, University of Murcia, 30120 Murcia, Spain
| |
Collapse
|
|
14
|
Mundluru VK, Naidu MJ, Mundluru RT, Jeyaraman N, Muthu S, Ramasubramanian S, Jeyaraman M. Non-enzymatic methods for isolation of stromal vascular fraction and adipose-derived stem cells: A systematic review. World J Methodol 2024; 14:94562. [PMID: 38983657 PMCID: PMC11229868 DOI: 10.5662/wjm.v14.i2.94562] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/03/2024] [Accepted: 05/30/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Adipose-derived stem cells (ADSCs) and the stromal vascular fraction (SVF) have garnered substantial interest in regenerative medicine due to their potential to treat a wide range of conditions. Traditional enzymatic methods for isolating these cells face challenges such as high costs, lengthy processing time, and regu-latory complexities. AIM This systematic review aimed to assess the efficacy and practicality of non-enzymatic, mechanical methods for isolating SVF and ADSCs, comparing these to conventional enzymatic approaches. METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a comprehensive literature search was conducted across multiple databases. Studies were selected based on inclusion criteria focused on non-enzymatic isolation methods for SVF and ADSCs from adipose tissue. The risk of bias was assessed, and a qualitative synthesis of findings was performed due to the methodological heterogeneity of the included studies. RESULTS Nineteen studies met the inclusion criteria, highlighting various mechanical techniques such as centrifugation, vortexing, and ultrasonic cavitation. The review identified significant variability in cell yield and viability, and the integrity of isolated cells across different non-enzymatic methods compared to enzymatic procedures. Despite some advantages of mechanical methods, including reduced processing time and avoidance of enzymatic reagents, the evidence suggests a need for optimization to match the cell quality and therapeutic efficacy achievable with enzymatic isolation. CONCLUSION Non-enzymatic, mechanical methods offer a promising alternative to enzymatic isolation of SVF and ADSCs, potentially simplifying the isolation process and reducing regulatory hurdles. However, further research is necessary to standardize these techniques and ensure consistent, high-quality cell yields for clinical applications. The development of efficient, safe, and reproducible non-enzymatic isolation methods could significantly advance the field of regenerative medicine.
Collapse
Affiliation(s)
- Vamsi Krishna Mundluru
- Department of Orthopaedics, MJ Naidu Super Speciality Hospital, Vijayawada 520002, Andhra Pradesh, India
- Department of Regenerative Medicine, StemC Clinics, Vijayawada 520002, Andhra Pradesh, India
| | - MJ Naidu
- Department of Orthopaedics, MJ Naidu Super Speciality Hospital, Vijayawada 520002, Andhra Pradesh, India
- Department of Regenerative Medicine, StemC Clinics, Vijayawada 520002, Andhra Pradesh, India
| | - Ravi Teja Mundluru
- Department of Orthopaedics, MJ Naidu Super Speciality Hospital, Vijayawada 520002, Andhra Pradesh, India
- Department of Regenerative Medicine, StemC Clinics, Vijayawada 520002, Andhra Pradesh, India
| | - Naveen Jeyaraman
- Department of Regenerative Medicine, StemC Clinics, Vijayawada 520002, Andhra Pradesh, India
- Department of Orthopaedics, ACS Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
| | - Sathish Muthu
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Orthopaedics, Government Medical College and Hospital, Karur 639004, Tamil Nadu, India
- Department of Biotechnology, Faculty of Engineering, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India
| | - Swaminathan Ramasubramanian
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
| | - Madhan Jeyaraman
- Department of Regenerative Medicine, StemC Clinics, Vijayawada 520002, Andhra Pradesh, India
- Department of Orthopaedics, ACS Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
| |
Collapse
|
|
15
|
Lavi Arab F, Hoseinzadeh A, Hafezi F, Sadat Mohammadi F, Zeynali F, Hadad Tehran M, Rostami A. Mesenchymal stem cell-derived exosomes for management of prostate cancer: An updated view. Int Immunopharmacol 2024; 134:112171. [PMID: 38701539 DOI: 10.1016/j.intimp.2024.112171] [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: 02/25/2024] [Revised: 04/16/2024] [Accepted: 04/27/2024] [Indexed: 05/05/2024]
Abstract
Prostate cancer represents the second most prevalent form of cancer found in males, and stands as the fifth primary contributor to cancer-induced mortality on a global scale. Research has shown that transplanted mesenchymal stem cells (MSCs) can migrate by homing to tumor sites in the body. In prostate cancer, researchers have explored the fact that MSC-based therapies (including genetically modified delivery vehicles or vectors) and MSC-derived exosomes are emerging as attractive options to improve the efficacy and safety of traditional cancer therapies. In addition, researchers have reported new insights into the application of extracellular vesicle (EV)-MSC therapy as a novel treatment option that could provide a more effective and targeted approach to prostate cancer treatment. Moreover, the new generation of exosomes, which contain biologically functional molecules as signal transducers between cells, can simultaneously deliver different therapeutic agents and induce an anti-tumor phenotype in immune cells and their recruitment to the tumor site. The results of the current research on the use of MSCs in the treatment of prostate cancer may be helpful to researchers and clinicians working in this field. Nevertheless, it is crucial to emphasize that although dual-role MSCs show promise as a therapeutic modality for managing prostate cancer, further investigation is imperative to comprehensively grasp their safety and effectiveness. Ongoing clinical trials are being conducted to assess the viability of MSCs in the management of prostate cancer. The results of these trials will help determine the viability of this approach. Based on the current literature, engineered MSCs-EV offer great potential for application in targeted tumor therapy.
Collapse
Affiliation(s)
- Fahimeh Lavi Arab
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Akram Hoseinzadeh
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.; Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Hafezi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Sadat Mohammadi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farid Zeynali
- Department of Urology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Melika Hadad Tehran
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Amirreza Rostami
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
16
|
Kitaeva KV, Solovyeva VV, Rizvanov AA. Development of a Three-Dimensional Multicellular Model of Human Neuroblastoma Using Matrigel as an Extracellular Matrix Analogue. Methods Mol Biol 2024. [PMID: 38797794 DOI: 10.1007/7651_2024_548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Neuroblastoma, the most prevalent extracranial solid tumor in children, poses therapeutic challenges due to its variable clinical course and propensity for metastasis. Despite advances in treatment strategies like chemotherapy, drug resistance remains a significant concern, highlighting the need for improved models to study tumor behavior and drug responses. This chapter proposes the development of a three-dimensional multicellular model of human neuroblastoma using Matrigel as an ECM analogue. Such models aim to replicate the complexity of the tumor microenvironment, providing valuable insights into tumor progression and drug resistance mechanisms. By recapitulating key features of neuroblastoma within a physiologically relevant context, these models offer a platform for preclinical drug screening and therapeutic development.
Collapse
Affiliation(s)
| | | | - Albert A Rizvanov
- Kazan (Volga Region) Federal University, Kazan, Russia
- Republic Clinical Hospital of the Ministry of Health of the Republic of Tatarstan, Kazan, Russia
- Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, Kazan, Russia
| |
Collapse
|
|
17
|
Wang X, Liang Y, Li J, Wang J, Yin G, Chen Z, Huang Z, Pu X. Artificial periosteum promotes bone regeneration through synergistic immune regulation of aligned fibers and BMSC-recruiting phages. Acta Biomater 2024; 180:262-278. [PMID: 38579918 DOI: 10.1016/j.actbio.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/07/2024] [Accepted: 04/01/2024] [Indexed: 04/07/2024]
Abstract
Given the crucial role of periosteum in bone repair, the use of artificial periosteum to induce spontaneous bone healing instead of using bone substitutes has become a potential strategy. Also, the proper transition from pro-inflammatory signals to anti-inflammatory signals is pivotal for achieving optimal repair outcomes. Hence, we designed an artificial periosteum loaded with a filamentous bacteriophage clone named P11, featuring an aligned fiber morphology. P11 endowed the artificial periosteum with the capacity to recruit bone marrow mesenchymal stem cells (BMSCs). The artificial periosteum also regulated the immune microenvironment at the bone injury site through the synergistic effects of biochemical factors and topography. Specifically, the inclusion of P11 preserved inflammatory signaling in macrophages and additionally facilitated the migration of BMSCs. Subsequently, aligned fibers stimulated macrophages, inducing alterations in cytoskeletal and metabolic activities, resulting in the polarization into the M2 phenotype. This progression encouraged the osteogenic differentiation of BMSCs and promoted vascularization. In vivo experiments showed that the new bone generated in the AP group exhibited the most efficient healing pattern. Overall, the integration of biochemical factors with topographical considerations for sequential immunomodulation during bone repair indicates a promising approach for artificial periosteum development. STATEMENT OF SIGNIFICANCE: The appropriate transition of macrophages from a pro-inflammatory to an anti-inflammatory phenotype is pivotal for achieving optimal bone repair outcomes. Hence, we designed an artificial periosteum featuring an aligned fiber morphology and loaded with specific phage clones. The artificial periosteum not only fostered the recruitment of BMSCs but also achieved sequential regulation of the immune microenvironment through the synergistic effects of biochemical factors and topography, and improved the effect of bone repair. This study indicates that the integration of biochemical factors with topographical considerations for sequential immunomodulation during bone repair is a promising approach for artificial periosteum development.
Collapse
Affiliation(s)
- Xingming Wang
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Yingyue Liang
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Jingtao Li
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Juan Wang
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Guangfu Yin
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Zhuo Chen
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhongbing Huang
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Ximing Pu
- College of Biomedical Engineering, Sichuan University, Chengdu, China.
| |
Collapse
|
|
18
|
Gui L, Wang Z, Lou W, Yekehfallah V, Basiri M, Gao WQ, Wang Y, Ma B. Comparative evaluation of antitumor effects of TNF superfamily costimulatory ligands delivered by mesenchymal stem cells. Int Immunopharmacol 2024; 126:111249. [PMID: 37995568 DOI: 10.1016/j.intimp.2023.111249] [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: 08/16/2023] [Revised: 10/28/2023] [Accepted: 11/14/2023] [Indexed: 11/25/2023]
Abstract
Stimulation of costimulatory receptors serves as an alternative immunotherapeutic strategy other than checkpoint inhibition. However, systemic administration of the agonistic antibodies is associated with severe toxicities, which is one of the major obstacles for their clinical application. This study aimed to develop a mesenchymal stem cell (MSC)-based system for tumor-targeted delivery of TNF superfamily ligands and assess their potential in enhancing antitumor immunity. Here we established an MSC-based system for tumor-targeted delivery of TNF superfamily ligands, including TNFSF4, 9 and 18. The TNFSF receptors (TNFRSFs) were evaluated in mouse models and patient samples for lung and colorectal cancers. TNFRSFs were all expressed at various levels on tumor-infiltrated lymphocytes, with TNFRSF18 being the most prevalent receptor. Human umbilical cord-derived MSCs expressing these costimulatory ligands (MSC-TNFSFs) effectively activated lymphocytes in vitro and elicited antitumor immunity in mice. TNFSF4 showed the least antitumor efficacy in both LLC1 and CT26 tumor models. MSC-TNFSF9 showed the most potent tumor-inhibiting effect in the LLC1 tumor model, while MSCs expressing TNFSF18 in combination with CXCL9 most significantly repressed CT26 tumor growth. Overall, TNFSF9 and TNFSF18 exhibited stronger lymphocyte-stimulating and antitumor activities than TNFSF4. Our study provides evidence that antitumor effects of agonism of different costimulatory receptors may vary in different tumor types and presents a promising approach for targeted delivery of TNF superfamily costimulatory ligands to avoid the systemic toxicities and side effects associated with immune agonist antibodies.
Collapse
Affiliation(s)
- Liming Gui
- Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Zhixue Wang
- Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Weihua Lou
- Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Vahid Yekehfallah
- Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China; Current address: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Mohsen Basiri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Wei-Qiang Gao
- Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - You Wang
- Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Bin Ma
- Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
|
19
|
Kitaeva KV, Solovyeva VV, Blatt NL, Rizvanov AA. Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies. Int J Mol Sci 2024; 25:643. [PMID: 38203812 PMCID: PMC10778954 DOI: 10.3390/ijms25010643] [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: 11/08/2023] [Revised: 12/21/2023] [Accepted: 12/30/2023] [Indexed: 01/12/2024] Open
Abstract
The improvement of human living conditions has led to an increase in average life expectancy, creating a new social and medical problem-aging, which diminishes the overall quality of human life. The aging process of the body begins with the activation of effector signaling pathways of aging in cells, resulting in the loss of their normal functions and deleterious effects on the microenvironment. This, in turn, leads to chronic inflammation and similar transformations in neighboring cells. The cumulative retention of these senescent cells over a prolonged period results in the deterioration of tissues and organs, ultimately leading to a reduced quality of life and an elevated risk of mortality. Among the most promising methods for addressing aging and age-related illnesses are pharmacological, genetic, and cellular therapies. Elevating the activity of aging-suppressing genes, employing specific groups of native and genetically modified cells, and utilizing senolytic medications may offer the potential to delay aging and age-related ailments over the long term. This review explores strategies and advancements in the field of anti-aging therapies currently under investigation, with a particular emphasis on gene therapy involving adeno-associated vectors and cell-based therapeutic approaches.
Collapse
Affiliation(s)
- Kristina V. Kitaeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.V.K.); (V.V.S.); (N.L.B.)
| | - Valeriya V. Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.V.K.); (V.V.S.); (N.L.B.)
| | - Nataliya L. Blatt
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.V.K.); (V.V.S.); (N.L.B.)
| | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (K.V.K.); (V.V.S.); (N.L.B.)
- Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, 420111 Kazan, Russia
| |
Collapse
|
|
20
|
E VB, Ranganath Pai KS. Stem Cells and Tumor-Killing Virus to Target Brain Tumor: In Pursuit to Bring a Potential Delivery Vehicle for the Central Nervous System Tumors. Curr Drug Deliv 2024; 21:2-15. [PMID: 36825709 DOI: 10.2174/1567201820666230220101052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 12/08/2022] [Accepted: 12/28/2022] [Indexed: 02/22/2023]
Abstract
To target brain cancer, various therapeutic options are present to fight against cancer cells. But the existing therapies are not showing a proper curation of cancer patients. Henceforth, activating the immune cells and targeting oncogenes/proteins might be an emerging therapeutic approach to target and destroy malignant brain tumor. Stem cells (SCs) are considered potential immunomodulators that trigger the highly suppressed immune system in the tumor microenvironment. Also, engineered SCs can repress the aberrantly expressed oncoproteins that cause tumor cell proliferation and growth. SCs have an excellent migration capability to reach the infected site and support the regeneration of damaged blood vessels and tissues. Likewise, oncolytic virotherapy (OVT) is a promising novel therapeutic molecule in which genetically modified viruses can selectively replicate and destroy cancer cells without harming healthy cells. Same as SCs, oncolytic viruses (OVs) tend to stimulate the host's innate and adaptive immune response to battle against the advanced brain tumor. In clinical studies, various OVs have shown good immunogenic responses with a high safety profile and tolerability against cancer patients with reduced morbidity and mortality rate. SCs act as an attractive cargo for OVs which helps to influence the tumor site and destroy the tumor volume. SCs protect the OVs from systemic degradation and promote therapeutic efficacy against cancer cells. SCs carried OVs might be a potential therapeutic way to bring an effective treatment option for brain tumors.
Collapse
Affiliation(s)
- Vignesh Balaji E
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| |
Collapse
|
|
21
|
Yue M, Hu S, Sun H, Tuo B, Jia B, Chen C, Wang W, Liu J, Liu Y, Sun Z, Hu J. Extracellular vesicles remodel tumor environment for cancer immunotherapy. Mol Cancer 2023; 22:203. [PMID: 38087360 PMCID: PMC10717809 DOI: 10.1186/s12943-023-01898-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023] Open
Abstract
Tumor immunotherapy has transformed neoplastic disease management, yet low response rates and immune complications persist as major challenges. Extracellular vesicles including exosomes have emerged as therapeutic agents actively involved in a diverse range of pathological conditions. Mounting evidence suggests that alterations in the quantity and composition of extracellular vesicles (EVs) contribute to the remodeling of the immune-suppressive tumor microenvironment (TME), thereby influencing the efficacy of immunotherapy. This revelation has sparked clinical interest in utilizing EVs for immune sensitization. In this perspective article, we present a comprehensive overview of the origins, generation, and interplay among various components of EVs within the TME. Furthermore, we discuss the pivotal role of EVs in reshaping the TME during tumorigenesis and their specific cargo, such as PD-1 and non-coding RNA, which influence the phenotypes of critical immune cells within the TME. Additionally, we summarize the applications of EVs in different anti-tumor therapies, the latest advancements in engineering EVs for cancer immunotherapy, and the challenges encountered in clinical translation. In light of these findings, we advocate for a broader understanding of the impact of EVs on the TME, as this will unveil overlooked therapeutic vulnerabilities and potentially enhance the efficacy of existing cancer immunotherapies.
Collapse
Affiliation(s)
- Ming Yue
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Shengyun Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Haifeng Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Baojing Tuo
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Bin Jia
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chen Chen
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Wenkang Wang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jinbo Liu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yang Liu
- Department of Radiotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450001, China.
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Junhong Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| |
Collapse
|
|
22
|
Hu D, Tian Y, Xu J, Xie D, Wang Y, Liu M, Wang Y, Yang L. Oncolytic viral therapy as promising immunotherapy against glioma. MEDCOMM – FUTURE MEDICINE 2023; 2. [DOI: 10.1002/mef2.61] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 09/22/2023] [Indexed: 03/19/2025]
Abstract
AbstractGlioma is a common primary central nervous system malignant tumor in clinical, traditional methods such as surgery and chemoradiotherapy are not effective in treatment. Therefore, more effective treatments need to be found. Oncolytic viruses (OVs) are a new type of immunotherapy that selectively infects and kills tumor cells instead of normal cells. OVs can mediate antitumor immune responses through a variety of mechanisms, and have the ability to activate antitumor immune responses, transform the tumor microenvironment from “cold” to “hot,” and enhance the efficacy of immune checkpoint inhibitors. Recently, a large number of preclinical and clinical studies have shown that OVs show great prospects in the treatment of gliomas. In this review, we summarize the current status of glioma therapies with a focus on OVs. First, this article introduces the current status of treatment of glioma and their respective shortcomings. Then, the important progress of OVs of in clinical trials of glioma is summarized. Finally, the urgent challenges of oncolytic virus treatment for glioma are sorted out, and related solutions are proposed. This review will help to further promote the use of OVs in the treatment of glioma.
Collapse
Affiliation(s)
- Die Hu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
| | - Yaomei Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
- College of Bioengineering Sichuan University of Science & Engineering Zigong China
| | - Jie Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
| | - Daoyuan Xie
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
| | - Yusi Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
| | - Mohan Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
| | - Yuanda Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
| | - Li Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital Sichuan University Chengdu China
| |
Collapse
|
|
23
|
Xing Z, Lin D, Hong Y, Ma Z, Jiang H, Lu Y, Sun J, Song J, Xie L, Yang M, Xie X, Wang T, Zhou H, Chen X, Wang X, Gao J. Construction of a prognostic 6-gene signature for breast cancer based on multi-omics and single-cell data. Front Oncol 2023; 13:1186858. [PMID: 38074669 PMCID: PMC10698552 DOI: 10.3389/fonc.2023.1186858] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 10/25/2023] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Breast cancer (BC) is one of the females' most common malignant tumors there are large individual differences in its prognosis. We intended to uncover novel useful genetic biomarkers and a risk signature for BC to aid determining clinical strategies. METHODS A combined significance (p combined) was calculated for each gene by Fisher's method based on the RNA-seq, CNV, and DNA methylation data from TCGA-BRCA. Genes with a p combined< 0.01 were subjected to univariate cox and Lasso regression, whereby an RS signature was established. The predicted performance of the RS signature would be assessed in GSE7390 and GSE20685, and emphatically analyzed in triple-negative breast cancer (TNBC) patients, while the expression of immune checkpoints and drug sensitivity were also examined. GSE176078, a single-cell dataset, was used to validate the differences in cellular composition in tumors between TNBC patients with different RS. RESULTS The RS signature consisted of C15orf52, C1orf228, CEL, FUZ, PAK6, and SIRPG showed good performance. It could distinguish the prognosis of patients well, even stratified by disease stages or subtypes and also showed a stronger predictive ability than traditional clinical indicators. The down-regulated expressions of many immune checkpoints, while the decreased sensitivity of many antitumor drugs was observed in TNBC patients with higher RS. The overall cells and lymphocytes composition differed between patients with different RS, which could facilitate a more personalized treatment. CONCLUSION The six genes RS signature established based on multi-omics data exhibited well performance in predicting the prognosis of BC patients, regardless of disease stages or subtypes. Contributing to a more personalized treatment, our signature might benefit the outcome of BC patients.
Collapse
Affiliation(s)
- Zeyu Xing
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dongcai Lin
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Yuting Hong
- Department of Scientific Research Projects, Beijing ChosenMed Clinical Laboratory Co. Ltd., Beijing, China
| | - Zihuan Ma
- Department of Scientific Research Projects, Beijing ChosenMed Clinical Laboratory Co. Ltd., Beijing, China
| | - Hongnan Jiang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Ye Lu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Jiale Sun
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Jiarui Song
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Li Xie
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Man Yang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Xintong Xie
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Tianyu Wang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Hong Zhou
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Xiaoqi Chen
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Xiang Wang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jidong Gao
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| |
Collapse
|
|
24
|
Coccè V, Bonelli M, La Monica S, Alfieri R, Doneda L, Martegani E, Alessandri G, Lagrasta CA, Giannì A, Sordi V, Petrella F, Roncoroni L, Paino F, Pessina A. Mesenchymal stromal cells loaded with Paclitaxel (PacliMES) a potential new therapeutic approach on mesothelioma. Biochem Pharmacol 2023; 214:115678. [PMID: 37399948 DOI: 10.1016/j.bcp.2023.115678] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/19/2023] [Accepted: 06/29/2023] [Indexed: 07/05/2023]
Abstract
Malignant pleural mesothelioma is an asbestos-related tumor originating in mesothelial cells of the pleura that poorly responds to chemotherapeutic approaches. Adult mesenchymal stromal cells derived either from bone marrow or from adipose tissue may be considered a good model for cell-based therapy, a treatment which has experienced significant interest in recent years. The present study confirms that Paclitaxel is effective on mesothelioma cell proliferation in 2D and 3D in vitro cultures, and that 80,000 mesenchymal stromal cells loaded with Paclitaxel inhibit tumor growth at a higher extent than Paclitaxel alone. An in vivo approach to treat in situ mesothelioma xenografts using a minimal amount of 106 mesenchymal stromal cells loaded with Paclitaxel showed the same efficacy of a systemic administration of 10 mg/kg of Paclitaxel. These data strongly support drug delivery system by mesenchymal stromal cells as a useful approach against many solid tumors. We look with interest at the favourable opinion recently expressed by the Italian Drug Agency on the procedure for the preparation of mesenchymal stromal cells loaded with Paclitaxel in large-scale bioreactor systems and their storage until clinical use. This new Advanced Medicinal Therapy Product, already approved for a Phase I clinical trial on mesothelioma patients, could pave the way for mesenchymal stromal cells use as drug delivery system on other solid tumors for adjuvant therapy associated with surgery and radiotherapy.
Collapse
Affiliation(s)
- Valentina Coccè
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Mara Bonelli
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Silvia La Monica
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Luisa Doneda
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Eleonora Martegani
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Giulio Alessandri
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | | | - Aldo Giannì
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Hospital, 20132 Milan, Italy
| | - Francesco Petrella
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; Department of Thoracic Surgery, IRCCS European Institute of Oncology, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Leda Roncoroni
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; Center for Prevention and Diagnosis of Celiac Disease, Gastroenterology and Endoscopy Unit. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Francesca Paino
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Augusto Pessina
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| |
Collapse
|
|
25
|
Chatree K, Sriboonaied P, Phetkong C, Wattananit W, Chanchao C, Charoenpanich A. Distinctions in bone matrix nanostructure, composition, and formation between osteoblast-like cells, MG-63, and human mesenchymal stem cells, UE7T-13. Heliyon 2023; 9:e15556. [PMID: 37153435 PMCID: PMC10160763 DOI: 10.1016/j.heliyon.2023.e15556] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 04/07/2023] [Accepted: 04/13/2023] [Indexed: 05/09/2023] Open
Abstract
Osteoblast-like cells and human mesenchymal stem cells (hMSCs) are frequently employed as osteoprogenitor cell models for evaluating novel biomaterials in bone healing and tissue engineering. In this study, the characterization of UE7T-13 hMSCs and MG-63 human osteoblast-like cells was examined. Both cells can undergo osteogenesis and produce calcium extracellular matrix; however, calcium nodules produced by MG-63 lacked a central mass and appeared flatter than UE7T-13. The absence of growing calcium nodules in MG-63 was discovered by SEM-EDX to be associated with the formation of alternating layers of cells and calcium extracellular matrix. The nanostructure and composition analysis showed that UE7T-13 had a finer nanostructure of calcium nodules with a higher calcium/phosphate ratio than MG-63. Both cells expressed high intrinsic levels of collagen type I alpha 1 chain, while only UE7T-13 expressed high levels of alkaline phosphatase, biomineralization associated (ALPL). High ALP activity in UE7T-13 was not further enhanced by osteogenic induction, but in MG-63, low intrinsic ALP activity was greatly induced by osteogenic induction. These findings highlight the differences between the two immortal osteoprogenitor cell lines, along with some technical notes that should be considered while selecting and interpreting the pertinent in vitro model.
Collapse
Affiliation(s)
- Kamonwan Chatree
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Patsawee Sriboonaied
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Chinnatam Phetkong
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Witoon Wattananit
- Scientific and Technological Equipment Centre, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Chanpen Chanchao
- Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Adisri Charoenpanich
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| |
Collapse
|
|
26
|
Wang X, Zhu X, Wang D, Li X, Wang J, Yin G, Huang Z, Pu X. Identification of a Specific Phage as Growth Factor Alternative Promoting the Recruitment and Differentiation of MSCs in Bone Tissue Regeneration. ACS Biomater Sci Eng 2023; 9:2426-2437. [PMID: 37023478 DOI: 10.1021/acsbiomaterials.2c01538] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Inefficient use and loss of exogenously implanted mesenchymal stem cells (MSCs) are major concerns in MSCs-based bone tissue engineering. It is a promising approach to overcome the above issues by recruiting and regulation of endogenous MSCs. However, there are few substances that can recruit MSCs effectively and specifically to the site of bone injury. In this study, we identified a phage clone (termed P11) with specific affinity for MSCs through phage display biopanning, and further investigated the effects of P11 on the cytological behavior of MSCs and macrophages. The results showed that P11 could bind MSCs specifically and promote the proliferation and migration of MSCs. Meanwhile, P11 could polarize macrophages to the M1 phenotype and significantly changed their morphology, which further enhanced the chemotaxis of MSCs. Additionally, RNA-seq results revealed that P11 could promote the secretion of osteogenesis-related markers in MSCs through the TPL2-MEK-ERK signaling pathway. Altogether, P11 has great potential to be used as growth factor alternatives in bone tissue engineering, with the advantages of cheaper and stable activity. Our study also advances the understanding of the effects of phages on macrophages and MSCs, and provides a new idea for the development in the field of phage-based tissue engineering.
Collapse
Affiliation(s)
- Xingming Wang
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, People's Republic of China
| | - Xiupeng Zhu
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, People's Republic of China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China
| | - Danni Wang
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, People's Republic of China
| | - Xiaoxu Li
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, People's Republic of China
| | - Juan Wang
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, People's Republic of China
| | - Guangfu Yin
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, People's Republic of China
| | - Zhongbing Huang
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, People's Republic of China
| | - Ximing Pu
- College of Biomedical Engineering, Sichuan University, Chengdu 610065, People's Republic of China
| |
Collapse
|
|
27
|
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: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [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.
Collapse
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
| |
Collapse
|
|
28
|
TLR3 stimulation improves the migratory potency of adipose-derived mesenchymal stem cells through the stress response pathway in the melanoma mouse model. Mol Biol Rep 2023; 50:2293-2304. [PMID: 36575321 DOI: 10.1007/s11033-022-08111-8] [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: 07/09/2022] [Accepted: 11/09/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are utilized as a carrier of anti-tumor agents in targeted anti-cancer therapy. Despite the improvements in this area, there are still some unsolved issues in determining the appropriate dose, method of administration and biodistribution of MSCs. The current study aimed to determine the influence of toll-like receptor 3 (TLR3) stimulation on the potential of MSCs migration to the neoplasm environment in the mouse melanoma model. METHODS AND RESULTS Adipose-derived MSCs (ADMSCs) were isolated from the GFP+ transgenic C57BL/6 mouse and treated with different doses (1 µg/ml and 10 µg/ml) of polyinosinic-polycytidylic acid, the related TLR3 agonist, at various time points (1 and 4 h). Following the treatment, the expression of targeted genes such as α4, α5, and β1 integrins and TGF-β and IL-10 anti-inflammatory cytokines was determined using real-time PCR. In vivo live imaging evaluated the migration index of the intraperitoneally (IP) injected treated ADMSCs in a lung tumor-bearing mouse (C57BL/6) melanoma model (n = 5). The presented findings demonstrated that TLR3 stimulation enhanced both migration of ADMSCs to the tumor area compared with control group (n = 5) and expression of α4, α5, and β1 integrins. It was also detected that the engagement of TLR3 resulted in the anti-inflammatory behavior of the cells, which might influence the directed movement of ADMSCs. CONCLUSION This research identified that TLR3 activation might improve the migration via the stimulation of stress response in the cells and depending on the agonist concentration and time exposure, this activated pathway drives the migratory behavior of MSCs.
Collapse
|
|
29
|
Ghasemi Darestani N, Gilmanova AI, Al-Gazally ME, Zekiy AO, Ansari MJ, Zabibah RS, Jawad MA, Al-Shalah SAJ, Rizaev JA, Alnassar YS, Mohammed NM, Mustafa YF, Darvishi M, Akhavan-Sigari R. Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment. Cell Commun Signal 2023; 21:43. [PMID: 36829187 PMCID: PMC9960453 DOI: 10.1186/s12964-022-01012-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/10/2022] [Indexed: 02/26/2023] Open
Abstract
Oncolytic viruses (OVs) infect, multiply, and finally remove tumor cells selectively, causing no damage to normal cells in the process. Because of their specific features, such as, the ability to induce immunogenic cell death and to contain curative transgenes in their genomes, OVs have attracted attention as candidates to be utilized in cooperation with immunotherapies for cancer treatment. This treatment takes advantage of most tumor cells' inherent tendency to be infected by certain OVs and both innate and adaptive immune responses are elicited by OV infection and oncolysis. OVs can also modulate tumor microenvironment and boost anti-tumor immune responses. Mesenchymal stem cells (MSC) are gathering interest as promising anti-cancer treatments with the ability to address a wide range of cancers. MSCs exhibit tumor-trophic migration characteristics, allowing them to be used as delivery vehicles for successful, targeted treatment of isolated tumors and metastatic malignancies. Preclinical and clinical research were reviewed in this study to discuss using MSC-released OVs as a novel method for the treatment of cancer. Video Abstract.
Collapse
Affiliation(s)
| | - Anna I Gilmanova
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | | | - Angelina O Zekiy
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Saif A J Al-Shalah
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Iraq
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, Samarkand, Uzbekistan
| | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Mohammad Darvishi
- Department of Aerospace and Subaquatic Medicine, Infectious Diseases and Tropical Medicine Research Center (IDTMRC), AJA University of Medical Sciences, Tehran, Iran.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany.,Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
| |
Collapse
|
|
30
|
Xu L, Xu M, Sun X, Feliu N, Feng L, Parak WJ, Liu S. Quantitative Comparison of Gold Nanoparticle Delivery via the Enhanced Permeation and Retention (EPR) Effect and Mesenchymal Stem Cell (MSC)-Based Targeting. ACS NANO 2023; 17:2039-2052. [PMID: 36717361 DOI: 10.1021/acsnano.2c07295] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
There are still some gaps in existing knowledge in the field of cancer nanotheranostics, e.g., the efficiency of nanoparticle-loaded cells for targeted delivery. In the current study, gold nanoparticles (Au NPs) were delivered to tumors in both subcutaneous tumor and lung metastasis tumor models by intravenous injection of either free Au NPs or of human bone marrow mesenchymal stem cells (MSCs), which were loaded with endocytosed Au NPs. By making injections with the same dose of administrated Au NPs, it was possible to directly compare tumor targeting of both delivery modes. Hereby, the passive targeting of tumor by the plain Au NPs was facilitated by the enhanced permeation and retention (EPR) effect. Au NP retention by tumors, as well as tumor penetration, were found to be improved up to 2.4-to-9.3-fold when comparing the MSC-mediated delivery of Au NPs to the delivery of the plain Au NPs via EPR effect on day 7 post administration. While the absolute retention of Au NPs in the tumor remained low, our data show that, upon injection of the same amount of Au NPs, in fact MSC-mediated delivery is quantitatively higher than EPR-mediated delivery of NPs by half an order of magnitude.
Collapse
Affiliation(s)
- Lining Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ming Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xing Sun
- Center for Hybrid Nanostructures (CHyN), Universität Hamburg, 22607 Hamburg, Germany
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Neus Feliu
- Fraunhofer Center for Applied Nanotechnology (CAN), 20146 Hamburg, Germany
| | - Liuxing Feng
- Division of Metrology in Chemistry, National Institute of Metrology, Beijing 100013, China
| | - Wolfgang J Parak
- Center for Hybrid Nanostructures (CHyN), Universität Hamburg, 22607 Hamburg, Germany
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| |
Collapse
|
|
31
|
Efficient Liposome Loading onto Surface of Mesenchymal Stem Cells via Electrostatic Interactions for Tumor-Targeted Drug Delivery. Biomedicines 2023; 11:biomedicines11020558. [PMID: 36831094 PMCID: PMC9953681 DOI: 10.3390/biomedicines11020558] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/06/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have a tumor-homing capacity; therefore, MSCs are a promising drug delivery carrier for cancer therapy. To maintain the viability and activity of MSCs, anti-cancer drugs are preferably loaded on the surface of MSCs, rather than directly introduced into MSCs. In this study, we attempted to load liposomes on the surface of MSCs by using the magnetic anionic liposome/atelocollagen complexes that we previously developed and assessed the characters of liposome-loaded MSCs as drug carriers. We observed that large-sized magnetic anionic liposome/atelocollagen complexes were abundantly associated with MSCs via electrostatic interactions under a magnetic field, and its cellular internalization was lower than that of the small-sized complexes. Moreover, the complexes with higher atelocollagen concentrations showed lower cellular internalization than the complexes with lower atelocollagen concentrations. Based on these results, we succeeded in the efficient loading of liposomes on the surface of MSCs by using large-sized magnetic anionic liposomes complexed with a high concentration of atelocollagen. The constructed liposome-loaded MSCs showed a comparable proliferation rate and differentiation potential to non-loaded MSCs. Furthermore, the liposome-loaded MSCs efficiently adhered to vascular endothelial cells and migrated toward the conditioned medium from cancer cells in vitro and solid tumor tissue in vivo. These findings suggest that liposome-loaded MSCs could serve as an efficient cell-based drug carrier for tumor-targeted delivery.
Collapse
|
|
32
|
Ma Z, Hua J, Liu J, Zhang B, Wang W, Yu X, Xu J. Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges. Int J Mol Sci 2023; 24:3559. [PMID: 36834969 PMCID: PMC9966548 DOI: 10.3390/ijms24043559] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 02/01/2023] [Indexed: 02/12/2023] Open
Abstract
Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer.
Collapse
Affiliation(s)
- Zhilong Ma
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
33
|
Chulpanova DS, Pukhalskaia TV, Gilazieva ZE, Filina YV, Mansurova MN, Rizvanov AA, Solovyeva VV. Cytochalasin B-Induced Membrane Vesicles from TRAIL-Overexpressing Mesenchymal Stem Cells Induce Extrinsic Pathway of Apoptosis in Breast Cancer Mouse Model. Curr Issues Mol Biol 2023; 45:571-592. [PMID: 36661524 PMCID: PMC9857211 DOI: 10.3390/cimb45010038] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/27/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
Tumor-necrosis-factor-associated apoptosis-inducing ligand (TRAIL) is one of the most promising therapeutic cytokines that selectively induce apoptosis in tumor cells. It is known that membrane vesicles (MVs) can carry the surface markers of parental cells. Therefore, MVs are of interest as a tool for cell-free cancer therapy. In this study, membrane vesicles were isolated from TRAIL-overexpressing mesenchymal stem cells using cytochalasin B treatment (CIMVs). To evaluate the antitumor effect of CIMVs-TRAIL in vivo, a breast cancer mouse model was produced. The animals were intratumorally injected with 50 µg of native CIMVs or CIMVs-TRAIL for 12 days with an interval of two days. Then, tumor growth rate, tumor necrotic area, the expression of the apoptosis-related genes CASP8, BCL-2, and BAX and the level of CASP8 protein were analyzed. A 1.8-fold increase in the CAS8 gene mRNA and a 1.7-fold increase in the CASP8 protein level were observed in the tumors injected with CIMVs-TRAIL. The expression of the anti-apoptotic BCL-2 gene in the CIMV-TRAIL group remained unchanged, while the mRNA level of the pro-apoptotic BAX gene was increased by 1.4 times, which indicated apoptosis activation in the tumor tissue. Thus, CIMVs-TRAIL were able to activate the extrinsic apoptosis pathway and induce tumor cell death in the breast cancer mouse model.
Collapse
|
|
34
|
The Role of Cancer Stem Cells and Their Extracellular Vesicles in the Modulation of the Antitumor Immunity. Int J Mol Sci 2022; 24:ijms24010395. [PMID: 36613838 PMCID: PMC9820747 DOI: 10.3390/ijms24010395] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Cancer stem cells (CSCs) are a population of tumor cells that share similar properties to normal stem cells. CSCs are able to promote tumor progression and recurrence due to their resistance to chemotherapy and ability to stimulate angiogenesis and differentiate into non-CSCs. Cancer stem cells can also create a significant immunosuppressive environment around themselves by suppressing the activity of effector immune cells and recruiting cells that support tumor escape from immune response. The immunosuppressive effect of CSCs can be mediated by receptors located on their surface, as well as by secreted molecules, which transfer immunosuppressive signals to the cells of tumor microenvironment. In this article, the ability of CSCs to regulate the antitumor immune response and a contribution of CSC-derived EVs into the avoidance of the immune response are discussed.
Collapse
|
|
35
|
Park JH, Choe HS, Kim SW, Im GB, Um SH, Kim JH, Bhang SH. Silica-Capped and Gold-Decorated Silica Nanoparticles for Enhancing Effect of Gold Nanoparticle-Based Photothermal Therapy. Tissue Eng Regen Med 2022; 19:1161-1168. [PMID: 36006602 PMCID: PMC9679086 DOI: 10.1007/s13770-022-00468-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/04/2022] [Accepted: 06/07/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Various methods based on gold nanoparticles (AuNPs) have been applied to enhance the photothermal effect. Among these methods, combining gold nanoparticles and stem cells has been suggested as a new technique for elevating the efficiency of photothermal therapy (PT) in terms of enhancing tumor targeting effect. However, to elicit the efficiency of PT using gold nanoparticles and stem cells, delivering large amounts of AuNPs into stem cells without loss should be considered. METHODS AuNPs, AuNPs-decorated silica nanoparticles, and silica-capped and AuNPs-decorated silica nanoparticles (SGSs) were synthesized and used to treat human mesenchymal stem cells (hMSCs). After evaluating physical properties of each nanoparticle, the concentration of each nanoparticle was estimated based on its cytotoxicity to hMSCs. The amount of AuNPs loss from each nanoparticle by exogenous physical stress was evaluated after exposing particles to a gentle shaking. After these experiments, in vitro and in vivo photothermal effects were then evaluated. RESULTS SGS showed no cytotoxicity when it was used to treat hMSCs at concentration up to 20 μg/mL. After intravenous injection to tumor-bearing mice, SGS-laden hMSCs group showed significantly higher heat generation than other groups following laser irradiation. Furthermore, in vivo photothermal effect in the hMSC-SGS group was significantly enhanced than those in other groups in terms of tumor volume decrement and histological outcome. CONCLUSION Our results suggest that additional silica layer in SGSs could protect AuNPs from physical stress induced AuNPs loss. The strategy applied in SGS may offer a prospective method to improve PT.
Collapse
Affiliation(s)
- Jung Hwan Park
- School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Hyun-Seok Choe
- Department of Chemical and Environmental Engineering, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Pusan, 46241, Republic of Korea
| | - Sung-Won Kim
- School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Gwang-Bum Im
- School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Soong Ho Um
- School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Jae-Hyuk Kim
- Department of Chemical and Environmental Engineering, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Pusan, 46241, Republic of Korea.
| | - Suk Ho Bhang
- School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea.
| |
Collapse
|
|
36
|
Bae J, Liu L, Moore C, Hsu E, Zhang A, Ren Z, Sun Z, Wang X, Zhu J, Shen J, Qiao J, Fu YX. IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8 + T cells to overcome immunotherapy resistance in cancer. Nat Cell Biol 2022; 24:1754-1765. [PMID: 36474070 DOI: 10.1038/s41556-022-01024-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 09/27/2022] [Indexed: 12/12/2022]
Abstract
Immune checkpoint blockade (ICB)-based immunotherapy depends on functional tumour-infiltrating lymphocytes (TILs), but essential cytokines are less understood. Here we uncover an essential role of endogenous IL-2 for ICB responsiveness and the correlation between insufficient IL-2 signalling and T-cell exhaustion as tumours progress. To determine if exogenous IL-2 in the tumour microenvironment can overcome ICB resistance, we engineered mesenchymal stem cells (MSCs) to successfully deliver IL-2 mutein dimer (SIL2-EMSC) to TILs. While MSCs have been used to suppress inflammation, SIL2-EMSCs elicit anti-tumour immunity and overcome ICB resistance without toxicity. Mechanistically, SIL2-EMSCs activate and expand pre-existing CD8+ TILs, sufficient for tumour control and induction of systemic anti-tumour effects. Furthermore, engineered MSCs create synergy of innate and adaptive immunity. The therapeutic benefits of SIL2-EMSCs were also observed in humanized mouse models. Overall, engineered MSCs rejuvenate CD8+ TILs and thus potentiate ICB and chemotherapy.
Collapse
Affiliation(s)
- Joonbeom Bae
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Longchao Liu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Casey Moore
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Eric Hsu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Anli Zhang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Zhenhua Ren
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Zhichen Sun
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xue Wang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jiankun Zhu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jiao Shen
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jian Qiao
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Yang-Xin Fu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. .,Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
| |
Collapse
|
|
37
|
Song Y, Li R, Ye M, Pan C, Zheng L, Wang ZW, Zhu X. Differences in chemotaxis of human mesenchymal stem cells and cervical cancer cells. Apoptosis 2022; 27:840-851. [PMID: 35849265 DOI: 10.1007/s10495-022-01749-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2022] [Indexed: 11/30/2022]
Abstract
In the last decade, there has been a rapid expansion in tumor targeted therapy using mesenchymal stem cells (MSCs) based on their unique tropism towards cancer cells. Despite similarities in morphology, immunophenotype, and differential potent in vitro, MSCs originated from different tissues do not necessarily have equivalent biological behaviors. It is important to screen the most chemotactic MSCs to cancer cells. In this study, different MSCs were isolated from various human tissues including adipose, umbilical cord, amniotic membrane, and chorion. The chemotaxis of human MSCs to cervical cancer cells was measured by CCK-8, ELISA and Transwell invasion assays. Western blotting was performed to explore the underlying mechanisms. MSCs derived from distinct sources can be differently recruited to cervical cancer cells, among which chorion-derived MSC (CD-MSC) possessed the strongest tropic capacity. CXCL12 was found to be highly secreted by cervical cancer cells, in parallel with the expression of CXCR4 in all MSCs. CD-MSC displayed the highest level of CXCR4. These results indicated that CXCL12/CXCR4 pathway contributed to the different chemotaxis to cervical cancer cells of each MSCs. This study proposed that CD-MSC with the highest CXCR4 expression is a promising therapeutic vehicle for targeted therapy in cervical cancer.
Collapse
Affiliation(s)
- Yizuo Song
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Ruyi Li
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Miaomiao Ye
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Chunyu Pan
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Lihong Zheng
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China
| | - Zhi-Wei Wang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China.
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027, Zhejiang, China.
| |
Collapse
|
|
38
|
Qu Q, Liu L, Cui Y, Chen Y, Wang Y, Wang Y. Exosomes from Human Omental Adipose-Derived Mesenchymal Stem Cells Secreted into Ascites Promote Peritoneal Metastasis of Epithelial Ovarian Cancer. Cells 2022; 11:3392. [PMID: 36359787 PMCID: PMC9655202 DOI: 10.3390/cells11213392] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/13/2022] [Accepted: 10/19/2022] [Indexed: 03/26/2024] Open
Abstract
Epithelial ovarian cancer (EOC) patients frequently develop peritoneal metastasis, especially in the human omentum. However, the mechanism underlying this propensity remains unknown. A previous study found that human omental adipose-derived mesenchymal stem cells are potentially involved in ovarian cancer growth and metastasis, but the results were inconsistent and even contradictory. In addition, the underlying mechanisms of visceral adipose metastasis remain poorly understood. Here, our goal is to clarify the role and mechanism of human omental adipose-derived mesenchymal stem cells (HO-ADSCs) in EOC cancer growth and metastasis. We first found that human omental tissue conditioned medium (HO-CM) enhances EOC cell function. Subsequent coculture studies indicated that HO-ADSCs increase the growth, migratory and invasive capabilities of ovarian cancer cells. Then, we demonstrated that exosomes secreted by HO-ADSCs (HO-ADSC exosomes) enhanced ovarian cancer cell function, and further mechanistic studies showed that the FOXM1, Cyclin F, KIF20A, and MAPK signaling pathways were involved in this process. In addition, subcutaneous tumorigenesis and peritoneal metastatic xenograft experiments provided evidence that HO-ADSC exosomes promote ovarian cancer growth and metastasis in vivo. Finally, our clinical studies provided evidence that ascites from ovarian cancer patients enhance EOC cell line proliferation, migration, and invasion in vitro. The present study indicated that HO-ADSC exosomes are secreted into ascites and exert a tumor-promoting effect on EOC growth and metastasis, providing a new perspective and method to develop future novel therapeutic strategies for the treatment of ovarian cancer.
Collapse
Affiliation(s)
- Qingxi Qu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Linghong Liu
- Research Center of Stem Cell and Regenerative Medicine, Shandong University, Jinan 250012, China
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yuqian Cui
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yu Chen
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yu Wang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yaodu Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, China
| |
Collapse
|
|
39
|
Emerging mechanisms of pyroptosis and its therapeutic strategy in cancer. Cell Death Dis 2022; 8:338. [PMID: 35896522 PMCID: PMC9329358 DOI: 10.1038/s41420-022-01101-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 12/20/2022]
Abstract
Pyroptosis, a type of inflammatory programmed cell death, is triggered by caspase cleavage of gasdermin family proteins. Based on accumulating evidence, pyroptosis is closely associated with tumour development, but the molecular mechanism underlying pyroptosis activation and the signalling pathways regulated by pyroptosis remain unclear. In this review, we first briefly introduce the definition, morphological characteristics, and activation pathways of pyroptosis and the effect of pyroptosis on anticancer immunity. Then we review recent progress concerning the complex role of pyroptosis in various tumours. Importantly, we summarise various FDA-approved chemotherapy drugs or natural compounds that exerted antitumor properties by inducing pyroptosis of cancer cells. Moreover, we also focus on the current application of nanotechnology-induced pyroptosis in tumour therapy. In addition, some unsolved problems and potential future research directions are also raised.
Collapse
|
|
40
|
Darvishi F, Jahanafrooz Z, Mokhtarzadeh A. Microbial L-asparaginase as a promising enzyme for treatment of various cancers. Appl Microbiol Biotechnol 2022; 106:5335-5347. [DOI: 10.1007/s00253-022-12086-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 11/30/2022]
|
|
41
|
Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185:114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 12/16/2022]
Abstract
The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.
Collapse
|
|
42
|
Pretreatment of umbilical cord derived MSCs with IFN-γ and TNF-α enhances the tumor-suppressive effect on acute myeloid leukemia. Biochem Pharmacol 2022; 199:115007. [DOI: 10.1016/j.bcp.2022.115007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/09/2022] [Accepted: 03/13/2022] [Indexed: 01/27/2023]
|
|
43
|
Sanmartin MC, Borzone FR, Giorello MB, Yannarelli G, Chasseing NA. Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Biological Carriers for Drug Delivery in Cancer Therapy. Front Bioeng Biotechnol 2022; 10:882545. [PMID: 35497332 PMCID: PMC9046597 DOI: 10.3389/fbioe.2022.882545] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/25/2022] [Indexed: 12/11/2022] Open
Abstract
Cancer is the second leading cause of death worldwide, with 10.0 million cancer deaths in 2020. Despite advances in targeted therapies, some pharmacological drawbacks associated with anticancer chemo and immunotherapeutic agents include high toxicities, low bioavailability, and drug resistance. In recent years, extracellular vesicles emerged as a new promising platform for drug delivery, with the advantage of their inherent biocompatibility and specific targeting compared to artificial nanocarriers, such as liposomes. Particularly, mesenchymal stem/stromal cells were proposed as a source of extracellular vesicles for cancer therapy because of their intrinsic properties: high in vitro self-renewal and proliferation, regenerative and immunomodulatory capacities, and secretion of extracellular vesicles that mediate most of their paracrine functions. Moreover, extracellular vesicles are static and safer in comparison with mesenchymal stem/stromal cells, which can undergo genetic/epigenetic or phenotypic changes after their administration to patients. In this review, we summarize currently reported information regarding mesenchymal stem/stromal cell-derived extracellular vesicles, their proper isolation and purification techniques - from either naive or engineered mesenchymal stem/stromal cells - for their application in cancer therapy, as well as available downstream modification methods to improve their therapeutic properties. Additionally, we discuss the challenges associated with extracellular vesicles for cancer therapy, and we review some preclinical and clinical data available in the literature.
Collapse
Affiliation(s)
- 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
| | - 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
| | - Gustavo Yannarelli
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro - CONICET, Buenos Aires, Argentina
| | - Norma Alejandra Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| |
Collapse
|
|
44
|
Analysis of the Interaction of Human Neuroblastoma Cell-Derived Cytochalasin B Induced Membrane Vesicles with Mesenchymal Stem Cells Using Imaging Flow Cytometry. BIONANOSCIENCE 2022; 12:293-301. [PMID: 35261871 PMCID: PMC8894839 DOI: 10.1007/s12668-021-00931-5] [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] [Accepted: 11/29/2021] [Indexed: 11/24/2022]
Abstract
At present, there is an increasing interest in the potential role of extracellular vesicles (EVs), acting as multi-signal messengers of the tumor stroma, in the development and progression of tumor. Tumor cell-derived EVs are considered a potential vector for the targeted delivery of antitumor agents due to the ability to fuse with parental cells through endocytosis and release their contents into the cytoplasm of the recipient cell. Tumor cell-derived EVs could be also used for priming immune cells and therapeutic vaccine development. It is also known that mesenchymal stem cells (MSCs) have a tropism toward tumor niches. It is believed that MSC migration to the tumor is due to its inflammatory signaling. Presumably, with the accumulation of MSCs at tumor sites, these cells differentiate into pericytes or tumor-associated fibroblasts, thereby forming a supporting tumor growth microenvironment. However, besides the ability to promote tumor progression, MSCs can also suppress its growth by inhibiting proliferation and cell cycle progression, and angiogenesis. Thus, the further studies of the MSC role in TME and MSC interaction with other cells of the tumor stroma, including through EVs, are of particular interest. To increase the yield of vesicles the isolation method based on pharmacological disorganization of the actin cytoskeleton induced by treating with cytochalasin B was used in this study. In this investigation the interaction of SH-SY5Y neuroblastoma cell-derived membrane vesicles, obtained using cytochalasin B (CIMVs), with human bone marrow-derived MSCs was analyzed using imaging flow cytometry. Using transmission electron microscopy, it was shown that CIMVs have a size similar to that of natural microvesicles, which is 100–1000 nm. Using imaging flow cytometry, it was shown that after 24 h of co-cultivation 6% of the MSCs contained a large number of CIMVs, and 42% of the MSCs contained a small amount of CIMVs. Cultivation of MSCs with SH-SY5Y cell-derived CIMVs also induced dose-dependent decrease in the expression of CD markers typical for MSCs. Thus, the internalization of SH-SY5Y cell-derived CIMVs within MSCs and the ability of the CIMVs to modulate immunophenotype of the recipient cells were shown. However, further studies are required to determine the effect of CIMVs on pro- or antioncogenic phenotype and function of MSCs.
Collapse
|
|
45
|
Szewc M, Radzikowska-Bűchner E, Wdowiak P, Kozak J, Kuszta P, Niezabitowska E, Matysiak J, Kubiński K, Masłyk M. MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents-A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives. Int J Mol Sci 2022; 23:2745. [PMID: 35269887 PMCID: PMC8911180 DOI: 10.3390/ijms23052745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure.
Collapse
Affiliation(s)
- Monika Szewc
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Elżbieta Radzikowska-Bűchner
- Department of Plastic, Reconstructive and Maxillary Surgery, Central Clinical Hospital MSWiA, 02-507 Warsaw, Poland;
| | - Paulina Wdowiak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Joanna Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Piotr Kuszta
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Ewa Niezabitowska
- Department of Urology and Urological Oncology, Multidisciplinary Hospital in Lublin, 20-400 Lublin, Poland;
| | - Joanna Matysiak
- Department of Chemistry, University of Life Sciences in Lublin, 20-950 Lublin, Poland;
| | - Konrad Kubiński
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
| | - Maciej Masłyk
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
| |
Collapse
|
|
46
|
Zhang Y, Liu C, Wang T, Kong F, Zhang H, Yi J, Dong X, Duan H, Tao N, Yang Y, Wang H. Therapeutic effects of mesenchymal stem cells loaded with oncolytic adenovirus carrying decorin on a breast cancer lung metastatic mouse model. Mol Ther Oncolytics 2022; 24:486-496. [PMID: 35229027 PMCID: PMC8850566 DOI: 10.1016/j.omto.2022.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 01/27/2022] [Indexed: 12/24/2022] Open
Abstract
Oncolytic adenoviruses (OAds) are alternative immune therapeutic strategies for tumors. However, liver uptake and antibody neutralization are two major barriers for systemic delivery during the treatment of tumor metastasis. Mesenchymal stem cells (MSCs) have emerged as potential vehicles to improve delivery. In this study, we loaded umbilical-cord-derived MSCs (UC-MSCs) with OAds expressing decorin (rAd.DCN) or without foreign genes (rAd.Null) to treat breast cancer lung metastasis. In vivo, rAd.Null, MSCs.Null, and rAd.DCN exhibited antitumor effects compared with other groups in a mouse model. Unexpectedly, MSCs.Null showed much greater antitumor responses than MSCs.DCN, including improved survival and reduced tumor burden. Compared with rAd.Null, both MSCs.Null and MSCs.DCN could improve the viral spread and distribution in metastatic tumor lesions in the lung. MSCs.DCN produced much more decorin in lungs than rAd.DCN; however, rAd.DCN reduced the downstream target genes of decorin much more strongly than MSCs.DCN, which was consistent with in vitro findings. In addition, rAd.DCN, MSCs.Null, and MSCs.DCN could reduce The cytokine levels in the lung. In conclusion, MSCs improved oncolytic adenoviral delivery and spread in tumor tissues and enhanced therapeutic effects. However, MSCs.DCN reduced OAd-evoked antitumor responses, possibly via a contact-dependent mechanism.
Collapse
|
|
47
|
Trébol J, Georgiev-Hristov T, Pascual-Miguelañez I, Guadalajara H, García-Arranz M, García-Olmo D. Stem cell therapy applied for digestive anastomosis: Current state and future perspectives. World J Stem Cells 2022; 14:117-141. [PMID: 35126832 PMCID: PMC8788180 DOI: 10.4252/wjsc.v14.i1.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/21/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Digestive tract resections are usually followed by an anastomosis. Anastomotic leakage, normally due to failed healing, is the most feared complication in digestive surgery because it is associated with high morbidity and mortality. Despite technical and technological advances and focused research, its rates have remained almost unchanged the last decades. In the last two decades, stem cells (SCs) have been shown to enhance healing in animal and human studies; hence, SCs have emerged since 2008 as an alternative to improve anastomoses outcomes. AIM To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture leaks. METHODS PubMed, Science Direct, Scopus and Cochrane searches were performed using the key words "anastomosis", "colorectal/colonic anastomoses", "anastomotic leak", "stem cells", "progenitor cells", "cellular therapy" and "cell therapy" in order to identify relevant articles published in English and Spanish during the years of 2000 to 2021. Studies employing SCs, performing digestive anastomoses in hollow viscera or digestive perforation sutures and monitoring healing were finally included. Reference lists from the selected articles were reviewed to identify additional pertinent articles.Given the great variability in the study designs, anastomotic models, interventions (SCs, doses and vehicles) and outcome measures, performing a reliable meta-analysis was considered impossible, so we present the studies, their results and limitations. RESULTS Eighteen preclinical studies and three review papers were identified; no clinical studies have been published and there are no registered clinical trials. Experimental studies, mainly in rat and porcine models and occasionally in very adverse conditions such as ischaemia or colitis, have been demonstrated SCs as safe and have shown some encouraging morphological, functional and even clinical results. Mesenchymal SCs are mostly employed, and delivery routes are mainly local injections and cell sheets followed by biosutures (sutures coated by SCs) or purely topical. As potential weaknesses, animal models need to be improved to make them more comparable and equivalent to clinical practice, and the SC isolation processes need to be standardised. There is notable heterogeneity in the studies, making them difficult to compare. Further investigations are needed to establish the indications, the administration system, potential adjuvants, the final efficacy and to confirm safety and exclude definitively oncological concerns. CONCLUSION The future role of SC therapy to induce healing processes in digestive anastomoses/sutures still needs to be determined and seems to be currently far from clinical use.
Collapse
Affiliation(s)
- Jacobo Trébol
- Servicio de Cirugía General y del Aparato Digestivo, Complejo Asistencial Universitario de Salamanca, Salamanca 37007, Spain
- Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, Salamanca 37007, Spain.
| | - Tihomir Georgiev-Hristov
- Servicio de Cirugía General y del Aparato Digestivo, Hospital General Universitario de Villalba, Madrid 28400, Spain
| | - Isabel Pascual-Miguelañez
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario La Paz, Madrid 28046, Spain
| | - Hector Guadalajara
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Mariano García-Arranz
- Grupo de Investigación en Nuevas Terapias, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damian García-Olmo
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz y Grupo Quiron-Salud Madrid, Madrid 28040, Spain
| |
Collapse
|
|
48
|
Vrana NE, Gupta S, Mitra K, Rizvanov AA, Solovyeva VV, Antmen E, Salehi M, Ehterami A, Pourchet L, Barthes J, Marquette CA, von Unge M, Wang CY, Lai PL, Bit A. From 3D printing to 3D bioprinting: the material properties of polymeric material and its derived bioink for achieving tissue specific architectures. Cell Tissue Bank 2022; 23:417-440. [PMID: 35000046 DOI: 10.1007/s10561-021-09975-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/31/2021] [Indexed: 12/22/2022]
Abstract
The application of 3D printing technologies fields for biological tissues, organs, and cells in the context of medical and biotechnology applications requires a significant amount of innovation in a narrow printability range. 3D bioprinting is one such way of addressing critical design challenges in tissue engineering. In a more general sense, 3D printing has become essential in customized implant designing, faithful reproduction of microenvironmental niches, sustainable development of implants, in the capacity to address issues of effective cellular integration, and long-term stability of the cellular constructs in tissue engineering. This review covers various aspects of 3D bioprinting, describes the current state-of-the-art solutions for all aforementioned critical issues, and includes various illustrative representations of technologies supporting the development of phases of 3D bioprinting. It also demonstrates several bio-inks and their properties crucial for being used for 3D printing applications. The review focus on bringing together different examples and current trends in tissue engineering applications, including bone, cartilage, muscles, neuron, skin, esophagus, trachea, tympanic membrane, cornea, blood vessel, immune system, and tumor models utilizing 3D printing technology and to provide an outlook of the future potentials and barriers.
Collapse
Affiliation(s)
| | | | - Kunal Mitra
- Florida Institute of Technology, Melbourne, USA
| | | | | | - Ezgi Antmen
- Center of Excellence in Biomaterials and Tissue Engineering, BIOMATEN, Middle East Technical University (METU), Ankara, Turkey
| | - Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Arian Ehterami
- Department of Mechanical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Lea Pourchet
- UMR 1121, Biomaterials and Bioengineering, INSERM, Strasbourg, France
| | - Julien Barthes
- UMR 1121, Biomaterials and Bioengineering, INSERM, Strasbourg, France
| | | | - Magnus von Unge
- Akershus University Hospital and University of Oslo, Oslo, Norway.,Center for Clinical Research, Uppsala University, Vasteras, Uppsala, Sweden
| | - Chi-Yun Wang
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.,Bone and Joint Research Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
| | - Po-Liang Lai
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.,Bone and Joint Research Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
| | - Arindam Bit
- National Institute of Technology, Raipur, India.
| |
Collapse
|
|
49
|
Yuan P, Zhou Y, Wang Z, Gui L, Ma B. Dendritic cell-targeting chemokines inhibit colorectal cancer progression. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:828-840. [PMID: 36654820 PMCID: PMC9834269 DOI: 10.37349/etat.2022.00115] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 10/29/2022] [Indexed: 12/29/2022] Open
Abstract
Aim Recent progress in cancer immunotherapy has shown its promise and prompted researchers to develop novel therapeutic strategies. Dendritic cells (DCs) are professional antigen-presenting cells crucial for initiating adaptive anti-tumor immunity, therefore a promising target for cancer treatment. Here, anti-tumor activities of DC-targeting chemokines were explored in murine colorectal tumor models. Methods The correlation of chemokine messenger RNA (mRNA) expression with DC markers was analyzed using The Cancer Genome Atlas (TCGA) dataset. Murine colorectal tumor cell lines (CT26 and MC38) stably overexpressing mouse C-C motif chemokine ligand 3 (CCL3), CCL19, CCL21, and X-C motif chemokine ligand 1 (XCL1) were established by lentiviral transduction. The effect of chemokines on tumor cell proliferation/survival was evaluated in vitro by cell counting kit-8 (CCK-8) assay and colony formation assay. Syngeneic subcutaneous tumor models were used to study the effects of these chemokines on tumor growth. Ki-67 expression in tumors was examined by immunohistochemistry. Immune cells in the tumor microenvironment (TME) and lymph nodes were analyzed by flow cytometry. Results Expression of the four chemokines was positively correlated with the two DC markers [integrin alpha X (ITGAX) and CLEC9A] in human colorectal tumor samples. Tumoral overexpression of DC-targeting chemokines had little or no effect on tumor cell proliferation/survival in vitro while significantly suppressing tumor growth in vivo. Fluorescence-activated cell sorting (FACS) analysis showed that CCL19, CCL21, and XCL1 boosted the ratios of DCs and T cells in CD45+ leukocytes while CCL3 increased the percentage of CD45+ leukocytes in total cells in MC38 tumor. XCL1 had an additional positive effect on antigen uptake by DCs in the TME and antigen transfer to tumor-draining lymph nodes. Conclusions CCL3, CCL19, CCL21, and XCL1 exhibited potent anti-tumor activities in vivo, although they might differentially regulate immune cells in the TME and antigen transfer to lymph nodes.
Collapse
Affiliation(s)
- Pengkun Yuan
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China,Zhejiang University–University of Edinburgh (ZJU-UoE) Institute, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Yunyi Zhou
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zhixue Wang
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Liming Gui
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Bin Ma
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China,Clinical Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China,Correspondence: Bin Ma, School of Biomedical Engineering Med-X Research Institute, Shanghai Jiao Tong University, No. 3 Teaching Building, 1954 Huashan RD, Xuhui District, Shanghai 200030, China.
| |
Collapse
|
|
50
|
Ebrahimian M, Shahgordi S, Yazdian-Robati R, Etemad L, Hashemi M, Salmasi Z. Targeted delivery of galbanic acid to colon cancer cells by PLGA nanoparticles incorporated into human mesenchymal stem cells. AVICENNA JOURNAL OF PHYTOMEDICINE 2022; 12:295-308. [PMID: 36186932 PMCID: PMC9482708 DOI: 10.22038/ajp.2022.20022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 11/06/2022]
Abstract
Objective The aim of this study was to investigate the efficacy of mesenchyme stem cells (MSCs) derived from human adipose tissue (hMSCs) as carriers for delivery of galbanic acid (GBA), a potential anticancer agent, loaded into poly (lactic-co-glycolic acid) (PLGA) nanoparticles (nano-engineered hMSCs) against tumor cells. Materials and Methods GBA-loaded PLGA nanoparticles (PLGA/GBA) were prepared by single emulsion method and their physicochemical properties were evaluated. Then, PLGA/GBA nanoparticles were incorporated into hMSCs (hMSC/PLGA-GBA) and their migration ability and cytotoxicity against colon cancer cells were investigated. Results The loading efficiency of PLGA/GBA nanoparticles with average size of 214±30.5 nm into hMSCs, was about 85 and 92% at GBA concentration of 20 and 40 μM, respectively. Nano-engineered hMSCs showed significant higher migration to cancer cells (C26) compared to normal cells (NIH/3T3). Furthermore, nano-engineered hMSCs could effectively induce cell death in C26 cells in comparison with non-engineered hMSCs. Conclusion hMSCs could be implemented for efficient loading of PLGA/GBA nanoparticles to produce a targeted cellular carrier against cancer cells. Thus, according to minimal toxicity on normal cells, it deserves to be considered as a valuable platform for drug delivery in cancer therapy.
Collapse
Affiliation(s)
- Mahboubeh Ebrahimian
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sanaz Shahgordi
- Department of Immunology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Rezvan Yazdian-Robati
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Leila Etemad
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Hashemi
- Nanotechnology 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 ,Corresponding Author: Tel: +98-5131801208, Fax: +98-38823251, ,
| | - Zahra Salmasi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran ,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran,Corresponding Author: Tel: +98-5131801208, Fax: +98-38823251, ,
| |
Collapse
|