|
1
|
Shi Y, Zhang J, Li Y, Feng C, Shao C, Shi Y, Fang J. Engineered mesenchymal stem/stromal cells against cancer. Cell Death Dis 2025; 16:113. [PMID: 39971901 PMCID: PMC11839947 DOI: 10.1038/s41419-025-07443-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/03/2025] [Accepted: 02/11/2025] [Indexed: 02/21/2025]
Abstract
Mesenchymal stem/stromal cells (MSCs) have garnered attention for their potential in cancer therapy due to their ability to home to tumor sites. Engineered MSCs have been developed to deliver therapeutic proteins, microRNAs, prodrugs, chemotherapy drugs, and oncolytic viruses directly to the tumor microenvironment, with the goal of enhancing therapeutic efficacy while minimizing off-target effects. Despite promising results in preclinical studies and clinical trials, challenges such as variability in delivery efficiency and safety concerns persist. Ongoing research aims to optimize MSC-based cancer eradication and immunotherapy, enhancing their specificity and efficacy in cancer treatment. This review focuses on advancements in engineering MSCs for tumor-targeted therapy.
Collapse
Affiliation(s)
- Yuzhu Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Jia Zhang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
- Department of Basic Medical Sciences, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yanan Li
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Chao Feng
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
- Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200025, China.
| | - Jiankai Fang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
| |
Collapse
|
|
2
|
Abo Qoura L, Morozova E, Ramaa СS, Pokrovsky VS. Smart nanocarriers for enzyme-activated prodrug therapy. J Drug Target 2024; 32:1029-1051. [PMID: 39045650 DOI: 10.1080/1061186x.2024.2383688] [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: 03/18/2024] [Revised: 06/26/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
Exogenous enzyme-activated prodrug therapy (EPT) is a potential cancer treatment strategy that delivers non-human enzymes into or on the surface of the cell and subsequently converts a non-toxic prodrug into an active cytotoxic substance at a specific location and time. The development of several pharmacological pairs based on EPT has been the focus of anticancer research for more than three decades. Numerous of these pharmacological pairs have progressed to clinical trials, and a few have achieved application in specific cancer therapies. The current review highlights the potential of enzyme-activated prodrug therapy as a promising anticancer treatment. Different microbial, plant, or viral enzymes and their corresponding prodrugs that advanced to clinical trials have been listed. Additionally, we discuss new trends in the field of enzyme-activated prodrug nanocarriers, including nanobubbles combined with ultrasound (NB/US), mesoscopic-sized polyion complex vesicles (PICsomes), nanoparticles, and extracellular vesicles (EVs), with special emphasis on smart stimuli-triggered drug release, hybrid nanocarriers, and the main application of nanotechnology in improving prodrugs.
Collapse
Affiliation(s)
- Louay Abo Qoura
- Research Institute of Molecular and Cellular Medicine, People's Friendship University of Russia (RUDN University), Moscow, Russia
- Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Elena Morozova
- Engelhardt Institute of Molecular Biology of the, Russian Academy of Sciences, Moscow, Russia
| | - С S Ramaa
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Mumbai, India
| | - Vadim S Pokrovsky
- Research Institute of Molecular and Cellular Medicine, People's Friendship University of Russia (RUDN University), Moscow, Russia
- Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| |
Collapse
|
|
3
|
Mohd Abas MD, Mohd Asri MF, Yusafawi NAS, Rosman NAZ, Baharudin NAZ, Taher M, Susanti D, Khotib J. Advancements of gene therapy in cancer treatment: A comprehensive review. Pathol Res Pract 2024; 261:155509. [PMID: 39121791 DOI: 10.1016/j.prp.2024.155509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024]
Abstract
Cancer is the main contributor for mortality in the world. Conventional therapy that available as the treatment options are chemotherapy, radiotherapy and surgery. However, these treatments are hardly cell-specific most of the time. Nowadays, extensive research and investigations are made to develop cell-specific approaches prior to cancer treatment. Some of them are photodynamic therapy, hyperthermia, immunotherapy, stem cell transplantation and targeted therapy. This review article will be focusing on the development of gene therapy in cancer. The objective of gene therapy is to correct specific mutant genes causing the excessive proliferation of the cell that leads to cancer. There are lots of explorations in the approach to modify the gene. The delivery of this therapy plays a big role in its success. If the inserted gene does not find its way to the target, the therapy is considered a failure. Hence, vectors are needed and the common vectors used are viral, non viral or synthetic, polymer based and lipid based vectors. The advancement of gene therapy in cancer treatment will be focussing on the top three cancer cases in the world which are breast, lung and colon cancer. In breast cancer, the discussed therapy are CRISPR/Cas9, siRNA and gene silencing whereas in colon cancer miRNA and suicide gene therapy and in lung cancer, replacement of tumor suppressor gene, CRISPR/Cas9 and miRNA.
Collapse
Affiliation(s)
- Muhammad Dhiyauddin Mohd Abas
- Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan, Pahang 25200, Malaysia
| | - Muhammad Fareez Mohd Asri
- Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan, Pahang 25200, Malaysia
| | - Nur Anis Suffiah Yusafawi
- Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan, Pahang 25200, Malaysia
| | - Nur Anis Zahra Rosman
- Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan, Pahang 25200, Malaysia
| | - Nur Arifah Zahidah Baharudin
- Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan, Pahang 25200, Malaysia
| | - Muhammad Taher
- Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan, Pahang 25200, Malaysia.
| | - Deny Susanti
- Department of Chemistry, Faculty of Science, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Kuantan, Pahang 25200, Malaysia.
| | - Junaidi Khotib
- Department of Pharmacy Practice, Faculty of Pharmacy, Airlangga University, Surabaya 60115, Indonesia.
| |
Collapse
|
|
4
|
Nethi SK, Li X, Bhatnagar S, Prabha S. Enhancing Anticancer Efficacy of Chemotherapeutics Using Targeting Ligand-Functionalized Synthetic Antigen Receptor-Mesenchymal Stem Cells. Pharmaceutics 2023; 15:1742. [PMID: 37376189 DOI: 10.3390/pharmaceutics15061742] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/08/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been studied for their potential in facilitating tumor-targeted delivery of chemotherapeutics due to their tumor-homing characteristics. We hypothesized that targeting effectiveness of MSCs can be further enhanced by incorporating tumor-targeting ligands on MSC surfaces that will allow for enhanced arrest and binding within the tumor tissue. We utilized a unique strategy of modifying MSCs with synthetic antigen receptors (SARs), targeting specific antigens overexpressed on cancer cells. MSCs were surface-functionalized by first incorporating recombinant protein G (PG) on the surface, followed by binding of the targeting antibody to the PG handle. We functionalized MSCs with antibodies targeting a tyrosine kinase transmembrane receptor protein, epidermal growth factor receptor (EGFR), overexpressed in non-small-cell lung cancer (NSCLC). The efficacy of MSCs functionalized with anti-EGFR antibodies (cetuximab and D8) was determined in murine models of NSCLC. Cetuximab-functionalized MSCs demonstrated improved binding to EGFR protein and to EGFR overexpressing A549 lung adenocarcinoma cells. Further, cetuximab-functionalized MSCs loaded with paclitaxel nanoparticles were efficient in slowing orthotopic A549 tumor growth and improving the overall survival relative to that of other controls. Biodistribution studies revealed a six-fold higher retention of EGFR-targeted MSCs than non-targeted MSCs. Based on these results, we conclude that targeting ligand functionalization could be used to enhance the concentration of therapeutic MSC constructs at the tumor tissue and to achieve improved antitumor response.
Collapse
Affiliation(s)
- Susheel Kumar Nethi
- Fels Cancer Institute for Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Xiaolei Li
- Fels Cancer Institute for Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | | | - Swayam Prabha
- Fels Cancer Institute for Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Molecular Therapeutics Program, Fox Chase Cancer Center, Temple University, Philadelphia, PA 19111, USA
| |
Collapse
|
|
5
|
Rahimi Tesiye M, Abrishami Kia Z, Rajabi-Maham H. Mesenchymal stem cells and prostate cancer: A concise review of therapeutic potentials and biological aspects. Stem Cell Res 2022; 63:102864. [PMID: 35878578 DOI: 10.1016/j.scr.2022.102864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/06/2022] [Accepted: 07/08/2022] [Indexed: 11/09/2022] Open
Abstract
Prostate cancer (PCa) arises from a cancer stem or progenitor cell with homogenous characteristics, especially among the aging men population. Over the past decade, the increasing PCa incidence has led to significant changes in both disease diagnosis and treatment. Recently, the therapeutic aspects of stem cells in many cancers, including PCa, have been debatable. The new generation of PCa studies seek to present definitive treatments with reduced therapeutic side effects. Since discovering unique properties of stem cells in modulating immunity, selective migration to inflammatory regions, and secretion of various growth factors, they have been a promising therapeutic target. The existing properties of stem cell therapy bring new opportunities for cancer inhibition: transferring chemotherapeutics, activating prodrugs, affecting the expression of genes involved in cancer, genetically modifying the production of anti-cancer compounds, proteins, and/or deriving extracellular vesicles (EVs) containing therapeutic agents from stem cells. However, their dual properties in carcinogenicity as well as their ability to inhibit cancer result in particular limitations studying them after administration. A clear understanding of the interaction between MSCs and the prostate cancer microenvironment will provide crucial information in revealing the precise applications and new practical protocols for clinical use of these cells..
Collapse
Affiliation(s)
- Maryam Rahimi Tesiye
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Zahra Abrishami Kia
- Faculty of Physical Education and Sport Sciences, University of Mazandaran, Babolsar, Iran.
| | - Hassan Rajabi-Maham
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| |
Collapse
|
|
6
|
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
|
|
7
|
Mercer-Smith AR, Findlay IA, Bomba HN, Hingtgen SD. Intravenously Infused Stem Cells for Cancer Treatment. Stem Cell Rev Rep 2021; 17:2025-2041. [PMID: 34138421 DOI: 10.1007/s12015-021-10192-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2021] [Indexed: 01/14/2023]
Abstract
Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be engineered to secrete cytotoxic products, loaded with oncolytic viruses or nanoparticles containing small molecule drugs, or conjugated with immunotherapies. Herein we describe these preclinical and clinical studies, discuss the distribution and migration of stem cells following intravenous infusion, and examine both the limitations of and the methods to improve the migration and therapeutic efficacy of tumoritropic, therapeutic stem cells.
Collapse
Affiliation(s)
- Alison R Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Ingrid A Findlay
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Hunter N Bomba
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA. .,Department of Neurosurgery, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA.
| |
Collapse
|
|
8
|
Wu Y, Zhang C, Guo R, Wu D, Shi J, Li L, Chu Y, Yuan X, Gao J. Mesenchymal Stem Cells: An Overview of Their Potential in Cell-Based Therapy for Diabetic Nephropathy. Stem Cells Int 2021; 2021:6620811. [PMID: 33815509 PMCID: PMC7990550 DOI: 10.1155/2021/6620811] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/11/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetic nephropathy (DN) is a devastating complication associated with diabetes mellitus, and it is the leading cause of end-stage renal diseases (ESRD). Over the last few decades, numerous studies have reported the beneficial effects of stem cell administration, specifically mesenchymal stem or stromal cells (MSCs), on tissue repair and regeneration. MSC therapy has been considered a promising strategy for ameliorating the progression of DN largely based on results obtained from several preclinical studies and recent Phase I/II clinical trials. This paper will review the recent literature on MSC treatment in DN. In addition, the roles and potential mechanisms involved in MSC treatment of DN will be summarized, which may present much needed new drug targets for this disease. Moreover, the potential benefits and related risks associated with the therapeutic action of MSCs are elucidated and may help in achieving a better understanding of MSCs.
Collapse
Affiliation(s)
- Yan Wu
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Chunlei Zhang
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Ran Guo
- Department of Physiology, Mudanjiang Medical University, Mudanjiang, China
| | - Dan Wu
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Jiayi Shi
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Luxin Li
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Yanhui Chu
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaohuan Yuan
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Jie Gao
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| |
Collapse
|
|
9
|
Chia YC, Anjum CE, Yee HR, Kenisi Y, Chan MKS, Wong MBF, Pan SY. Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain? Stem Cells Int 2020; 2020:8889061. [PMID: 32952573 PMCID: PMC7487096 DOI: 10.1155/2020/8889061] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/11/2020] [Accepted: 08/20/2020] [Indexed: 01/14/2023] Open
Abstract
Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.
Collapse
Affiliation(s)
- Yvonne Cashinn Chia
- Baden R&D Laboratories GmbH, Germany
- Baden Research and Testing (Asia Pac) Sdn Bhd, Malaysia
| | - Clarice Evey Anjum
- Baden R&D Laboratories GmbH, Germany
- Baden Research and Testing (Asia Pac) Sdn Bhd, Malaysia
| | - Hui Rong Yee
- Baden R&D Laboratories GmbH, Germany
- Baden Research and Testing (Asia Pac) Sdn Bhd, Malaysia
| | - Yenny Kenisi
- Baden R&D Laboratories GmbH, Germany
- Baden Research and Testing (Asia Pac) Sdn Bhd, Malaysia
| | - Mike K. S. Chan
- Baden R&D Laboratories GmbH, Germany
- Baden Research and Testing (Asia Pac) Sdn Bhd, Malaysia
| | - Michelle B. F. Wong
- Baden R&D Laboratories GmbH, Germany
- Baden Research and Testing (Asia Pac) Sdn Bhd, Malaysia
| | - Shing Yi Pan
- Baden R&D Laboratories GmbH, Germany
- Baden Research and Testing (Asia Pac) Sdn Bhd, Malaysia
| |
Collapse
|
|
10
|
Rai N, Singh AK, Singh SK, Gaurishankar B, Kamble SC, Mishra P, Kotiya D, Barik S, Atri N, Gautam V. Recent technological advancements in stem cell research for targeted therapeutics. Drug Deliv Transl Res 2020; 10:1147-1169. [DOI: 10.1007/s13346-020-00766-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
11
|
Yang J, Lv K, Sun J, Guan J. Anti-tumor effects of engineered mesenchymal stem cells in colon cancer model. Cancer Manag Res 2019; 11:8443-8450. [PMID: 31571999 PMCID: PMC6755954 DOI: 10.2147/cmar.s209880] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 08/13/2019] [Indexed: 12/20/2022] Open
Abstract
Background Cell-based gene therapy is considered as a promising strategy for the treatment of human malignancy. In many different types of cancer, mesenchymal stem cells (MSCs) are observed as valuable and potential anti-cancer agents. However, the exact mechanisms of MSCs involved in tumor microenvironment are not well understood. Aim Our aims are to elucidate the MSCs-mediated tumor microenvironment. Materials and methods In this study, colon cancer model was established by injecting the HT29 cells into the subcutaneous of right axilla of nude mice. We applied the human placenta-derived MSCs (hP-MSCs) armed with a double fusion gene containing the herpes simplex virus truncated thymidine kinase and firefly luciferase for treatment of colon cancer on days 10, 15, and 20 after HT29 cells injection. Molecular imaging methods were used for real-time imaging tumor progression and tracking transplanted hP-MSCs by bioluminescence imaging. Furthermore, proliferation and apoptosis-related proteins levels in colon cancer tissues were examined by immunofluorescence and Western blotting. Results Our results demonstrated that the administration of engineered hP-MSCs significantly inhibited the tumors and this effect was enhanced by ganciclovir application. Further analysis demonstrated the anti-tumor effect of engineered hP-MSCs in vivo depended on inhibiting tumor proliferation and inducing tumor apoptosis. Conclusion Collectively, this work showed that engineered hP-MSCs could inhibit colon cancer progression and metastasis by inducing tumor cell death and suppressing proliferation.
Collapse
Affiliation(s)
- Jianying Yang
- Department of Emergency, Anhui No. 2 Provincial People's Hospital, Hefei, People's Republic of China
| | - Kui Lv
- Department of Emergency, Anhui No. 2 Provincial People's Hospital, Hefei, People's Republic of China
| | - Junfeng Sun
- Department of Emergency, Anhui No. 2 Provincial People's Hospital, Hefei, People's Republic of China
| | - Jianguo Guan
- Department of Emergency, Anhui No. 2 Provincial People's Hospital, Hefei, People's Republic of China
| |
Collapse
|
|
12
|
Cheng S, Nethi SK, Rathi S, Layek B, Prabha S. Engineered Mesenchymal Stem Cells for Targeting Solid Tumors: Therapeutic Potential beyond Regenerative Therapy. J Pharmacol Exp Ther 2019; 370:231-241. [PMID: 31175219 PMCID: PMC6640188 DOI: 10.1124/jpet.119.259796] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 06/05/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have previously demonstrated considerable promise in regenerative medicine based on their ability to proliferate and differentiate into cells of different lineages. More recently, there has been a significant interest in using MSCs as cellular vehicles for targeted cancer therapy by exploiting their tumor homing properties. Initial studies focused on using genetically modified MSCs for targeted delivery of various proapoptotic, antiangiogenic, and therapeutic proteins to a wide variety of tumors. However, their use as drug delivery vehicles has been limited by poor drug load capacity. This review discusses various strategies for the nongenetic modification of MSCs that allows their use in tumor-targeted delivery of small molecule chemotherapeutic agents. SIGNIFICANCE STATEMENT: There has been considerable interest in exploiting the tumor homing potential of MSCs to develop them as a vehicle for the targeted delivery of cytotoxic agents to tumor tissue. The inherent tumor-tropic and drug-resistant properties make MSCs ideal carriers for toxic payload. While significant progress has been made in the area of the genetic modification of MSCs, studies focused on identification of molecular mechanisms that contribute to the tumor tropism along with optimization of the engineering conditions can further improve their effectiveness as drug delivery vehicles.
Collapse
Affiliation(s)
- Shen Cheng
- Departments of Experimental and Clinical Pharmacology (S.C., S.K.N., B.L., S.P.) and Pharmaceutics (S.R., S.P.), College of Pharmacy, University of Minnesota, Twin Cities, Minnesota
| | - Susheel Kumar Nethi
- Departments of Experimental and Clinical Pharmacology (S.C., S.K.N., B.L., S.P.) and Pharmaceutics (S.R., S.P.), College of Pharmacy, University of Minnesota, Twin Cities, Minnesota
| | - Sneha Rathi
- Departments of Experimental and Clinical Pharmacology (S.C., S.K.N., B.L., S.P.) and Pharmaceutics (S.R., S.P.), College of Pharmacy, University of Minnesota, Twin Cities, Minnesota
| | - Buddhadev Layek
- Departments of Experimental and Clinical Pharmacology (S.C., S.K.N., B.L., S.P.) and Pharmaceutics (S.R., S.P.), College of Pharmacy, University of Minnesota, Twin Cities, Minnesota
| | - Swayam Prabha
- Departments of Experimental and Clinical Pharmacology (S.C., S.K.N., B.L., S.P.) and Pharmaceutics (S.R., S.P.), College of Pharmacy, University of Minnesota, Twin Cities, Minnesota
| |
Collapse
|
|
13
|
Xu L, Lin W, Wen L, Li G. Lgr5 in cancer biology: functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy. Stem Cell Res Ther 2019; 10:219. [PMID: 31358061 PMCID: PMC6664754 DOI: 10.1186/s13287-019-1288-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cancer remains one of the leading lethal diseases worldwide. Identifying biomarkers of cancers might provide insights into the strategies for the development of novel targeted anti-cancer therapies. Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) has been recently discovered as a candidate marker of cancer stem cell populations. Aberrant increased expression of Lgr5 may represent one of the most common molecular alterations in some human cancers, leading to long-term potentiation of canonical Wnt/β-catenin signaling. On the other hand, however, Lgr5-mediated suppression in canonical Wnt/β-catenin signaling has also been reported in certain cancers, such as B cell malignancies. Until now, therapeutic approaches targeting Lgr5-associated signaling axis are not yet clinically available. Increasing evidence have indicated that endogenous Lgr5+ cell population is implicated in tumor initiation, progression, and metastasis. This review is to summarize our current knowledge about the importance of Lgr5 in cancer biology and the underlying molecular mechanisms of Lgr5-mediated tumor-promoting/suppressive activities, as well as potentially useful preventive strategies in treating tumor. Therefore, targeted therapeutic modulation of Lgr5+ cancer cell population by targeting Wnt/β-catenin signaling through targeted drug delivery system or targeted genome editing might be promising for potential novel anti-cancer treatments. Simultaneously, combination of therapeutics targeting both Lgr5+ and Lgr5- cancer cells may deserve further consideration considering the plasticity of cancer cells. Also, a more specific targeting of cancer cells using double biomarkers may be much safer and more effective for anti-cancer therapy.
Collapse
Affiliation(s)
- Liangliang Xu
- Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
- Laboratory of Orthopaedics and Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Weiping Lin
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR PRC
- Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR PRC
| | - Longping Wen
- Nanobio Laboratory, Institute of Life Sciences, South China University of Technology, Guangzhou, Guangdong People’s Republic of China
| | - Gang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR PRC
- Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR PRC
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People’s Republic of China
| |
Collapse
|
|
14
|
Mesenchymal Stem Cells and Cancer: Clinical Challenges and Opportunities. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2820853. [PMID: 31205939 PMCID: PMC6530243 DOI: 10.1155/2019/2820853] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 03/19/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023]
Abstract
Stem cell-based therapies exhibit profound therapeutic potential for treating various human diseases, including cancer. Among the cell types that can be used for this purpose, mesenchymal stem cells (MSCs) are considered as promising source of stem cells in personalized cell-based therapies. The inherent tumor-tropic property of MSCs can be used to target cancer cells. Although the impacts of MSCs on tumor progression remain elusive, they have been genetically modified or engineered as targeted anticancer agents which could inhibit tumor growth by blocking different processes of tumor. In addition, there are close interactions between MSCs and cancer stem cells (CSCs). MSCs can regulate the growth of CSCs through paracrine mechanisms. This review aims to focus on the current knowledge about MSCs-based tumor therapies, the opportunities and challenges, as well as the prospective of its further clinical implications.
Collapse
|
|
15
|
Tumoricidal effect of human olfactory ensheathing cell mediated suicide gene therapy in human glioblastoma cells. Mol Biol Rep 2018; 45:2263-2273. [PMID: 30242665 DOI: 10.1007/s11033-018-4388-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 09/15/2018] [Indexed: 12/22/2022]
Abstract
The potential of herpes simplex virus type 1 thymidine kinase (HSV-tk)-expressing olfactory ensheathing cells (OEC) treated with ganciclovir (GCV) to induce cell death in adjacent HSV-tk-negative cells (bystander effect) has been well demonstrated. Although it has been shown that bystander effect occurs through the delivery of phosphorylated GCV, the bystander effect mechanism and the role of gap junctions for human OECs mediated suicide gene therapy in primary astrocytes of human glioblastma remain obscure. In the present study, the efficacy of a new method for the transfer of phosphorylated GCV from OECs into primary astrocytes was evaluated. Surgical biopsy of glioblastoma was used to isolate primary astrocyte. Biopsy of olfactory mucosa was applied to isolate olfactory ensheathing cell. Expression of S100-beta antigen was confirmed immunocytochemically in astrocytes and OECs. OECs were transduced to lentiviral containing thymidine kinase gene (TK) and co-cultured with astrocytes. Fluorescent dye transfer and western blot analysis indicated the expression of connexin43 between olfactory ensheathing cells and astrocytes whereas, expression of the gap junction protein connexin43 was inhibited by the gap junction inhibitor 18α-glycyrrhethinic acid (AGA, 20 µg/ml). Furthermore, co-culture of astrocytes with OEC-TK in the presence of concentration of 30 µg/ml GCV led to a decrease in astrocytes survival rate. Also, apoptosis hallmarks, including DNA fragmentation in cell nuclear, expression increase of Bax to Bcl-2 ratio and increase of caspase3 activation were observed in this study. Our findings suggest that human olfactory ensheathing cells can deliver phosphorylated GCV into the glioblastoma derived astrocytes through gap junction communication for apoptosis induction.
Collapse
|
|
16
|
Layek B, Sadhukha T, Panyam J, Prabha S. Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting. Mol Cancer Ther 2018; 17:1196-1206. [PMID: 29592881 DOI: 10.1158/1535-7163.mct-17-0682] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 01/10/2018] [Accepted: 03/09/2018] [Indexed: 12/18/2022]
Abstract
Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor-targeting strategy that relies on engineering mesenchymal stem cells (MSC) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Furthermore, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count, whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUClung of PTX (1.5 μg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 μg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor-specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Mol Cancer Ther; 17(6); 1196-206. ©2018 AACR.
Collapse
Affiliation(s)
- Buddhadev Layek
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Tanmoy Sadhukha
- Albany Molecular Research Inc., Albany, New York.,Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Jayanth Panyam
- Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Swayam Prabha
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota. .,Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| |
Collapse
|
|
17
|
Moradian Tehrani R, Verdi J, Noureddini M, Salehi R, Salarinia R, Mosalaei M, Simonian M, Alani B, Ghiasi MR, Jaafari MR, Mirzaei HR, Mirzaei H. Mesenchymal stem cells: A new platform for targeting suicide genes in cancer. J Cell Physiol 2017; 233:3831-3845. [DOI: 10.1002/jcp.26094] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 07/11/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Rana Moradian Tehrani
- Department of Applied Cell SciencesSchool of Medicine, Kashan University of Medical SciencesKashanIran
| | - Javad Verdi
- Department of Applied Cell SciencesSchool of Medicine, Kashan University of Medical SciencesKashanIran
- Department of Applied Cell Sciences School of Advanced Technologies in Medicine, Tehran University of Medical SciencesTehranIran
| | - Mahdi Noureddini
- Department of Applied Cell SciencesSchool of Medicine, Kashan University of Medical SciencesKashanIran
| | - Rasoul Salehi
- Department of Genetic and Molecular BiologyIsfahan University of Medical SciencesIsfahanIran
| | - Reza Salarinia
- Department of Medical Biotechnology and Molecular SciencesSchool of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Meysam Mosalaei
- Department of Genetic and Molecular BiologyIsfahan University of Medical SciencesIsfahanIran
| | - Miganosh Simonian
- Department of Genetic and Molecular BiologyIsfahan University of Medical SciencesIsfahanIran
| | - Behrang Alani
- Department of Applied Cell SciencesSchool of Medicine, Kashan University of Medical SciencesKashanIran
| | - Moosa Rahimi Ghiasi
- Department of Genetic and Molecular BiologyIsfahan University of Medical SciencesIsfahanIran
| | - Mahmoud Reza Jaafari
- School of PharmacyNanotechnology Research CenterMashhad University of Medical SciencesMashhadIran
| | - Hamed Reza Mirzaei
- Department of Clinical Laboratory SciencesSchool of Allied Medical SciencesKashan University of Medical SciencesKashanIran
- Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashington
| | - Hamed Mirzaei
- Department of Medical Biotechnology, School of MedicineMashhad University of Medical SciencesMashhadIran
| |
Collapse
|
|
18
|
Abstract
Stem cell-based drug delivery for cancer therapy has steadily gained momentum in the past decade as several studies have reported stem cells' inherent tropism towards tumors. Since this science is still in its early stages and there are many factors that could significantly impact tumor tropism of stem cells, some contradictory results have been observed. This review starts by examining a number of proof-of-concept studies that demonstrate the potential application of stem cells in cancer therapy. Studies that illustrate stem cells' tumor tropism and discuss the technical difficulties that could impact the therapeutic outcome are also highlighted. The discussion also emphasizes stem cell imaging/tracking, as it plays a crucial role in performing reliable dose-response studies and evaluating the therapeutic outcome of treatment protocols. In each section, the pros and cons associated with each method are highlighted, limitations are underlined, and potential solutions are discussed. The overall intention is to familiarize the reader with important practical issues related to stem cell cancer tropism and in vivo tracking, underline the shortcomings, and emphasize critical factors that need to be considered for effective translation of this science into the clinic.
Collapse
|
|
19
|
Kaneti L, Bronshtein T, Malkah Dayan N, Kovregina I, Letko Khait N, Lupu-Haber Y, Fliman M, Schoen BW, Kaneti G, Machluf M. Nanoghosts as a Novel Natural Nonviral Gene Delivery Platform Safely Targeting Multiple Cancers. NANO LETTERS 2016; 16:1574-82. [PMID: 26901695 DOI: 10.1021/acs.nanolett.5b04237] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Nanoghosts derived from mesenchymal stem cells and retaining their unique surface-associated tumor-targeting capabilities were redesigned as a selective and safe universal nonviral gene-therapy platform. pDNA-loaded nanoghosts efficiently targeted and transfected diverse cancer cells, in vitro and in vivo, in subcutaneous and metastatic orthotopic tumor models, leading to no adverse effects. Nanoghosts loaded with pDNA encoding for a cancer-toxic gene inhibited the growth of metastatic orthotopic lung cancer and subcutaneous prostate cancer models and dramatically prolonged the animals' survival.
Collapse
Affiliation(s)
- Limor Kaneti
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Tomer Bronshtein
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Natali Malkah Dayan
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Inna Kovregina
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Nitzan Letko Khait
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Yael Lupu-Haber
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Miguel Fliman
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Beth W Schoen
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Galoz Kaneti
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| | - Marcelle Machluf
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology , Haifa 3200003, Israel
| |
Collapse
|
|
20
|
NAMBA HIROKI, KAWAJI HIROSHI, YAMASAKI TOMOHIRO. Use of genetically engineered stem cells for glioma therapy. Oncol Lett 2016; 11:9-15. [PMID: 26870161 PMCID: PMC4726949 DOI: 10.3892/ol.2015.3860] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 09/24/2015] [Indexed: 12/18/2022] Open
Abstract
Glioblastoma, the most common and most malignant type of primary brain tumor, is associated with poor prognosis, even when treated using combined therapies, including surgery followed by concomitant radiotherapy with temozolomide-based chemotherapy. The invasive nature of this type of tumor is a major reason underlying treatment failure. The tumor-tropic ability of neural and mesenchymal stem cells offers an alternative therapeutic approach, where these cells may be used as vehicles for the invasion of tumors. Stem cell-based therapy is particularly attractive due to its tumor selectivity, meaning that the stem cells are able to target tumor cells without harming healthy brain tissue, as well as the extensive tumor tropism of stem cells when delivering anti-tumor substances, even to distant tumor microsatellites. Stem cells have previously been used to deliver cytokine genes, suicide genes and oncolytic viruses. The present review will summarize current trends in experimental studies of stem cell-based gene therapy against gliomas, and discuss the potential concerns for translating these promising strategies into clinical use.
Collapse
Affiliation(s)
- HIROKI NAMBA
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - HIROSHI KAWAJI
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - TOMOHIRO YAMASAKI
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| |
Collapse
|
|
21
|
Zhang TY, Huang B, Wu HB, Wu JH, Li LM, Li YX, Hu YL, Han M, Shen YQ, Tabata Y, Gao JQ. Synergistic effects of co-administration of suicide gene expressing mesenchymal stem cells and prodrug-encapsulated liposome on aggressive lung melanoma metastases in mice. J Control Release 2015; 209:260-71. [PMID: 25966361 DOI: 10.1016/j.jconrel.2015.05.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 04/17/2015] [Accepted: 05/08/2015] [Indexed: 11/30/2022]
Abstract
The success of conventional suicide gene therapy for cancer treatment is still limited because of lack of efficient delivery methods, as well as poor penetration into tumor tissues. Mesenchymal stem cells (MSCs) have recently emerged as potential vehicles in improving delivery issues. However, these stem cells are usually genetically modified using viral gene vectors for suicide gene overexpression to induce sufficient therapeutic efficacy. This approach may result in safety risks for clinical translation. Therefore, we designed a novel strategy that uses non-viral gene vector in modifying MSCs with suicide genes to reduce risks. In addition, these cells were co-administrated with prodrug-encapsulated liposomes for synergistic anti-tumor effects. Results demonstrate that this strategy is effective for gene and prodrug delivery, which co-target tumor tissues, to achieve a significant decrease in tumor colonization and a subsequent increase in survival in a murine melanoma lung metastasis model. Moreover, for the first time, we demonstrated the permeability of MSCs within tumor nests by using an in vitro 3D tumor spheroid model. Thus, the present study provides a new strategy to improve the delivery problem in conventional suicide gene therapy and enhance the therapeutic efficacy. Furthermore, this study also presents new findings to improve our understanding of MSCs in tumor-targeted gene delivery.
Collapse
Affiliation(s)
- Tian-Yuan Zhang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Bing Huang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Hai-Bin Wu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Jia-He Wu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Li-Ming Li
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Yan-Xin Li
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Yu-Lan Hu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Min Han
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - You-Qing Shen
- Center for Bionanoengineering and State Key Laboratory of Chemical Engineering, Zhejiang University, Hangzhou, PR China
| | - Yasuhiko Tabata
- Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Jian-Qing Gao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
| |
Collapse
|
|
22
|
Nouri FS, Wang X, Hatefi A. Genetically engineered theranostic mesenchymal stem cells for the evaluation of the anticancer efficacy of enzyme/prodrug systems. J Control Release 2015; 200:179-87. [PMID: 25575867 DOI: 10.1016/j.jconrel.2015.01.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 12/30/2014] [Accepted: 01/03/2015] [Indexed: 12/27/2022]
Abstract
Over the past decade, various enzyme/prodrug systems such as thymidine kinase/ganciclovir (TK/GCV), yeast cytosine deaminase/5-fluorocytosine (yCD/5-FC) and nitroreductase/CB1954 (NTR/CB1954) have been used for stem cell mediated suicide gene therapy of cancer. Yet, no study has been conducted to compare and demonstrate the advantages and disadvantages of using one system over another. Knowing that each enzyme/prodrug system has its own strengths and weaknesses, we utilized mesenchymal stem cells (MSCs) as a medium to perform for the first time a comparative study that illustrated the impact of subtle differences among these systems on the therapeutic outcome. For therapeutic purposes, we first genetically modified MSCs to stably express a panel of four suicide genes including TK (TK007 and TK(SR39) mutants), yeast cytosine deaminase:uracil phosphoribosyltransferase (yCD:UPRT) and nitroreductase (NTR). Then, we evaluated the anticancer efficacies of the genetically engineered MSCs in vitro and in vivo by using SKOV3 cell line which is sensitive to all four enzyme/prodrug systems. In addition, all MSCs were engineered to stably express luciferase gene making them suitable for quantitative imaging and dose-response relationship studies in animals. Considering the limitations imposed by the prodrugs' bystander effects, our findings show that yCD:UPRT/5-FC is the most effective enzyme/prodrug system among the ones tested. Our findings also demonstrate that theranostic MSCs are a reliable medium for the side-by-side evaluation and screening of the enzyme/prodrug systems at the preclinical level. The results of this study could help scientists who utilize cell-based, non-viral or viral vectors for suicide gene therapy of cancer make more informed decisions when choosing enzyme/prodrug systems.
Collapse
Affiliation(s)
- Faranak Salman Nouri
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Xing Wang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Arash Hatefi
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
| |
Collapse
|
|
23
|
Abstract
Stem cell-based therapeutic strategies have emerged as very attractive treatment options over the past decade. Stem cells are now being utilized as delivery vehicles especially in cancer therapy to deliver a number of targeted proteins and viruses. This chapter aims to shed light on numerous studies that have successfully employed these strategies to target various cancer types with a special emphasis on numerous aspects that are critical to the success of future stem cell-based therapies for cancer.
Collapse
|
|
24
|
Wright RC, Khakhar A, Eshleman JR, Ostermeier M. Advancements in the development of HIF-1α-activated protein switches for use in enzyme prodrug therapy. PLoS One 2014; 9:e114032. [PMID: 25426963 PMCID: PMC4245239 DOI: 10.1371/journal.pone.0114032] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 11/03/2014] [Indexed: 12/25/2022] Open
Abstract
While gene-directed enzyme prodrug therapy has shown potential as a cancer therapeutic in animal and clinical trials, concerns over the efficacy, selectivity, and safety of gene delivery vehicles have restricted its advance. In an attempt to relieve some of the demands on targeted gene delivery vehicles and achieve the full potential of enzyme prodrug therapy, cancer-targeted activity can be engineered into the enzyme itself. We previously engineered a switchable prodrug-activating enzyme that selectively kills human cancer cells accumulating the cancer marker hypoxia-inducible factor-1α (HIF-1α). This HIF-1α-activated protein switch (Haps59) is designed to increase its ability to convert the prodrug 5-fluorocytosine into the chemotherapeutic 5-fluorouracil in a HIF-1α-dependent manner. However, in cancer cell lines expressing Haps59 the 5FC sensitivity difference between the presence and absence of HIF-1α was not as large as desired. In this work, we aimed to improve the cancer specificity of this switch via a directed evolution approach utilizing random mutagenesis, linker mutagenesis, and random insertion and circular permutation. We identified improved HIF-1α-activated protein switches that confer E. coli with modest increases in HIF-1α-dependent 5FC toxicity. Additionally, the current bottleneck in the development of improved HIF-1α-activated protein switches is screening switch candidates in mammalian cells. To accommodate higher throughput and reduce experimental variability, we explored the use of Flp recombinase-mediated isogenic integration in 293 cells. These experiments raised the possibility that Haps59 can be activated by other interactors of the CH1 domain, and experiments in E. coli indicated that CITED2 can also activate Haps59. Although many CH1 binding partners are also oncogenes, CH1's promiscuous binding and subsequent off-target activation of Haps59 needs to be examined under normal physiological conditions to identify off-target activators. With aberrant activating molecules identified, further directed evolution can be performed to improve the cancer specificity of HIF-1α-activated protein switches.
Collapse
Affiliation(s)
- R. Clay Wright
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Arjun Khakhar
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - James R. Eshleman
- Departments of Pathology and Oncology, Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Marc Ostermeier
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- * E-mail:
| |
Collapse
|
|
25
|
Kim JH, Lee HJ, Song YS. Stem cell based gene therapy in prostate cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:549136. [PMID: 25121103 PMCID: PMC4120795 DOI: 10.1155/2014/549136] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 07/02/2014] [Indexed: 02/08/2023]
Abstract
Current prostate cancer treatment, especially hormone refractory cancer, may create profound iatrogenic outcomes because of the adverse effects of cytotoxic agents. Suicide gene therapy has been investigated for the substitute modality for current chemotherapy because it enables the treatment targeting the cancer cells. However the classic suicide gene therapy has several profound side effects, including immune-compromised due to viral vector. Recently, stem cells have been regarded as a new upgraded cellular vehicle or vector because of its homing effects. Suicide gene therapy using genetically engineered mesenchymal stem cells or neural stem cells has the advantage of being safe, because prodrug administration not only eliminates tumor cells but consequently kills the more resistant therapeutic stem cells as well. The attractiveness of prodrug cancer gene therapy by stem cells targeted to tumors lies in activating the prodrug directly within the tumor mass, thus avoiding systemic toxicity. Therapeutic achievements using stem cells in prostate cancer include the cytosine deaminase/5-fluorocytosine prodrug system, herpes simplex virus thymidine kinase/ganciclovir, carboxyl esterase/CPT11, and interferon-beta. The aim of this study is to review the stem cell therapy in prostate cancer including its proven mechanisms and also limitations.
Collapse
Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang University, College of Medicine, Soonchunyang University Hospital, Seoul 140-743, Republic of Korea
| | - Hong Jun Lee
- Medical Research Institute, Chung-Ang School of Medicine, Seoul 156-756, Republic of Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang University, College of Medicine, Soonchunyang University Hospital, Seoul 140-743, Republic of Korea
| |
Collapse
|
|
26
|
Lee WYW, Zhang T, Lau CPY, Wang CC, Chan KM, Li G. Immortalized human fetal bone marrow-derived mesenchymal stromal cell expressing suicide gene for anti-tumor therapy in vitro and in vivo. Cytotherapy 2014; 15:1484-97. [PMID: 24199592 DOI: 10.1016/j.jcyt.2013.06.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 04/28/2013] [Accepted: 06/19/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND AIMS Cancer is one of the greatest health challenges facing the world today with >10 million new cases of cancer every year. The self-renewal, tumor-homing ability and low immunogenicity of mesenchymal stromal cells (MSCs) make them potential delivery candidates for suicide genes for anti-tumor therapy. However, unstable supply and short life span of adult MSCs in vitro have limited this therapeutic potential. In this study, we aimed to evaluate if immortalization of human fetal bone marrow-derived mesenchymal stromal cells by simian virus 40 (SV40-hfBMSCs) could be a stable source of MSCs for clinical application of suicide gene therapy. METHODS AND RESULTS Transduction of SV40 and herpes simplex virus thymidine kinase-IRES-green fluorescent protein (TK-GFP) did not cause significant change in the stem cell properties of hfBMSCs. The anti-tumor effect of SV40-TK-hfBMSCs in the presence of the prodrug ganciclovir was demonstrated in vitro and in nude mice bearing human prostate cancer cells, DU145 and PC3, which had been transduced with luciferase and GFP for imaging evaluation by an in vivo live imaging system (IVIS 200 imaging system; Caliper Life Sciences). Repeated injection of low doses (1 × 10(6) cells/kg) of SV40-TK-hfBMSCs was as effective as previously reported and did not cause observable harmful side effects in multiple organs. Mixed lymphocyte reaction showed that SV40-TK-hfBMSCs did not induce significant proliferation of lymphocytes isolated from healthy adults. CONCLUSIONS Taken together, immortalized hfBMSCs represent a reliable and safe source of MSCs for further clinical translational study.
Collapse
Affiliation(s)
- Wayne Y W Lee
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | | | | | | | | | | |
Collapse
|
|
27
|
Brennen WN, Denmeade SR, Isaacs JT. Mesenchymal stem cells as a vector for the inflammatory prostate microenvironment. Endocr Relat Cancer 2013; 20:R269-90. [PMID: 23975882 PMCID: PMC3994592 DOI: 10.1530/erc-13-0151] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) have an inherent tropism for sites of inflammation, which are frequently present in sites of cancer, including prostatic lesions. MSCs have been defined as CD73/CD90/CD105 triple-positive cells in the absence of hematopoietic lineage markers with the ability to differentiate into multiple mesodermal lineages, including osteoblasts, adipocytes, and chondrocytes. Our group has previously demonstrated that MSCs represent between 0.01 and 1.1% of the total cells present in human prostatectomy tissue. In addition to their multi-lineage differentiation potential, MSCs are immunoprivileged in nature and have a range of immunomodulatory effects on both the innate and adaptive arms of the immune system. MSCs have been detected in an increasing array of tissues, and evidence suggests that they are likely present in perivascular niches throughout the body. These observations suggest that MSCs represent critical mediators of the overall immune response during physiological homeostasis and likely contribute to pathophysiological conditions as well. Chronic inflammation has been suggested as an initiating event and progression factor in prostate carcinogenesis, a process in which the immunosuppressive properties of MSCs may play a role. MSCs have also been shown to influence malignant progression through a variety of other mechanisms, including effects on tumor proliferation, angiogenesis, survival, and metastasis. Additionally, human bone marrow-derived MSCs have been shown to traffic to human prostate cancer xenografts in immunocompromised murine hosts. The trafficking properties and immunoprivileged status of MSCs suggest that they can be exploited as an allogeneic cell-based vector to deliver cytotoxic or diagnostic agents for therapy.
Collapse
Affiliation(s)
- W Nathaniel Brennen
- Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21287, USA
| | | | | |
Collapse
|
|
28
|
Wang T, Liao TA, Zhong SB. Transfection of bone marrow mesenchymal stem cells using green fluorescence protein labeled hVEGF165 recombinant plasmid mediated by liposome. ASIAN PAC J TROP MED 2013; 6:739-42. [DOI: 10.1016/s1995-7645(13)60129-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 06/15/2013] [Accepted: 07/15/2013] [Indexed: 11/26/2022] Open
|
|
29
|
Brennen WN, Chen S, Denmeade SR, Isaacs JT. Quantification of Mesenchymal Stem Cells (MSCs) at sites of human prostate cancer. Oncotarget 2013; 4:106-17. [PMID: 23362217 PMCID: PMC3702211 DOI: 10.18632/oncotarget.805] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Circulating bone marrow-derived Mesenchymal Stem Cells (BM-MSCs) have an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. The prostate is bombarded by numerous infectious & inflammatory insults over a lifetime. Chronic inflammation is associated with CXCL12, CCL5, and CCL2, which are highly overexpressed in prostate cancer. Among other cell types, these chemoattractant stimuli recruit BM-MSCs to the tumor. MSCs are minimally defined as plastic-adhering cells characterized by the expression of CD90, CD73, and CD105 in the absence of hematopoietic markers, which can differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs are immunoprivileged and have been implicated in tumorigenesis through multiple mechanisms, including promoting proliferation, angiogenesis, and metastasis, in addition to the generation of an immunosuppressive microenvironment. We have demonstrated that MSCs represent 0.01-1.1% of the total cells present in core biopsies from primary human prostatectomies. Importantly, these analyses were performed on samples prior to expansion in tissue culture. MSCs in these prostatectomy samples are FAP-, CD90-, CD73-, and CD105-positive, and CD14-, CD20-, CD34-, CD45-, and HLA-DR-negative. Additionally, like BM-MSCs, these prostate cancer-derived stromal cells (PrCSCs) were shown to differentiate into osteoblasts, adipocytes, & chondrocytes. In contrast to primary prostate cancer-derived epithelial cells, fluorescently-labeled PrCSCs & BM-MSCs were both shown to home to CWR22RH prostate cancer xenografts following IV injection. These studies demonstrate that not only are MSCs present in sites of prostate cancer where they may contribute to carcinogenesis, but these cells may also potentially be used to deliver cytotoxic or imaging agents for therapeutic and/or diagnostic purposes.
Collapse
Affiliation(s)
- W Nathaniel Brennen
- Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | | | | | | |
Collapse
|
|
30
|
Abstract
Development of antitumor preparations with low toxicity and high selectivity of action is one of the top priorities of cancer gene therapy. Mesenchymal stem cells possess natural tropism towards tumors, a property that makes possible their use as a vehicle for targeted delivery of therapeutic genes into tumors of various etiologies. At present, genes encoding enzymes (cytosine deaminase, thymidine kinase, carboxyl esterase), cytokines (IL-2, IL-4, IL-12, IFN-beta) and apoptosis inducing factors (TRAIL) are used as therapeutic genes. Mesenchymal stem cells, as demonstrated using experimental models of tumors of various etiologies as well as animals with metastases in brain and lungs, are able to successfully deliver therapeutic genes into tumors and produce significant antitumor effect. However, to effectively use this therapeutic strategy in clinic, one still has to solve a number of technical problems.
Collapse
|
|
31
|
Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors. Stem Cell Res Ther 2013; 4:70. [PMID: 23763837 PMCID: PMC3707041 DOI: 10.1186/scrt221] [Citation(s) in RCA: 164] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Accepted: 06/03/2013] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. METHODS Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. RESULTS Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage inflammatory protein-2, vascular endothelial growth factor, transforming growth factor-beta and IL-6) was increased. CONCLUSION These results indicate that BM-MSCs promote tumor growth and suggest that the crosstalk between tumor cells and BM-MSCs increased the expression of pro-angiogenic factors, which may have induced tumor cell proliferation and angiogenesis thereby increasing solid tumor growth.
Collapse
|
|
32
|
Gene recombinant bone marrow mesenchymal stem cells as a tumor-targeted suicide gene delivery vehicle in pulmonary metastasis therapy using non-viral transfection. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2013; 10:257-67. [PMID: 23770065 DOI: 10.1016/j.nano.2013.06.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 05/21/2013] [Accepted: 06/06/2013] [Indexed: 12/13/2022]
Abstract
UNLABELLED One of the main limitations of anti-tumor gene therapy is the lack of an effective way to deliver therapeutic genes to tumor sites. Bone marrow mesenchymal stem cells (BMSCs) have been proposed as cellular delivery vehicles to tumor sites in tumor-targeted cancer gene therapy. Here, we investigated the therapeutic effects of cytomegalovirus-thymidine kinase expressing BMSCs (TK-BMSCs) on pulmonary melanoma metastasis combined with prodrug ganciclovir. BMSCs were successfully engineered through a non-viral gene vector. The gene recombinant BMSCs migrated to the pulmonary area and were found to have the tendency to target tumor nodules after systemic delivery. In vitro results demonstrate that the engineered BMSCs have significant suicide effects in the presence of ganciclovir in a dose-dependent manner and can exert a sufficient bystander effect on B16F10 tumor cells in co-culture experiments. In vivo studies confirmed the therapeutic effects of TK-BMSCs/ganciclovir on the metastasis tumor model. FROM THE CLINICAL EDITOR This study investigates the possibility of gene transfer via bone marrow mesenchymal stem cells in anti-cancer gene therapy using a metastatic melanoma model and cytomegalovirus-thymidine kinase expressing stem cells, demonstrating clear therapeutic effects.
Collapse
|
|
33
|
Abstract
Stem cells have inherent tumor‑trophic migratory properties and can serve as vehicles for delivering effective, targeted therapy to isolated tumors and metastatic disease, making them promising anti‑cancer agents. Encapsulation of therapeutically engineered stem cells in hydrogels has been utilized to provide a physical barrier to protect the cells from hostile extrinsic factors and significantly improve the therapeutic efficacy of transplanted stem cells in different models of cancer. This review aims to discuss the potential of different stem cell types for cancer therapy, various engineered stem cell based therapies for cancer, stem cell encapsulation process and provide an in depth overview of current applications of therapeutic stem cell encapsulation in the highly malignant brain tumor, glioblastoma multiforme (GBM), as well as the prospects for their clinical translation.
Collapse
Affiliation(s)
- Khalid Shah
- Molecular Neurotherapy and Imaging Laboratory; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA; Department of Radiology; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA; Department of Neurology; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA; Harvard Stem Cell Institute; Harvard University; Cambridge, MA USA
| |
Collapse
|
|
34
|
Barar J, Omidi Y. Translational Approaches towards Cancer Gene Therapy: Hurdles and Hopes. BIOIMPACTS : BI 2012; 2:127-43. [PMID: 23678451 DOI: 10.5681/bi.2012.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Revised: 09/02/2012] [Accepted: 09/11/2012] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Of the cancer gene therapy approaches, gene silencing, suicide/apoptosis inducing gene therapy, immunogene therapy and targeted gene therapy are deemed to sub-stantially control the biological consequences of genomic changes in cancerous cells. Thus, a large number of clinical trials have been conducted against various malignancies. In this review, we will discuss recent translational progresses of gene and cell therapy of cancer. METHODS Essential information on gene therapy of cancer were reviewed and discussed towards their clinical translations. RESULTS Gene transfer has been rigorously studied in vitro and in vivo, in which some of these gene therapy endeavours have been carried on towards translational investigations and clinical applications. About 65% of gene therapy trials are related to cancer therapy. Some of these trials have been combined with cell therapy to produce personalized medicines such as Sipuleucel-T (Provenge®, marketed by Dendreon, USA) for the treatment of asymptomatic/minimally symptomatic metastatic hormone-refractory prostate cancer. CONCLUSION Translational approach links two diverse boundaries of basic and clinical researches. For successful translation of geno-medicines into clinical applications, it is essential 1) to have the guidelines and standard operating procedures for development and application of the genomedicines specific to clinically relevant biomarker(s); 2) to conduct necessary animal experimental studies to show the "proof of concept" for the proposed genomedicines; 3) to perform an initial clinical investigation; and 4) to initiate extensive clinical trials to address all necessary requirements. In short, translational researches need to be refined to accelerate the geno-medicine development and clinical applications.
Collapse
Affiliation(s)
- Jaleh Barar
- Ovarian Cancer Research Center, Translational Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | | |
Collapse
|
|
35
|
Wang CC, Xu H, Man GCW, Zhang T, Chu KO, Chu CY, Cheng JTY, Li G, He YX, Qin L, Lau TS, Kwong J, Chan TH. Prodrug of green tea epigallocatechin-3-gallate (Pro-EGCG) as a potent anti-angiogenesis agent for endometriosis in mice. Angiogenesis 2012; 16:59-69. [PMID: 22948799 DOI: 10.1007/s10456-012-9299-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 08/22/2012] [Indexed: 01/31/2023]
Abstract
Green tea epigallocatechin-3-gallate (EGCG) can inhibit angiogenesis and development of an experimental endometriosis model in mice, but it suffers from poor bioavailability. A prodrug of EGCG (pro-EGCG, EGCG octaacetate) is utilized to enhance the stability and bioavailability of EGCG in vivo. In this study, the potential of pro-EGCG as a potent anti-angiogenesis agent for endometriosis in mice was investigated. Homologous endometrium was subcutaneously transplanted into mice to receive either saline, vitamin E, EGCG or pro-EGCG treatment for 4 weeks. The growth of the endometrial implants were monitored by IVIS(®) non-invasive in vivo imaging during the interventions. Angiogenesis of the endometriotic lesions was determined by Cellvizio(®) in vivo imaging and SCANCO(®) Microfil microtomography. The bioavailability, anti-oxidation and anti-angiogenesis capacities of the treatments were measured in plasma and lesions. The implants with adjacent outer subcutaneous and inner abdominal muscle layers were collected for histological, microvessel and apoptosis examinations. The result showed that EGCG and pro-EGCG significantly decreased the growth of endometrial implants from the 2nd week to the 4th week of intervention. EGCG and pro-EGCG significantly reduced the lesion size and weight, inhibited functional and structural microvessels in the lesions, and enhanced lesion apoptosis at the end of interventions. The inhibition by pro-EGCG in all the angiogenesis parameters was significantly greater than that by EGCG, and pro-EGCG also had better bioavailability and greater anti-oxidation and anti-angiogenesis capacities than EGCG. Ovarian follicles and uterine endometrial glands were not affected by either EGCG or pro-EGCG. Vitamin E had no effect on endometriosis. In conclusion, pro-EGCG significantly inhibited the development, growth and angiogenesis of experimental endometriosis in mice with high efficacy, bioavailability, anti-oxidation and anti-angiogenesis capacities. Pro-EGCG could be a potent anti-angiogenesis agent for endometriosis.
Collapse
Affiliation(s)
- Chi Chiu Wang
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Mesenchymal stem cells in drug/gene delivery: implications for cell therapy. Ther Deliv 2012; 3:997-1004. [DOI: 10.4155/tde.12.69] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
|
|
37
|
Rameshwar P. Would cancer stem cells affect the future investment in stem cell therapy. World J Exp Med 2012; 2:26-9. [PMID: 24520530 PMCID: PMC3905576 DOI: 10.5493/wjem.v2.i2.26] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Revised: 04/01/2012] [Accepted: 04/10/2012] [Indexed: 02/06/2023] Open
Abstract
The common goal within the overwhelming interests in stem cell research is to safely translate the science to patients. Although there are various methods by which this goal can be reached, this editorial emphasizes the safety of mesenchymal stem cell (MSC) transplant and possible confounds by the growing information on cancer stem cells (CSCs). There are several ongoing clinical trials with MSCs and their interactions with CSCs need to be examined. The rapid knowledge on MSCs and CSCs has now collided with regards to the safe treatment of MSCs. The information discussed on MSCs can be extrapolated to other stem cells with similar phenotype and functions such as placenta stem cells. MSCs are attractive for cell therapy, mainly due to reduced ethical concerns, ease in expansion and reduced ability to be transformed. Also, MSCs can exert both immune suppressor and tissue regeneration simultaneously. It is expected that any clinical trial with MSCs will take precaution to ensure that the cells are not transformed. However, going forward, the different centers should be aware that MSCs might undergo oncogenic events, especially as undifferentiated cells or early differentiated cells. Another major concern for MSC therapy is their ability to promote tumor growth and perhaps, to protect CSCs by altered immune responses. These issues are discussed in light of a large number of undiagnosed cancers.
Collapse
Affiliation(s)
- Pranela Rameshwar
- Pranela Rameshwar, Department of Medicine, UMDNJ-New Jersey Medical School, 185 South Orange Ave, MSB, Room E-579, Newark, NJ 07103, United States
| |
Collapse
|
|
38
|
Tang J, Zhang L, She X, Zhou G, Yu F, Xiang J, Li G. Inhibiting CD164 expression in colon cancer cell line HCT116 leads to reduced cancer cell proliferation, mobility, and metastasis in vitro and in vivo. Cancer Invest 2012; 30:380-9. [PMID: 22409183 DOI: 10.3109/07357907.2012.666692] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND CD164 (Endolyn) is a sialomucin, which has been found to play roles in regulating proliferation, adhesion, and differentiation of hematopoietic stem cells. Possible association of CD164 with solid cancer development remains unknown. METHODS AND RESULTS We first studied CD164 expression in biopsies from colorectal cancer, breast, and ovary cancer patients by semi-quantitative immunohistochemistry, and found that CD164 was strongly expressed in all the colorectal cancer samples compared to the matching normal colon tissues. The possible roles of CD164 in colon cancer development were further investigated using a well-established human colon cancer cell line HCT116. We found that knockdown of CD164 expression in HCT116 cells significantly inhibited cell proliferation, mobility, and metastasis in vitro and in vivo. The knockdown of CD164 expression was associated with decreased chemokine receptor CXCR4 expression HCT116 cell surface and immunoprecipitation studies showed that CD164 formed complexes with CXCR4. CONCLUSIONS CD164 is highly expressed in the colon cancer sites, and it promotes HCT116 colon cancer cell proliferation and metastasis both in vitro and in vivo, and the effects may act through regulating CXCR4 signaling pathway. Therefore, CD164 may be a new target for diagnosis and treatment for colon cancer.
Collapse
Affiliation(s)
- Jingqun Tang
- Department of Cardiothoracic Surgery, Xiangya Second Hospital, Central South University, Changsha, Hunan, P.R. China
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Zhang L, Tang A, Zhou Y, Tang J, Luo Z, Jiang C, Li X, Xiang J, Li G. Tumor-conditioned mesenchymal stem cells display hematopoietic differentiation and diminished influx of Ca2+. Stem Cells Dev 2011; 21:1418-28. [PMID: 21905919 DOI: 10.1089/scd.2011.0319] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) that are present in many adult tissues can generate new cells either continuously or in response to injury/cancer. An increasing number of studies demonstrated that MSCs have the ability to differentiate into cells of mesodermal origin and transdifferentiate into cells such as hepatocytes, neural cells. There has been growing interest in the application of MSCs to cancer therapy. The relationship between MSCs and cancer cells remains highly controversial. In this study, we analyzed the interaction of bone marrow-derived MSCs and cancer cells by cell-cell contact and transwell culture system. The flow cytometry and real-time polymerase chain reaction showed that after coculture of MSCs and cancer cells, MSCs displayed the hematopoietic cell markers such as CD34, CD45, and CD11b. The CD68, MRCI, and CSF1R were dramatically upregulated after coculture. The cytokine array showed that MSCs after coculture secreted monokines and chemokines much more than that of intact MSCs. The MSCs under tumor conditions were responsive to stimulation with lipopolysaccharide by cytokines release. The tumor-conditioned MSCs showed phagocytic ability and enhanced release of nitric oxide, which are the characteristics of macrophages. Calcium ion is an important intracellular messenger responsible for differentiation and gene expression regulations. The influx of Ca(2+) into MSCs was obviously reduced after coculture. The blocking of calcium channel with verapamil obviously increased the expression of CD34, CD45, and CD11b, thus indicating that the diminished calcium ion influx is coupled with the hematopoietic differentiation of MSCs under tumor conditions. Taken together, in a cancer environment, MSCs could effectively differentiate into immune hematopoietic cells, precisely macrophages. Diminished transient influx of Ca(2+) may mediate the hematopoietic differentiation of MSCs.
Collapse
Affiliation(s)
- Liyang Zhang
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, People's Republic of China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Abstract
The attractiveness of prodrug cancer gene therapy by stem cells targeted to tumors lies in activating the prodrug directly within the tumor mass, thus avoiding systemic toxicity. Suicide gene therapy using genetically engineered mesenchymal stem cells has the advantage of being safe, because prodrug administration not only eliminates tumor cells but consequently kills the more resistant therapeutic stem cells as well. This review provides an explanation of the stem cell-targeted prodrug cancer gene therapy principle, with focus on the choice of prodrug, properties of bone marrow and adipose tissue-derived mesenchymal stem and neural stem cells as well as the mechanisms of their tumor homing ability. Therapeutic achievements of the cytosine deaminase/5-fluorocytosine prodrug system and Herpes simplex virus thymidine kinase/ganciclovir are discussed. In addition, delivery of immunostimulatory cytokines, apoptosis inducing genes, nanoparticles and antiangiogenic proteins by stem cells to tumors and metastases is discussed as a promising approach for antitumor therapy. Combinations of traditional, targeted and stem cell-directed gene therapy could significantly advance the treatment of cancer.
Collapse
Affiliation(s)
- Marina Cihova
- Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia
| | | | | |
Collapse
|