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Taeb S, Rostamzadeh D, Amini SM, Rahmati M, Golshekan M, Abedinzade M, Ahmadi E, Neha S, Najafi M. Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment. Curr Top Med Chem 2025; 25:243-262. [PMID: 38797895 DOI: 10.2174/0115680266299112240514103048] [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: 12/17/2023] [Revised: 04/03/2024] [Accepted: 04/16/2024] [Indexed: 05/29/2024]
Abstract
In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Seyed Mohammad Amini
- Radiation Biology Research center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Rahmati
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mostafa Golshekan
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mahmoud Abedinzade
- Department of Medical Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Elham Ahmadi
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Singh Neha
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Ma XN, Ho YK, Goie JYG, Ma CX, Sun ZB, Yao LQ, Zhu XL, Woo JY, Too HP, Li X. Evaluating the potential of off-the-shelf engineered mesenchymal stem cells for targeted Hepatocellular Carcinoma treatment: A multisite proof-of-concept study. Biomed Pharmacother 2024; 181:117676. [PMID: 39522266 DOI: 10.1016/j.biopha.2024.117676] [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: 08/28/2024] [Revised: 10/29/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
Although combining 5-fluorouracil (5-FU) and Interferon-beta (IFNb) improves response rates in Hepatocellular Carcinoma (HCC), the outcomes remain suboptimal. This study investigates the feasibility of using highly transfected Mesenchymal Stem Cells (MSCs) to deliver a chemotherapeutic (5-FU) and an immunomodulator (IFNb) for localized HCC treatment. Considering the crucial role of cold-chain transportation in off-the-shelf allogeneic therapy, the study also assesses the quality and efficacy of frozen-thawed engineered MSCs, simulating a multisite study process. The engineered MSCs maintained their phenotypes and tumour tropism. With just 10 % engineered MSCs, a killing efficiency of over 70 % was achieved in Huh-7 and HepG2 cell lines in vitro. Coculture studies, soft agar assays, and in vivo experiments confirmed that MSCs are neither tumorigenic nor tumour-promoting. Tumour mass growth was inhibited by >80 % in the treated mice group. TUNEL, Annexin-V, and Ki67 staining confirmed DNA damage, cell death, and proliferation inhibition post-treatment. Blood chemistry and the weight of the mice were comparable to the control group, indicating a good safety profile. This proof-of-concept study demonstrates the efficacy and safety of off-the-shelf CDUPRT-IFNβ_MSCs in targeting hepatocellular carcinoma (HCC) growth. Evaluating the complete value chain of MSC therapy in early-stage preclinical studies is essential for justifying further investigation and clinical translation of this cell product.
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Affiliation(s)
- Xiao Ni Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China; Medicine Laboratory Centre, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Yoon Khei Ho
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; AGeM Bio, Singapore 119276, Singapore; Singapore Innovate, Singapore 059911, Singapore
| | - Jian Yi Gerald Goie
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Cheng-Xu Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China; Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Zong-Bin Sun
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China
| | - Li-Qiong Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China; Medicine Laboratory Centre, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Xiao Liang Zhu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jun Yung Woo
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Heng-Phon Too
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China; Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China.
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Panda SK, Robinson N, Desiderio V. Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance. Biochim Biophys Acta Rev Cancer 2024; 1879:189205. [PMID: 39481663 DOI: 10.1016/j.bbcan.2024.189205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024]
Abstract
Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance. However, even with the third-generation inhibitors available, we are still far from effectively inhibiting the efflux transporters. Additionally, Cancer stem cells (CSCs) pose another significant challenge, contributing to cancer recurrence even after successful treatment. The ability of CSCs to enter dormancy and evade detection makes them almost invulnerable to chemotherapeutic drug treatment. In this review, we discuss how Mesenchymal stem cells (MSCs), one of the key components of the Tumor Microenvironment (TME), regulate both the CSCs and efflux transporters. We propose a new approach focusing on MSCs, which can be crucial to successfully address CSCs and efflux transporters.
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Affiliation(s)
- Sameer Kumar Panda
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy; Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Nirmal Robinson
- Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
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Baj J, Kołodziej M, Kobak J, Januszewski J, Syty K, Portincasa P, Forma A. Significance of Immune and Non-Immune Cell Stroma as a Microenvironment of Hepatocellular Carcinoma-From Inflammation to Hepatocellular Carcinoma Progression. Int J Mol Sci 2024; 25:10233. [PMID: 39408564 PMCID: PMC11475949 DOI: 10.3390/ijms251910233] [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: 07/28/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer as well as the most prevalent cause of death in the adult patient population with cirrhosis. The occurrence of HCC is primarily caused by chronic liver inflammation that might occur because of a viral infection, non-alcoholic fatty liver disease (NAFLD), or various lifestyle-associated factors. The objective of this review was to summarize the current knowledge regarding the microenvironment of HCC, indicating how immune- and non-immune-cell stroma might affect the onset and progression of HCC. Therefore, in the following narrative review, we described the role of tumor-infiltrating neutrophils, bone-marrow-derived cells, tumor-associated mast cells, cancer-associated fibroblasts, tumor-associated macrophages, liver-sinusoidal endothelial cells, lymphocytes, and certain cytokines in liver inflammation and the further progression to HCC. A better understanding of the HCC microenvironment might be crucial to introducing novel treatment strategies or combined therapies that could lead to more effective clinical outcomes.
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Affiliation(s)
- Jacek Baj
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Magdalena Kołodziej
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Joanna Kobak
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Jacek Januszewski
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Kinga Syty
- Institute of Health Sciences, John Paul the II Catholic University of Lublin, Konstantynów 1G, 20-708 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
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Wang H, Liu F, Wu X, Zhu G, Tang Z, Qu W, Zhao Q, Huang R, Tian M, Fang Y, Jiang X, Tao C, Gao J, Liu W, Zhou J, Fan J, Wu D, Shi Y. Cancer-associated fibroblasts contributed to hepatocellular carcinoma recurrence and metastasis via CD36-mediated fatty-acid metabolic reprogramming. Exp Cell Res 2024; 435:113947. [PMID: 38301989 DOI: 10.1016/j.yexcr.2024.113947] [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: 10/15/2023] [Revised: 01/18/2024] [Accepted: 01/21/2024] [Indexed: 02/03/2024]
Abstract
Cancer-associated fibroblasts (CAFs) are the main components in the tumor microenvironment. Tumors activate fibroblasts from quiescent state into activated state by secreting cytokines, and activated CAFs may in turn promote tumor progression and metastasis. Therefore, studies targeting CAFs could enrich the therapeutic options for tumor treatment. In this study, we demonstrate that the content of lipid droplets and the expression of autophagosomes were higher in CAFs than in peri-tumor fibroblasts (PTFs), which was inhibited by 5-(tetradecyloxy)-2-furoic acid(TOFA). The expression of CD36 in CAFs was higher than that in PTFs at both mRNA and protein levels. Inhibition of CD36 activity using either the CD36 inhibitor SSO or siRNA had a significant negative impact on the proliferation and migration abilities of CAFs, which was associated with reduced levels of relevant activated genes (α-SMA, FAP, Vimentin) and cytokines (IL-6, TGF-β and VEGF-α). SSO also inhibited HCC growth and tumorigenesis in nude mice orthotopically implanted with CAFs and HCC cells. Our data further show that CD36+CAFs affected the expression of PD-1 in CTLs leading to CTL exhaustion, and that patients with high CD36 expression in CAFs were correlated with shorter overall survival (OS). Together, our data demonstrate that CAFs were active in lipid metabolism with increased lipid content and lipophagy activity. CD36 may play a key role in the regulation of the biological behaviors of CAFs, which may influence the proliferation and migration of tumor cells by reprograming the lipid metabolism in tumor cells. Thus, CD36 could be an effective therapeutic target for the treatment of HCC.
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Affiliation(s)
- Han Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Department of General Surgery, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Fangming Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Xiaoling Wu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Guiqi Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Zheng Tang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Weifeng Qu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Qianfu Zhao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Run Huang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mengxin Tian
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Fang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Xifei Jiang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Chenyang Tao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Jun Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Weiren Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
| | - Duojiao Wu
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yinghong Shi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China; Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
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He JL, You YX, Pei X, Jiang W, Zeng QM, Chen B, Wang YH, Chen EQ, Tang H, Gao XF, Wu DB. Tracking of Stem Cells in Chronic Liver Diseases: Current Trends and Developments. Stem Cell Rev Rep 2024; 20:447-454. [PMID: 37993759 DOI: 10.1007/s12015-023-10659-2] [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] [Accepted: 11/15/2023] [Indexed: 11/24/2023]
Abstract
Stem cell therapy holds great promise for future clinical practice for treatment of advanced liver diseases. However, the fate of stem cells after transplantation, including the distribution, viability, and the cell clearance, has not been fully elucidated. Herein, recent advances regarding the imaging tools for stem cells tracking mainly in chronic liver diseases with the advantages and disadvantages of each approach have been described. Magnetic resonance imaging is a promising clinical imaging modality due to non-radioactivity, excellent penetrability, and high spatial resolution. Fluorescence imaging and radionuclide imaging demonstrate relatively increased sensitivity, with the latter excelling in real-time monitoring. Reporter genes specialize in long-term tracing. Nevertheless, the disadvantages of low sensitivity, radiation, exogenous gene risk are inevitably present in each of these means, respectively. In this review, we aim to comprehensively evaluate the current state of methods for tracking of stem cell, highlighting their strengths and weaknesses, and providing insights into their future potential. Multimodality imaging strategies may overcome the inherent limitations of single-modality imaging by combining the strengths of different imaging techniques to provide more comprehensive information in the clinical setting.
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Affiliation(s)
- Jin-Long He
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610065, China
| | - Yi-Xian You
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiong Pei
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing-Min Zeng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bin Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiu-Feng Gao
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610065, China.
| | - Dong-Bo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Lyu ZZ, Li M, Yang MY, Han MH, Yang Z. Exosome-mediated transfer of circRNA563 promoting hepatocellular carcinoma by targeting the microRNA148a-3p/metal-regulatory transcription factor-1 pathway. World J Gastroenterol 2023; 29:6060-6075. [PMID: 38130740 PMCID: PMC10731156 DOI: 10.3748/wjg.v29.i46.6060] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/24/2023] [Accepted: 11/17/2023] [Indexed: 12/13/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) exert anti-oncogenic effects via exosomes containing non-coding RNA (ncRNA), which play important roles in tumor biology. Our preliminary study identified the interaction of the ncRNA hsa_circ_0000563 (circ563) and the circ563-associated miR-148a-3p in exosomes, as miR-148a-3p and its target metal-regulatory transcription factor-1 (MTF-1) are implicated in hepatocellular carcinoma (HCC) progression. AIM To identify the clinical significance, functional implications, and mechanisms of circ563 in HCC. METHODS The expression levels of miR-148a-3p and MTF-1 in exosomes derived from MSC and HCC cells were compared, and their effects on HCC cells were assessed. Using a dual-luciferase reporter assay, miR-148a-3p was identified as an associated microRNA of circ563, whose role in HCC regulation was assessed in vitro and in vivo. RESULTS The silencing of circ563 blocked the HCC cell proliferation and invasion and induced apoptosis. Co-culturing of HCC cells with MSC-derived exosomes following circ563 overexpression promoted cell proliferation and metastasis and elicited changes in miR-148a-3p and MTF-1 expression. The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or MTF-1 depletion. Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth by upregulating the expression of MTF-1. In HCC tissues, circ563 expression was negatively correlated with miR-148a-3p expression but positively correlated with MTF-1 levels. CONCLUSION MSCs may exhibit anti-HCC activity through the exosomal circ563/miR-148a-3p/MTF-1 pathway, while exosomes can transmit circ563 to promote oncogenic behavior by competitively binding to miR-148a-3p to activate MTF-1.
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Affiliation(s)
- Zhuo-Zhen Lyu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Meng Li
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Ming-Yu Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Mei-Hong Han
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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Shams F, Pourjabbar B, Hashemi N, Farahmandian N, Golchin A, Nuoroozi G, Rahimpour A. Current progress in engineered and nano-engineered mesenchymal stem cells for cancer: From mechanisms to therapy. Biomed Pharmacother 2023; 167:115505. [PMID: 37716113 DOI: 10.1016/j.biopha.2023.115505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
Mesenchymal stem cells (MSCs), as self-renewing multipotent stromal cells, have been considered promising agents for cancer treatment. A large number of studies have demonstrated the valuable properties of MSC-based treatment, such as low immunogenicity and intrinsic tumor-trophic migratory properties. To enhance the potency of MSCs for therapeutic purposes, equipping MSCs with targeted delivery functions using genetic engineering is highly beneficial. Genetically engineered MSCs can express tumor suppressor agents such as pro-apoptotic, anti-proliferative, anti-angiogenic factors and act as ideal delivery vehicles. MSCs can also be loaded with nanoparticle drugs for increased efficacy and externally moderated targeting. Moreover, exosomes secreted by MSCs have important physiological properties, so they can contribute to intercellular communication and transfer cargo into targeted tumor cells. The precise role of genetically modified MSCs in tumor environments is still up for debate, but the beginning of clinical trials has been confirmed by promising results from preclinical investigations of MSC-based gene therapy for a wide range of malignancies. This review highlights the advanced techniques of engineering/nano-engineering and MSC-derived exosomes in tumor-targeted therapy.
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Affiliation(s)
- Forough Shams
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Navid Farahmandian
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Golchin
- Cellular & Molecular Research Center, Cellular & Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia 57157993313, Iran; Department of Clinical Biochemistry & Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia 57157993313, Islamic Republic of Iran
| | - Ghader Nuoroozi
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azam Rahimpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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9
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Kitzberger C, Shehzad K, Morath V, Spellerberg R, Ranke J, Steiger K, Kälin RE, Multhoff G, Eiber M, Schilling F, Glass R, Weber WA, Wagner E, Nelson PJ, Spitzweg C. Interleukin-6-controlled, mesenchymal stem cell-based sodium/iodide symporter gene therapy improves survival of glioblastoma-bearing mice. Mol Ther Oncolytics 2023; 30:238-253. [PMID: 37701849 PMCID: PMC10493263 DOI: 10.1016/j.omto.2023.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 08/11/2023] [Indexed: 09/14/2023] Open
Abstract
New treatment strategies are urgently needed for glioblastoma (GBM)-a tumor resistant to standard-of-care treatment with a high risk of recurrence and extremely poor prognosis. Based on their intrinsic tumor tropism, adoptively applied mesenchymal stem cells (MSCs) can be harnessed to deliver the theranostic sodium/iodide symporter (NIS) deep into the tumor microenvironment. Interleukin-6 (IL-6) is a multifunctional, highly expressed cytokine in the GBM microenvironment including recruited MSCs. MSCs engineered to drive NIS expression in response to IL-6 promoter activation offer the possibility of a new tumor-targeted gene therapy approach of GBM. Therefore, MSCs were stably transfected with an NIS-expressing plasmid controlled by the human IL-6 promoter (IL-6-NIS-MSCs) and systemically applied in mice carrying orthotopic GBM. Enhanced radiotracer uptake by 18F-Tetrafluoroborate-PET/magnetic resonance imaging (MRI) was detected in tumors after IL-6-NIS-MSC application as compared with mice that received wild-type MSCs. Ex vivo analysis of tumors and non-target organs showed tumor-specific NIS protein expression. Subsequent 131I therapy after IL-6-NIS-MSC application resulted in significantly delayed tumor growth assessed by MRI and improved median survival up to 60% of GBM-bearing mice as compared with controls. In conclusion, the application of MSC-mediated NIS gene therapy focusing on IL-6 biology-induced NIS transgene expression represents a promising approach for GBM treatment.
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Affiliation(s)
- Carolin Kitzberger
- Department of Internal Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Khuram Shehzad
- Department of Internal Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Volker Morath
- Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Rebekka Spellerberg
- Department of Internal Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Julius Ranke
- Department of Internal Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Roland E. Kälin
- Neurosurgical Research, Department of Neurosurgery, LMU University Hospital, LMU Munich, Munich, Germany
- Walter Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Gabriele Multhoff
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Radiation Immuno-Oncology Group, Munich, Germany
- Department of Radiation Oncology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Matthias Eiber
- Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Franz Schilling
- Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Rainer Glass
- Neurosurgical Research, Department of Neurosurgery, LMU University Hospital, LMU Munich, Munich, Germany
- Walter Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Wolfgang A. Weber
- Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Centre for System-Based Drug Research and Centre for Nanoscience, LMU Munich, Munich, Germany
| | - Peter J. Nelson
- Department of Internal Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA
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10
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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.
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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
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11
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Ma Z, Hua J, Liu J, Zhang B, Wang W, Yu X, Xu J. Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges. Int J Mol Sci 2023; 24:3559. [PMID: 36834969 PMCID: PMC9966548 DOI: 10.3390/ijms24043559] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 02/01/2023] [Indexed: 02/12/2023] Open
Abstract
Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer.
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Affiliation(s)
- Zhilong Ma
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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12
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Ho YK, Loke KM, Woo JY, Lee YL, Too HP. Cryopreservation does not change the performance and characteristics of allogenic mesenchymal stem cells highly over-expressing a cytoplasmic therapeutic transgene for cancer treatment. Stem Cell Res Ther 2022; 13:519. [PMID: 36376945 PMCID: PMC9663191 DOI: 10.1186/s13287-022-03198-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 10/26/2022] [Indexed: 11/16/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) driven gene directed enzyme prodrug therapy is a promising approach to deliver therapeutic agents to target heterogenous solid tumours. To democratize such a therapy, cryopreservation along with cold chain transportation is an essential part of the logistical process and supply chain. Previously, we have successfully engineered MSCs by a non-viral DNA transfection approach for prolonged and exceptionally high expression of the fused transgene cytosine deaminase, uracil phosphoribosyl transferase and green fluorescent protein (CD::UPRT::GFP). The aim of this study was to determine the effects of cryopreservation of MSCs engineered to highly overexpress this cytoplasmic therapeutic transgene. Methods Modified MSCs were preserved in a commercially available, GMP-grade cryopreservative—CryoStor10 (CS10) for up to 11 months. Performance of frozen-modified MSCs was compared to freshly modified equivalents in vitro. Cancer killing potency was evaluated using four different cancer cell lines. Migratory potential was assessed using matrigel invasion assay and flow cytometric analysis for CXCR4 expression. Frozen-modified MSC was used to treat canine patients via intra-tumoral injections, or by intravenous infusion followed by a daily dose of 5-flucytosine (5FC). Results We found that cryopreservation did not affect the transgene expression, cell viability, adhesion, phenotypic profile, and migration of gene modified canine adipose tissue derived MSCs. In the presence of 5FC, the thawed and freshly modified MSCs showed comparable cytotoxicity towards one canine and three human cancer cell lines in vitro. These cryopreserved cells were stored for about a year and then used to treat no-option-left canine patients with two different types of cancers and notably, the patients showed progression-free interval of more than 20 months, evidence of the effectiveness in treating spontaneously occurring cancers. Conclusion This study supports the use of cryopreserved, off-the-shelf transiently transfected MSCs for cancer treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03198-z.
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13
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Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185:114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 12/16/2022]
Abstract
The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.
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Szewc M, Radzikowska-Bűchner E, Wdowiak P, Kozak J, Kuszta P, Niezabitowska E, Matysiak J, Kubiński K, Masłyk M. MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents-A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives. Int J Mol Sci 2022; 23:2745. [PMID: 35269887 PMCID: PMC8911180 DOI: 10.3390/ijms23052745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure.
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Affiliation(s)
- Monika Szewc
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Elżbieta Radzikowska-Bűchner
- Department of Plastic, Reconstructive and Maxillary Surgery, Central Clinical Hospital MSWiA, 02-507 Warsaw, Poland;
| | - Paulina Wdowiak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Joanna Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Piotr Kuszta
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Ewa Niezabitowska
- Department of Urology and Urological Oncology, Multidisciplinary Hospital in Lublin, 20-400 Lublin, Poland;
| | - Joanna Matysiak
- Department of Chemistry, University of Life Sciences in Lublin, 20-950 Lublin, Poland;
| | - Konrad Kubiński
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
| | - Maciej Masłyk
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
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15
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Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, Mazzucato M, Agostini F. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J Stem Cells 2022; 14:54-75. [PMID: 35126828 PMCID: PMC8788179 DOI: 10.4252/wjsc.v14.i1.54] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.
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Affiliation(s)
- Carla Vicinanza
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Elisabetta Lombardi
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Da Ros
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Miriam Marangon
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Cristina Durante
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Mario Mazzucato
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Agostini
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
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16
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Takayama Y, Kusamori K, Nishikawa M. Mesenchymal stem/stromal cells as next-generation drug delivery vehicles for cancer therapeutics. Expert Opin Drug Deliv 2021; 18:1627-1642. [PMID: 34311638 DOI: 10.1080/17425247.2021.1960309] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Drug delivery to solid tumors remains a significant therapeutic challenge. Mesenchymal stem/stromal cells (MSCs) home to tumor tissues and can be employed as tumor targeted drug/gene delivery vehicles. Reportedly, therapeutic gene- or anti-cancer drug-loaded MSCs have shown remarkable anti-tumor effects in preclinical studies, and some clinical trials for assessing therapeutic MSCs in patients with cancer have been registered. AREAS COVERED In the present review, we first discuss the source and interdonor heterogeneity of MSCs, their tumor-homing mechanism, and the route of MSC administration in MSC-based cancer therapy. We then summarize the therapeutic applications of MSCs as a drug delivery vehicle for therapeutic genes or anti-cancer drugs and the drug delivery mechanism from drug-loaded MSCs to cancer cells. EXPERT OPINION Although numerous preclinical studies have revealed significant anti-tumor effects, several clinical trials assessing MSC-based cancer gene therapy have failed to demonstrate corroborative results, documenting limited therapeutic effects. Notably, a successful clinical outcome with MSC-based cancer therapy would require the interdonor heterogeneity of administered MSCs to be resolved, along with improved tumor-homing efficiency and optimized drug delivery efficiency from MSCs to cancer cells.
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Affiliation(s)
- Yukiya Takayama
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba Japan
| | - Kosuke Kusamori
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba Japan
| | - Makiya Nishikawa
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba Japan
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Hassanzadeh A, Altajer AH, Rahman HS, Saleh MM, Bokov DO, Abdelbasset WK, Marofi F, Zamani M, Yaghoubi Y, Yazdanifar M, Pathak Y, Chartrand MS, Jarahian M. Mesenchymal Stem/Stromal Cell-Based Delivery: A Rapidly Evolving Strategy for Cancer Therapy. Front Cell Dev Biol 2021; 9:686453. [PMID: 34322483 PMCID: PMC8311597 DOI: 10.3389/fcell.2021.686453] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapy has become an attractive and advanced scientific research area in the context of cancer therapy. This interest is closely linked to the MSC-marked tropism for tumors, suggesting them as a rational and effective vehicle for drug delivery for both hematological and solid malignancies. Nonetheless, the therapeutic application of the MSCs in human tumors is still controversial because of the induction of several signaling pathways largely contributing to tumor progression and metastasis. In spite of some evidence supporting that MSCs may sustain cancer pathogenesis, increasing proofs have indicated the suppressive influences of MSCs on tumor cells. During the last years, a myriad of preclinical and some clinical studies have been carried out or are ongoing to address the safety and efficacy of the MSC-based delivery of therapeutic agents in diverse types of malignancies. A large number of studies have focused on the MSC application as delivery vehicles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemotherapeutic drug such as gemcitabine (GCB), paclitaxel (PTX), and doxorubicin (DOX), prodrugs such as 5-fluorocytosine (5-FC) and ganciclovir (GCV), and immune cell-activating cytokines along with oncolytic virus. In the current review, we evaluate the latest findings rendering the potential of MSCs to be employed as potent gene/drug delivery vehicle for inducing tumor regression with a special focus on the in vivo reports performed during the last two decades.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Sciences, University of Anbar, Ramadi, Iraq
| | - Dmitry O. Bokov
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Yoda Yaghoubi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Yashwant Pathak
- Professor and Associate Dean for Faculty Affairs, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
- Adjunct Professor, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
| | | | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
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18
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Hassanzadeh A, Shamlou S, Yousefi N, Nikoo M, Verdi J. Genetically-Modified Stem Cell in Regenerative Medicine and Cancer Therapy; A New Era. Curr Gene Ther 2021; 22:23-39. [PMID: 34238158 DOI: 10.2174/1566523221666210707125342] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/20/2021] [Accepted: 04/25/2021] [Indexed: 11/22/2022]
Abstract
Recently, genetic engineering by various strategies to stimulate gene expression in a specific and controllable mode is a speedily growing therapeutic approach. Genetic modification of human stem or progenitor cells, such as embryonic stem cells (ESCs), neural progenitor cells (NPCs), mesenchymal stem/stromal cells (MSCs), and hematopoietic stem cells (HSCs) for direct delivery of specific therapeutic molecules or genes has been evidenced as an opportune plan in the context of regenerative medicine due to their supported viability, proliferative features, and metabolic qualities. On the other hand, a large number of studies have investigated the efficacy of modified stem cells in cancer therapy using cells from various sources, disparate transfection means for gene delivery, different transfected yields, and wide variability of tumor models. Accordingly, cell-based gene therapy holds substantial aptitude for the treatment of human malignancy as it could relieve signs or even cure cancer succeeding expression of therapeutic or suicide transgene products; however, there exist inconsistent results in this regard. Herein, we deliver a brief overview of stem cell potential to use in cancer therapy and regenerative medicine and importantly discuss stem cells based gene delivery competencies to stimulate tissue repair and replacement in concomitant with their potential to use as an anti-cancer therapeutic strategy, focusing on the last two decades in vivo studies.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloufar Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Javad Verdi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Wang LL, Janes ME, Kumbhojkar N, Kapate N, Clegg JR, Prakash S, Heavey MK, Zhao Z, Anselmo AC, Mitragotri S. Cell therapies in the clinic. Bioeng Transl Med 2021; 6:e10214. [PMID: 34027097 PMCID: PMC8126820 DOI: 10.1002/btm2.10214] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/30/2021] [Accepted: 02/09/2021] [Indexed: 12/16/2022] Open
Abstract
Cell therapies have emerged as a promising therapeutic modality with the potential to treat and even cure a diverse array of diseases. Cell therapies offer unique clinical and therapeutic advantages over conventional small molecules and the growing number of biologics. Particularly, living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot; cell therapies have expanded the spectrum of available therapeutic options to include key cellular functions and processes. As such, cell therapies are currently one of the most investigated therapeutic modalities in both preclinical and clinical settings, with many products having been approved and many more under active clinical investigation. Here, we highlight the diversity and key advantages of cell therapies and discuss their current clinical advances. In particular, we review 28 globally approved cell therapy products and their clinical use. We also analyze >1700 current active clinical trials of cell therapies, with an emphasis on discussing their therapeutic applications. Finally, we critically discuss the major biological, manufacturing, and regulatory challenges associated with the clinical translation of cell therapies.
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Affiliation(s)
- Lily Li‐Wen Wang
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
- Harvard‐MIT Division of Health Sciences and Technology, Massachusetts Institute of TechnologyCambridgeMassachusettsUSA
| | - Morgan E. Janes
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
- Harvard‐MIT Division of Health Sciences and Technology, Massachusetts Institute of TechnologyCambridgeMassachusettsUSA
| | - Ninad Kumbhojkar
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Neha Kapate
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
- Harvard‐MIT Division of Health Sciences and Technology, Massachusetts Institute of TechnologyCambridgeMassachusettsUSA
| | - John R. Clegg
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Supriya Prakash
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Mairead K. Heavey
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Zongmin Zhao
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Aaron C. Anselmo
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Samir Mitragotri
- John A. Paulson School of Engineering & Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired EngineeringBostonMassachusettsUSA
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20
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Mesenchymal stem/stromal cells: Developmental origin, tumorigenesis and translational cancer therapeutics. Transl Oncol 2020; 14:100948. [PMID: 33190044 PMCID: PMC7672320 DOI: 10.1016/j.tranon.2020.100948] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/27/2020] [Accepted: 11/05/2020] [Indexed: 12/20/2022] Open
Abstract
While a large and growing body of research has demonstrated that mesenchymal stem/stromal cells (MSCs) play a dual role in tumor growth and inhibition, studies exploring the capability of MSCs to contribute to tumorigenesis are rare. MSCs are key players during tumorigenesis and cancer development, evident in their faculty to increase cancer stem cells (CSCs) population, to generate the precursors of certain forms of cancer (e.g. sarcoma), and to induce epithelial-mesenchymal transition to create the CSC-like state. Indeed, the origin and localization of the native MSCs in their original tissues are not known. MSCs are identified in the primary tumor sites and the fetal and extraembryonic tissues. Acknowledging the developmental origin of MSCs and tissue-resident native MSCs is essential for better understanding of MSC contributions to the cellular origin of cancer. This review stresses that the plasticity of MSCs can therefore instigate further risk in select therapeutic strategies for some patients with certain forms of cancer. Towards this end, to explore the safe and effective MSC-based anti-cancer therapies requires a strong understanding of the cellular and molecular mechanisms of MSC action, ultimately guiding new strategies for delivering treatment. While clinical trial efforts using MSC products are currently underway, this review also provides new insights on the underlying mechanisms of MSCs to tumorigenesis and focuses on the approaches to develop MSC-based anti-cancer therapeutic applications.
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21
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Yang X, Meng Y, Han Z, Ye F, Wei L, Zong C. Mesenchymal stem cell therapy for liver disease: full of chances and challenges. Cell Biosci 2020; 10:123. [PMID: 33117520 PMCID: PMC7590738 DOI: 10.1186/s13578-020-00480-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
Liver disease is a major health problem that endangers human health worldwide. Currently, whole organ allograft transplantation is the gold standard for the treatment of end-stage liver disease. A shortage of suitable organs, high costs and surgical complications limit the application of liver transplantation. Mesenchymal stem cell therapy has been considered as a promising alternative approach for end-stage liver disease. Some clinical trials have confirmed the effectiveness of MSC therapy for liver disease, but its application has not been promoted and approved. There are still many issues that should be solved prior to using MSC therapy in clinical applications. The types of liver disease that are most suitable for MSC application should be determined, and the preparation and engraftment of MSCs should be standardized. These may be bottlenecks that limit the use of MSCs. We investigated 22 completed and several ongoing clinical trials to discuss these questions from a clinical perspective. We also discussed the important mechanisms by which MSCs play a therapeutic role in liver disease. Finally, we also proposed novel prospective approaches that can improve the therapeutic effect of MSCs.
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Affiliation(s)
- Xue Yang
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
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22
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Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy. Mol Ther 2020; 29:788-803. [PMID: 33068779 DOI: 10.1016/j.ymthe.2020.10.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/22/2020] [Accepted: 10/12/2020] [Indexed: 12/13/2022] Open
Abstract
The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6-48 h after or 24-48 h before hyperthermia treatment. Using 123I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of 123I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated 131I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.
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23
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A highly efficient non-viral process for programming mesenchymal stem cells for gene directed enzyme prodrug cancer therapy. Sci Rep 2020; 10:14257. [PMID: 32868813 PMCID: PMC7458920 DOI: 10.1038/s41598-020-71224-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) driven gene-directed enzyme prodrug therapy has emerged as a potential strategy for cancer treatment. The tumour-nesting properties of MSCs enable these vehicles to target tumours and metastases with effective therapies. A crucial step in engineering MSCs is the delivery of genetic material with low toxicity and high efficiency. Due to the low efficiency of current transfection methods, viral vectors are used widely to modify MSCs in preclinical and clinical studies. We show, for the first time, the high transfection efficiency (> 80%) of human adipose tissue derived-MSCs (AT-MSCs) using a cost-effective and off-the-shelf Polyethylenimine, in the presence of histone deacetylase 6 inhibitor and fusogenic lipids. Notably, the phenotypes of MSCs remained unchanged post-modification. AT-MSCs engineered with a fused transgene, yeast cytosine deaminase::uracil phosphoribosyltransferase (CDy::UPRT) displayed potent cytotoxic effects against breast, glioma, gastric cancer cells in vitro. The efficiency of eliminating gastric cell lines were effective even when using 7-day post-transfected AT-MSCs, indicative of the sustained expression and function of the therapeutic gene. In addition, significant inhibition of temozolomide resistant glioma tumour growth in vivo was observed with a single dose of therapeutic MSC. This study demonstrated an efficient non-viral modification process for MSC-based prodrug therapy.
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24
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Wei D, Hou J, Zheng K, Jin X, Xie Q, Cheng L, Sun X. Suicide Gene Therapy Against Malignant Gliomas by the Local Delivery of Genetically Engineered Umbilical Cord Mesenchymal Stem Cells as Cellular Vehicles. Curr Gene Ther 2020; 19:330-341. [PMID: 31657679 DOI: 10.2174/1566523219666191028103703] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 10/13/2019] [Accepted: 10/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Glioblastoma (GBM) is a malignant tumor that is difficult to eliminate, and new therapies are thus strongly desired. Mesenchymal stem cells (MSCs) have the ability to locate to injured tissues, inflammation sites and tumors and are thus good candidates for carrying antitumor genes for the treatment of tumors. Treating GBM with MSCs that have been transduced with the herpes simplex virus thymidine kinase (HSV-TK) gene has brought significant advances because MSCs can exert a bystander effect on tumor cells upon treatment with the prodrug ganciclovir (GCV). OBJECTIVE In this study, we aimed to determine whether HSV-TK-expressing umbilical cord mesenchymal stem cells (MSCTKs) together with prodrug GCV treatment could exert a bystander killing effect on GBM. METHODS AND RESULTS Compared with MSCTK: U87 ratio at 1:10,1:100 and 1:100, GCV concentration at 2.5µM or 250µM, when MSCTKs were cocultured with U87 cells at a ratio of 1:1, 25 µM GCV exerted a more stable killing effect. Higher amounts of MSCTKs cocultured with U87 cells were correlated with a better bystander effect exerted by the MSCTK/GCV system. We built U87-driven subcutaneous tumor models and brain intracranial tumor models to evaluate the efficiency of the MSCTK/GCV system on subcutaneous and intracranial tumors and found that MSCTK/GCV was effective in both models. The ratio of MSCTKs and tumor cells played a critical role in this therapeutic effect, with a higher MSCTK/U87 ratio exerting a better effect. CONCLUSION This research suggested that the MSCTK/GCV system exerts a strong bystander effect on GBM tumor cells, and this system may be a promising assistant method for GBM postoperative therapy.
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Affiliation(s)
- Dan Wei
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China
| | - JiaLi Hou
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China
| | - Ke Zheng
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China
| | - Xin Jin
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China
| | - Qi Xie
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China
| | - Lamei Cheng
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China
| | - Xuan Sun
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China
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25
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Levy O, Kuai R, Siren EMJ, Bhere D, Milton Y, Nissar N, De Biasio M, Heinelt M, Reeve B, Abdi R, Alturki M, Fallatah M, Almalik A, Alhasan AH, Shah K, Karp JM. Shattering barriers toward clinically meaningful MSC therapies. SCIENCE ADVANCES 2020; 6:eaba6884. [PMID: 32832666 PMCID: PMC7439491 DOI: 10.1126/sciadv.aba6884] [Citation(s) in RCA: 405] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 06/05/2020] [Indexed: 05/11/2023]
Abstract
More than 1050 clinical trials are registered at FDA.gov that explore multipotent mesenchymal stromal cells (MSCs) for nearly every clinical application imaginable, including neurodegenerative and cardiac disorders, perianal fistulas, graft-versus-host disease, COVID-19, and cancer. Several companies have or are in the process of commercializing MSC-based therapies. However, most of the clinical-stage MSC therapies have been unable to meet primary efficacy end points. The innate therapeutic functions of MSCs administered to humans are not as robust as demonstrated in preclinical studies, and in general, the translation of cell-based therapy is impaired by a myriad of steps that introduce heterogeneity. In this review, we discuss the major clinical challenges with MSC therapies, the details of these challenges, and the potential bioengineering approaches that leverage the unique biology of MSCs to overcome the challenges and achieve more potent and versatile therapies.
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Affiliation(s)
- Oren Levy
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Rui Kuai
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Erika M. J. Siren
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Deepak Bhere
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Yuka Milton
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Nabeel Nissar
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael De Biasio
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Martina Heinelt
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Brock Reeve
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Reza Abdi
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Meshael Alturki
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Mohanad Fallatah
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Abdulaziz Almalik
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Ali H. Alhasan
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Khalid Shah
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Jeffrey M. Karp
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
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26
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Cheng YQ, Wang SB, Liu JH, Jin L, Liu Y, Li CY, Su YR, Liu YR, Sang X, Wan Q, Liu C, Yang L, Wang ZC. Modifying the tumour microenvironment and reverting tumour cells: New strategies for treating malignant tumours. Cell Prolif 2020; 53:e12865. [PMID: 32588948 PMCID: PMC7445401 DOI: 10.1111/cpr.12865] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023] Open
Abstract
The tumour microenvironment (TME) plays a pivotal role in tumour fate determination. The TME acts together with the genetic material of tumour cells to determine their initiation, metastasis and drug resistance. Stromal cells in the TME promote the growth and metastasis of tumour cells by secreting soluble molecules or exosomes. The abnormal microenvironment reduces immune surveillance and tumour killing. The TME causes low anti‐tumour drug penetration and reactivity and high drug resistance. Tumour angiogenesis and microenvironmental hypoxia limit the drug concentration within the TME and enhance the stemness of tumour cells. Therefore, modifying the TME to effectively attack tumour cells could represent a comprehensive and effective anti‐tumour strategy. Normal cells, such as stem cells and immune cells, can penetrate and disrupt the abnormal TME. Reconstruction of the TME with healthy cells is an exciting new direction for tumour treatment. We will elaborate on the mechanism of the TME to support tumours and the current cell therapies for targeting tumours and the TME—such as immune cell therapies, haematopoietic stem cell (HSC) transplantation therapies, mesenchymal stem cell (MSC) transfer and embryonic stem cell‐based microenvironment therapies—to provide novel ideas for producing breakthroughs in tumour therapy strategies.
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Affiliation(s)
- Ya Qi Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shou Bi Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jia Hui Liu
- Affiliated Dongguan People's Hospital, Southern Medical University, Dongguan, China
| | - Lin Jin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ying Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chao Yang Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ya Ru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yu Run Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xuan Sang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Qi Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chang Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Liu Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zhi Chong Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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27
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Li JN, Li W, Cao LQ, Liu N, Zhang K. Efficacy of mesenchymal stem cells in the treatment of gastrointestinal malignancies. World J Gastrointest Oncol 2020; 12:365-382. [PMID: 32368316 PMCID: PMC7191336 DOI: 10.4251/wjgo.v12.i4.365] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/03/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs), which are a kind of stem cell, possess an immune privileged nature, tumour homing features, and multi-lineage differentiation ability. MSCs have been studied in many fields, such as tissue engineering, nervous system diseases, and cancer treatment. In recent years, an increasing number of researchers have focused on the effects of MSCs on various kinds of tumours. However, the concrete anticancer efficacy of MSCs is still controversial. Gastrointestinal (GI) malignancies are the major causes of cancer-related death worldwide. The interactions of MSCs and GI cancer cells in specific conditions have attracted increasing attention. In this review, we introduce the characteristics of MSCs and analyse the effects of MSCs on GI malignancies, including gastric cancer, hepatoma, pancreatic cancer, and colorectal cancer. In addition, we also provide our perspectives on why MSCs may play different roles in GI malignancies and further research directions to increase the treatment efficacy of MSCs on GI malignancies.
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Affiliation(s)
- Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Wei Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Lan-Qing Cao
- Department of Pathology, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Ning Liu
- Department of Central Laboratory, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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28
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Liu J, Shi Y, Han J, Zhang Y, Cao Z, Cheng J. Quantitative Tracking Tumor Suppression Efficiency of Human Umbilical Cord-Derived Mesenchymal Stem Cells by Bioluminescence Imaging in Mice Hepatoma Model. Int J Stem Cells 2020; 13:104-115. [PMID: 31887848 PMCID: PMC7119203 DOI: 10.15283/ijsc19098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 10/07/2019] [Accepted: 11/07/2019] [Indexed: 01/02/2023] Open
Abstract
Background and Objectives Tracking of the tumor progression by MSCs-based therapy is being increasingly important in evaluating relative therapy effectively. Herein, Bioluminescence imaging (BLI) technology was used to dynamically and quantitatively track the hepatocellular carcinoma suppressive effects by human umbilical cord mesenchymal stem cells (UC-MSCs). Methods and Results The stem cells present typical phenotypic characteristics and differentiation ability by morphology and flow cytometry analysis of marker expression. Then, the growth inhibition effect of conditioned medium and UC-MSC on H7402 cells was studied. It is found both the conditioned medium and UC-MSC can effectively decrease the proliferation of H7402 cells compared with the control group. Meanwhile, the relative migration of UC-MSC to H7402 is also increased through the transwell migration assay. In addition, a mice hepatoma tumor model was built by H7402 cells which can express a pLenti-6.3/DEST-CMV-luciferase 2-mKate2 gene. The effect of stem cells on growth inhibition of tumor in a mice transplantation model was dynamically monitored by bioluminescence imaging within 5 weeks. It has shown the bioluminescence signal intensity of the tumor model was significantly higher than that of the UC-MSC co-acting tumor model, indicating that the inhibition of UC-MSC on liver cancer resulted in low expression of bioluminescent signals. Conclusions The microenvironment of UC-MSCs can effectively inhibit the growth of liver cancer cells, and this therapeutic effect can be dynamically and quantitatively monitored in vivo by BLI. This is of great significance for the imaging research and application of stem cells in anticancer therapy.
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Affiliation(s)
- Jingjing Liu
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yupeng Shi
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Han
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Zhang
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenghao Cao
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingliang Cheng
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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29
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Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 16:204-224. [PMID: 32071924 PMCID: PMC7012781 DOI: 10.1016/j.omtm.2020.01.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess several fairly unique properties that, when combined, make them ideally suited for cellular-based immunotherapy and as vehicles for gene and drug delivery for a wide range of diseases and disorders. Key among these are: (1) their relative ease of isolation from a variety of tissues; (2) the ability to be expanded in culture without a loss of functionality, a property that varies to some degree with tissue source; (3) they are relatively immune-inert, perhaps obviating the need for precise donor/recipient matching; (4) they possess potent immunomodulatory functions that can be tailored by so-called licensing in vitro and in vivo; (5) the efficiency with which they can be modified with viral-based vectors; and (6) their almost uncanny ability to selectively home to damaged tissues, tumors, and metastases following systemic administration. In this review, we summarize the latest research in the immunological properties of MSCs, their use as immunomodulatory/anti-inflammatory agents, methods for licensing MSCs to customize their immunological profile, and their use as vehicles for transferring both therapeutic genes in genetic disease and drugs and genes designed to destroy tumor cells.
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30
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Schmohl KA, Müller AM, Nelson PJ, Spitzweg C. Thyroid Hormone Effects on Mesenchymal Stem Cell Biology in the Tumour Microenvironment. Exp Clin Endocrinol Diabetes 2019; 128:462-468. [PMID: 31648351 DOI: 10.1055/a-1022-9874] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Non-classical thyroid hormone signalling via cell surface receptor integrin αvβ3, expressed on most cancer cells and proliferating endothelial cells, has been shown to drive tumour cell proliferation and survival, as well as angiogenesis. Tumours develop within a complex microenvironment that is composed of many different cell types, including mesenchymal stem cells. These multipotent progenitor cells actively home to growing tumours where they differentiate into cancer-associated fibroblast-like cells and blood vessel-stabilising pericytes and thus support the tumour's fibrovascular network. Integrin αvβ3 expression on mesenchymal stem cells makes them susceptible to thyroid hormone stimulation. Indeed, our studies demonstrated - for the first time - that thyroid hormones stimulate the differentiation of mesenchymal stem cells towards a carcinoma-associated fibroblast-/pericyte-like and hypoxia-responsive, pro-angiogenic phenotype, characterised by the secretion of numerous paracrine pro-angiogenic factors, in addition to driving their migration, invasion, and recruitment to the tumour microenvironment in an experimental hepatocellular carcinoma model. The deaminated thyroid hormone metabolite tetrac, a specific inhibitor of thyroid hormone action at the integrin site, reverses these effects. The modulation of mesenchymal stem cell signalling and recruitment by thyroid hormones via integrin αvβ3 adds a further layer to the multifaceted effects of thyroid hormones on tumour progression, with important implications for the management of cancer patients and suggests a novel mechanism for the anti-tumour activity of tetrac.
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Affiliation(s)
| | - Andrea Maria Müller
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Peter Jon Nelson
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
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von Einem JC, Guenther C, Volk HD, Grütz G, Hirsch D, Salat C, Stoetzer O, Nelson PJ, Michl M, Modest DP, Holch JW, Angele M, Bruns C, Niess H, Heinemann V. Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT-ME-1 trial. Int J Cancer 2019; 145:1538-1546. [PMID: 30801698 DOI: 10.1002/ijc.32230] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/29/2019] [Accepted: 01/30/2019] [Indexed: 12/24/2022]
Abstract
TREAT-ME-1, a Phase 1/2 open-label multicenter, first-in-human, first-in-class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC), MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Immunological and inflammatory markers were also assessed. All patients (3 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 at one dose level on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer's instructions for 48─72 h after MSC_apceth_101 injection. Ten patients were treated with a total dose of 3.0 x 106 cells/kg MSC_apceth_101. 36 adverse events and six serious adverse events were reported. Five patients achieved stable disease (change in target lesions of -2 to +28%). For all patients, the median time to progression was 1.8 months (95% CI: 0.5, 3.9 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (1 year) and therefore censored. Post-study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease.
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Affiliation(s)
- Jobst Christian von Einem
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | | | - Hans-Dieter Volk
- Institute for Medical Immunology and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany
| | - Gerald Grütz
- Institute for Medical Immunology and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany
| | | | - Christoph Salat
- Medizinisches Zentrum für Haematologie und Onkologie Muenchen MVZ GmbH, Munich, Germany
| | - Oliver Stoetzer
- Medizinisches Zentrum für Haematologie und Onkologie Muenchen MVZ GmbH, Munich, Germany
| | - Peter J Nelson
- Department of Medicine IV, University Hospital of Munich, LMU, Munich, Germany
| | - Marlies Michl
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | - Dominik P Modest
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | - Julian W Holch
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Christiane Bruns
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Hanno Niess
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Volker Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
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32
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Schug C, Urnauer S, Jaeckel C, Schmohl KA, Tutter M, Steiger K, Schwenk N, Schwaiger M, Wagner E, Nelson PJ, Spitzweg C. TGFB1-driven mesenchymal stem cell-mediated NIS gene transfer. Endocr Relat Cancer 2019; 26:89-101. [PMID: 30121623 DOI: 10.1530/erc-18-0173] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 08/13/2018] [Indexed: 01/01/2023]
Abstract
Based on their excellent tumor-homing capacity, genetically engineered mesenchymal stem cells (MSCs) are under investigation as tumor-selective gene delivery vehicles. Transgenic expression of the sodium iodide symporter (NIS) in genetically engineered MSCs allows noninvasive tracking of MSC homing by imaging of functional NIS expression as well as therapeutic application of 131I. The use of tumor stroma-activated promoters can improve tumor-specific MSC-mediated transgene delivery. The essential role of transforming growth factor B1 (TGFB1) and the SMAD downstream target in the signaling between tumor and the surrounding stroma makes the biology of this pathway a potential option to better control NIS expression within the tumor milieu. Bone marrow-derived MSCs were stably transfected with a NIS-expressing plasmid driven by a synthetic SMAD-responsive promoter (SMAD-NIS-MSCs). Radioiodide uptake assays revealed a 4.9-fold increase in NIS-mediated perchlorate-sensitive iodide uptake in SMAD-NIS-MSCs after TGFB1 stimulation compared to unstimulated cells demonstrating the successful establishment of MSCs, which induce NIS expression in response to activation of TGFB1 signaling using a SMAD-responsive promoter. 123I-scintigraphy revealed significant tumor-specific radioiodide accumulation and thus NIS expression after systemic application of SMAD-NIS-MSCs into mice harboring subcutaneous tumors derived from the human hepatocellular carcinoma (HCC) cell line HuH7, which express TGFB1. 131I therapy in SMAD-NIS-MSCs-treated mice demonstrated a significant delay in tumor growth and prolonged survival. Making use of the tumoral TGFB1 signaling network in the context of MSC-mediated NIS gene delivery is a promising approach to foster tumor stroma-selectivity of NIS transgene expression and tailor NIS-based gene therapy to TGFB1-rich tumor environments.
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Affiliation(s)
- Christina Schug
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Sarah Urnauer
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Carsten Jaeckel
- Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Mariella Tutter
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Klinikum Rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Markus Schwaiger
- Department of Nuclear Medicine, Klinikum Rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
| | - Peter J Nelson
- Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
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Yin Z, Jiang K, Li R, Dong C, Wang L. Multipotent mesenchymal stromal cells play critical roles in hepatocellular carcinoma initiation, progression and therapy. Mol Cancer 2018; 17:178. [PMID: 30593276 PMCID: PMC6309092 DOI: 10.1186/s12943-018-0926-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 12/16/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with high morbidity, relapse and mortality rates. Multipotent mesenchymal stromal cells (MSCs) can be recruited to and become integral components of the HCC microenvironment and can influence tumor progression. This review discusses MSC migration to liver fibrosis and the HCC microenvironment, MSC involvement in HCC initiation and progression and the widespread application of MSCs in HCC-targeted therapy, thus clarifying the critical roles of MSCs in HCC.
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Affiliation(s)
- Zeli Yin
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China.,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China.,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China
| | - Keqiu Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China.,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China.,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China
| | - Rui Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China.,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China.,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China
| | - Chengyong Dong
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China. .,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China. .,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China.
| | - Liming Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China. .,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China. .,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China.
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Mesenchymal stem cell-based drug delivery strategy: from cells to biomimetic. J Control Release 2018; 294:102-113. [PMID: 30553849 DOI: 10.1016/j.jconrel.2018.12.019] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 12/11/2018] [Accepted: 12/12/2018] [Indexed: 12/13/2022]
Abstract
Owing to the diversity and ease of preparation of nanomaterials, the rational nanocarriers with a rational design have become increasingly popular in medical researches. Although nanoparticle-based drug delivery exhibits great potential, there are some challenges facing like rapid plasma clearance, triggering or aggravation of immune response, etc. Herein, cell-based targeted drug delivery systems have drawn more and more attention owing to low immunogenicity and intrinsic mutation rate, and innate ability to allow targeted delivery. Mesenchymal stem cells (MSCs) have been used in gene and drug delivery. The use of MSCs is a promising approach for the development of gene transfer systems and drug loading strategies because of their intrinsic properties, including homing ability and tumor tropism. By combining the inherent cell properties and merits of synthetic nanoparticles (NPs), cell membrane coated NPs emerge as the time requires. Overall, we provide a comprehensive overview of the utility of MSCs in drug and gene delivery as well as MSC membrane coated nanoparticles for therapy and drug delivery, aiming to figure out the significant room for development and highlight the potential future directions.
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35
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Schug C, Gupta A, Urnauer S, Steiger K, Cheung PFY, Neander C, Savvatakis K, Schmohl KA, Trajkovic-Arsic M, Schwenk N, Schwaiger M, Nelson PJ, Siveke JT, Spitzweg C. A Novel Approach for Image-Guided 131I Therapy of Pancreatic Ductal Adenocarcinoma Using Mesenchymal Stem Cell-Mediated NIS Gene Delivery. Mol Cancer Res 2018; 17:310-320. [PMID: 30224540 DOI: 10.1158/1541-7786.mcr-18-0185] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 05/28/2018] [Accepted: 08/22/2018] [Indexed: 11/16/2022]
Abstract
The sodium iodide symporter (SLC5A5/NIS) as theranostic gene would allow for non-invasive imaging of functional NIS expression and therapeutic radioiodine application. Genetically engineered mesenchymal stem cells (MSC), based on their tumor-homing abilities, show great promise as tumor-selective NIS gene delivery vehicles for non-thyroidal tumors. As a next step towards clinical application, tumor specificity and efficacy of MSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Syngeneic murine MSCs were stably transfected with a NIS-expressing plasmid driven by the CMV-promoter (NIS-MSC). In vivo 123I-scintigraphy and 124I-PET revealed significant perchlorate-sensitive NIS-mediated radioiodide accumulation in PDAC after systemic injection of NIS-MSCs. Active MSC recruitment into the tumor stroma was confirmed using NIS immunohistochemistry (IHC). A therapeutic strategy, consisting of three cycles of systemic MSC-mediated NIS delivery, followed by 131I application, resulted in a significant delay and reduction in tumor growth as compared to controls. Furthermore, IHC analysis of α-SMA and Ki67 revealed differences in the amount and behavior of activated fibroblasts in tumors of mice injected with NIS-MSCs as compared with saline-treated mice. Taken together, MSCs as NIS gene delivery vehicles in this advanced endogenous PDAC mouse model demonstrated high stromal targeting of NIS by selective recruitment of NIS-MSCs after systemic application resulting in an impressive 131I therapeutic effect. IMPLICATIONS: These data expand the prospect of MSC-mediated radioiodine imaging-guided therapy of pancreatic cancer using the sodium iodide symporter as a theranostic gene in a clinical setting.
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Affiliation(s)
- Christina Schug
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Aayush Gupta
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Sarah Urnauer
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Phyllis Fung-Yi Cheung
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christian Neander
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Konstantinos Savvatakis
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Marija Trajkovic-Arsic
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Markus Schwaiger
- Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Peter J Nelson
- Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens T Siveke
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.,Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
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Schug C, Sievert W, Urnauer S, Müller AM, Schmohl KA, Wechselberger A, Schwenk N, Lauber K, Schwaiger M, Multhoff G, Wagner E, Nelson PJ, Spitzweg C. External Beam Radiation Therapy Enhances Mesenchymal Stem Cell-Mediated Sodium-Iodide Symporter Gene Delivery. Hum Gene Ther 2018; 29:1287-1300. [PMID: 29724129 DOI: 10.1089/hum.2018.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The tumor-homing properties of mesenchymal stem cells (MSC) have led to their development as delivery vehicles for the targeted delivery of therapeutic genes such as the sodium-iodide symporter (NIS) to solid tumors. External beam radiation therapy may represent an ideal setting for the application of engineered MSC-based gene therapy, as tumor irradiation may enhance MSC recruitment into irradiated tumors through the increased production of select factors linked to MSC migration. In the present study, the irradiation of human liver cancer cells (HuH7; 1-10 Gy) showed a strong dose-dependent increase in steady-state mRNA levels of CXCL8, CXCL12, FGF2, PDGFB, TGFB1, THBS1, and VEGF (0-48 h), which was verified for most factors at the protein level (after 48 h). Radiation effects on directed MSC migration were tested in vitro using a live cell tracking migration assay and supernatants from control and irradiated HuH7 cells. A robust increase in mean forward migration index, mean center of mass, and mean directionality of MSCs toward supernatants was seen from irradiated as compared to non-irradiated tumor cells. Transferability of this effect to other tumor sources was demonstrated using the human breast adenocarcinoma cell line (MDA-MB-231), which showed a similar behavior to radiation as seen with HuH7 cells in quantitative polymerase chain reaction and migration assay. To evaluate this in a more physiologic in vivo setting, subcutaneously growing HuH7 xenograft tumors were irradiated with 0, 2, or 5 Gy followed by CMV-NIS-MSC application 24 h later. Tumoral iodide uptake was monitored using 123I-scintigraphy. The results showed increased tumor-specific dose-dependent accumulation of radioiodide in irradiated tumors. The results demonstrate that external beam radiation therapy enhances the migratory capacity of MSCs and may thus increase the therapeutic efficacy of MSC-mediated NIS radionuclide therapy.
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Affiliation(s)
- Christina Schug
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Wolfgang Sievert
- 2 Department of Radiation Oncology, Technische Universitaet Muenchen , Munich, Germany
| | - Sarah Urnauer
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Andrea M Müller
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Kathrin A Schmohl
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Alexandra Wechselberger
- 3 Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Nathalie Schwenk
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Kirsten Lauber
- 4 Department of Radiation Oncology, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Markus Schwaiger
- 5 Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen , Munich, Germany
| | - Gabriele Multhoff
- 2 Department of Radiation Oncology, Technische Universitaet Muenchen , Munich, Germany
| | - Ernst Wagner
- 6 Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
| | - Peter J Nelson
- 3 Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Christine Spitzweg
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
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37
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Müller AM, Schmohl KA, Knoop K, Schug C, Urnauer S, Hagenhoff A, Clevert DA, Ingrisch M, Niess H, Carlsen J, Zach C, Wagner E, Bartenstein P, Nelson PJ, Spitzweg C. Hypoxia-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated sodium iodide symporter gene delivery. Oncotarget 2018; 7:54795-54810. [PMID: 27458162 PMCID: PMC5342382 DOI: 10.18632/oncotarget.10758] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 07/10/2016] [Indexed: 12/18/2022] Open
Abstract
Adoptively transferred mesenchymal stem cells (MSCs) home to solid tumors. Biologic features within the tumor environment can be used to selectively activate transgenes in engineered MSCs after tumor invasion. One of the characteristic features of solid tumors is hypoxia. We evaluated a hypoxia-based imaging and therapy strategy to target expression of the sodium iodide symporter (NIS) gene to experimental hepatocellular carcinoma (HCC) delivered by MSCs. MSCs engineered to express transgenes driven by a hypoxia-responsive promoter showed robust transgene induction under hypoxia as demonstrated by mCherry expression in tumor cell spheroid models, or radioiodide uptake using NIS. Subcutaneous and orthotopic HCC xenograft mouse models revealed significant levels of perchlorate-sensitive NIS-mediated tumoral radioiodide accumulation by tumor-recruited MSCs using 123I-scintigraphy or 124I-positron emission tomography. Functional NIS expression was further confirmed by ex vivo123I-biodistribution analysis. Administration of a therapeutic dose of 131I in mice treated with NIS-transfected MSCs resulted in delayed tumor growth and reduced tumor perfusion, as shown by contrast-enhanced sonography, and significantly prolonged survival of mice bearing orthotopic HCC tumors. Interestingly, radioiodide uptake into subcutaneous tumors was not sufficient to induce therapeutic effects. Our results demonstrate the potential of using tumor hypoxia-based approaches to drive radioiodide therapy in non-thyroidal tumors.
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Affiliation(s)
- Andrea M Müller
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Kerstin Knoop
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christina Schug
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Sarah Urnauer
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Anna Hagenhoff
- Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Dirk-André Clevert
- Department of Clinical Radiology, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Michael Ingrisch
- Department of Clinical Radiology, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Hanno Niess
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Janette Carlsen
- Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christian Zach
- Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Ludwig Maximilian University of Munich, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Peter J Nelson
- Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
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Soluble factors from adipose tissue-derived mesenchymal stem cells promote canine hepatocellular carcinoma cell proliferation and invasion. PLoS One 2018; 13:e0191539. [PMID: 29346427 PMCID: PMC5773216 DOI: 10.1371/journal.pone.0191539] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 01/05/2018] [Indexed: 12/21/2022] Open
Abstract
The potential effects of adipose tissue-derived mesenchymal stem cells (AT-MSCs) on the growth and invasion of canine tumours including hepatocellular carcinoma (HCC) are not yet understood. Moreover in humans, the functional contribution of AT-MSCs to malignancies remains controversial. The purpose of this study was to investigate the effects of AT-MSCs on the proliferation and invasion of canine HCC cells in vitro. The effect of AT-MSCs on mRNA levels of factors related to HCC progression were also evaluated. Conditioned medium from AT-MSCs (AT-MSC-CM) significantly enhanced canine HCC cell proliferation and invasion. Moreover, mRNA expression levels of transforming growth factor-beta 1, epidermal growth factor A, hepatocyte growth factor, platelet-derived growth factor-beta, vascular endothelial growth factor, and insulin-like growth factor 2 were 2.3 ± 0.4, 2.0 ± 0.5, 5.7 ± 1.9, 1.7 ± 0.2, 2.1 ± 0.4, and 1.4 ± 0.3 times higher, respectively (P < 0.05). The mRNA expression level of MMP-2 also increased (to 4.0 ± 1.2 times control levels) in canine HCC cells co-cultured with AT-MSCs, but MMP-9 mRNA significantly decreased (to 0.5 ± 0.1 times control levels). These findings suggest that soluble factors from AT-MSCs promote the proliferation and invasion of canine HCC cells.
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Promotion of Cell-Based Therapy: Special Focus on the Cooperation of Mesenchymal Stem Cell Therapy and Gene Therapy for Clinical Trial Studies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1119:103-118. [PMID: 30155859 DOI: 10.1007/5584_2018_256] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Regenerative medicine (RM) is a promising new field of medicine that has mobilized several new tools to repair or replace lost or damaged cells or tissues by stimulating natural regenerative mechanisms nearby cell and tissue-based therapy approaches. However, mesenchymal stem cell (MSC) based therapy has been shown to be safe and effective to a certain degree in multiple clinical trial studies (CTSs) of several diseases, in most MSC CTSs the efficacy of treatment has been reported low. Therefore, researchers have focused on efficacy enhancing of MSC to improve migratory and homing, survival, stemness, differentiation and other therapeutic applicable properties by using different approaches. Gene therapy is one of the experimental technique tools that uses genes to change cells for therapeutic and investigation purposes. In this study has been focused on genetically modified MSCs for use in RM with an emphasis on CTSs. We highlight the basic concept of genetic modifications and also discuss recent clinical studies aspects. Recently reviewed studies show that MSC therapy with assistant gene therapy can be used in cancer therapy, heart diseases, Fanconi anemia and several other diseases.
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Marofi F, Vahedi G, Biglari A, Esmaeilzadeh A, Athari SS. Mesenchymal Stromal/Stem Cells: A New Era in the Cell-Based Targeted Gene Therapy of Cancer. Front Immunol 2017; 8:1770. [PMID: 29326689 PMCID: PMC5741703 DOI: 10.3389/fimmu.2017.01770] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
In recent years, in light of the promising potentials of mesenchymal stromal/stem cells (MSCs) for carrying therapeutic anticancer genes, a complete revisitation on old chemotherapy-based paradigms has been established. This review attempted to bring forward and introduce the novel therapeutic opportunities of using genetically engineered MSCs. The simplicities and advantages of MSCs for medical applications make them a unique and promising option in the case of cancer therapy. Some of the superiorities of using MSCs as therapeutic gene micro-carriers are the easy cell-extraction procedures and their abundant proliferation capacity in vitro without losing their main biological properties. Targeted therapy by using MSCs as the delivery vehicles of therapeutic genes is a new approach in the treatment of various types of cancers. Some of the distinct properties of MSCs, such as tumor-tropism, non-immunogenicity, stimulatory effect on the anti-inflammatory molecules, inhibitory effect on inflammatory responses, non-toxicity against the normal tissues, and easy processes for the clinical use, have formed the basis of attention to MSCs. They can be easily used for the treatment of damaged or injured tissues, regenerative medicine, and immune disorders. This review focused on the drugability of MSCs and their potential for the delivery of candidate anticancer genes. It also briefly reviewed the vectors and methods used for MSC-mediated gene therapy of malignancies. Also, the challenges, limitations, and considerations in using MSCs for gene therapy of cancer and the new methods developed for resolution of these problems are reviewed.
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Affiliation(s)
- Faroogh Marofi
- Department of Hematology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ghasem Vahedi
- Research Center for Food Hygiene and Safety, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alireza Biglari
- Department of Genetics and Molecular Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Abdolreza Esmaeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran.,Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
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The future of mesenchymal stem cell-based therapeutic approaches for cancer - From cells to ghosts. Cancer Lett 2017; 414:239-249. [PMID: 29175461 DOI: 10.1016/j.canlet.2017.11.025] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 11/19/2017] [Accepted: 11/21/2017] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells which can differentiate into a variety of cell types including osteoblasts, adipocytes and chondrocytes. They are normally resident in adipose tissue, bone marrow and the umbilical cord, but can also be found in other tissues and are known to be recruited to sites of wound healing as well as growing tumours. The therapeutic potential of MSCs has been explored in a number of phase I/II and III clinical trials, of which several were targeted against graft-versus-host disease and to support engraftment of haematopoietic stem cells (HSCs), but currently only very few in the oncology field. There are now three clinical trials either ongoing or recruiting patients that use MSCs to treat tumour disease. In these, MSCs target gastrointestinal, lung and ovarian cancer, respectively. The first study uses MSCs loaded with a HSV-TK expression construct under the control of the CCL5 promoter, and has recently reported successful completion of Phase I/II. While no adverse side effects were seen during this study, no outcomes with respect to therapeutic benefits have been published. The other clinical trials targeting lung and ovarian cancer will be using MSCs expressing cytokines as therapeutic payload. Despite these encouraging early steps towards their clinical use, many questions are still unanswered regarding the biology of MSCs in normal and pathophysiological settings. In this review, in addition to summarising the current state of MSC-based therapeutic approaches for cancer, we will describe the remaining questions, obstacles and risks, as well as novel developments such as MSC-derived nanoghosts.
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Li TR, Yu MH, Huang XB, Yang ZJ, Lu GM, Li YJ. Magnetic Resonance Gd-RGD Imaging Study of Hepatocellular Carcinoma with High and Low Metastatic Potential before and after Human Bone Marrow-derived Mesenchymal Stem Cell Intervention. Chin Med J (Engl) 2017; 130:2591-2600. [PMID: 29067958 PMCID: PMC5678260 DOI: 10.4103/0366-6999.217089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background: Biotherapy based on human bone marrow-derived mesenchymal stem cells (BMSCs) is currently the focus of research, especially in the field of autologous stem cell transplantation. A novel type of metastasis-associated magnetic resonance (MR) molecular imaging probe was constructed, and the changes in metastasis and proliferation of hepatocellular carcinoma (HCC) before and after BMSC intervention were observed through MR imaging (MRI). Methods: Metastasis-associated MR molecular imaging probe, integrin αvβ3 ligand cRGD-PEG-DGL-DTPA-Gd (Gd-RGD), were constructed. After human BMSC intervention was performed for 6 weeks, tumor weight inhibition rates were calculated, and the RGD molecular probe was imaged through MRI with molecular imaging agent Gd-DTPA as control. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the MRI experiment were used as semi-quantitative indicators. Polymerase chain reaction method was performed to detect proliferation- and metastasis-associated indicators, transforming growth factor β-1 (TGFβ1), osteopontin (OPN), and integrin subunit αv and β3. Results: The highest tumor weight inhibition rates were observed 3 weeks after the BMSC transplantation. The MR Gd-RGD in the HCC tissues after the BMSC intervention showed less enhancement than Gd-DTPA. The Gd-DTPA MRI of control group had higher SNR and CNR than Gd-RGD MRI in the experimental groups (P < 0.05). For high metastatic potential hepatocellular carcinoma (MHCC97-H), significant differences were observed in the SNRs and CNRs of Gd-RGD MRI before and after the BMSC intervention (P < 0.05). For low metastatic potential hepatocellular carcinoma (MHCC97-L), the CNRs of Gd-RGD MRI were statistically different before and after BMSC intervention (P < 0.05). With regard to MHCC97-H, OPN, β3, and TGFβ1 expression significantly decreased after BMSC intervention (P < 0.05). In MHCC97-L and OPN, β3, TGFβ1, and αv expression after BMSC intervention decreased, and the difference was statistically significant (P < 0.05). Conclusions: The CNR index of MRI is a good indicator for distinguishing high- and low-metastatic potential HCC tissues. After BMSC transplantation of MRI through the two kinds of tracer, the SNR and CNR indexes can distinguish two kinds of high and low metastatic potential HCC tissues, and Gd-RGD imaging is more suitable in distinguishing the metastatic potential changes through BMSC intervention.
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Affiliation(s)
- Tian-Ran Li
- Department of Radiology, The 1st Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China
| | - Ming-Hui Yu
- Department of Radiology, The 1st Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China
| | - Xiao-Bin Huang
- Department of Radiology, Chinese PLA 95th Hospital, Putian, Fujian 351100, China
| | - Zhi-Jie Yang
- Department of Radiology, Chinese PLA 95th Hospital, Putian, Fujian 351100, China
| | - Guang-Ming Lu
- Department of Radiology, Chinese PLA Nanjing General Hospital, Nanjing, Jiangsu 210000, China
| | - Yan-Jun Li
- Department of Radiology, Chinese PLA Nanjing General Hospital, Nanjing, Jiangsu 210000, China
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Qin Y, Zhuo L, Cai J, He X, Liu B, Feng C, Zhang L. In vivo monitoring of magnetically labeled mesenchymal stem cells homing to rabbit hepatic VX2 tumors using magnetic resonance imaging. Mol Med Rep 2017; 17:452-458. [PMID: 29115453 DOI: 10.3892/mmr.2017.7902] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 07/20/2017] [Indexed: 11/05/2022] Open
Abstract
Although mesenchymal stem cells (MSCs) have been demonstrated to possess a tumor‑homing feature, their tropism to liver tumors has not been delineated in a visible manner. The aim of the present study was to evaluate the tumor‑homing capacity of MSCs and to investigate the spatial and temporal distributions of MSCs in liver tumors using magnetic resonance imaging (MRI). MSCs were colabeled with superparamagnetic iron oxide (SPIO) particles and 4',6‑diamidino‑2‑phenylindole (DAPI), and then transplanted into rabbits with VX2 liver tumors through intravenous injections. The rabbits were subjected to MRI before and at 3, 7 and 14 days after cell transplantation using a clinical 1.5‑T MRI system. Immediately after the MRI examination, histological analyses were performed using fluorescence and Prussian blue staining. At 3 days after injection with labeled MSCs, heterogeneous hypointensity was detected on the MRI images of the tumor. At 7 days after transplantation, the tumor exhibited anisointense MRI signal, whereas a hypointense ring was detected at the border of the tumor. At 14 days after transplantation, the MRI signal recovered the hyperintensity. As demonstrated in the histological analyses, the distribution of the iron particles visualized with Prussian blue staining was consistent with the DAPI‑stained bright fluorescent nuclei, and the particles corresponded to the hypointense region on the MR images. Thus, systemically administered MSCs could localize to liver tumors with high specificity and possessed a migration feature with active tumor growth. These results demonstrated that the targeting and distribution of the magnetically labeled stem cells in the tumor could be tracked for 7 days in vivo using a clinical 1.5‑T MRI scanner.
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Affiliation(s)
- Yong Qin
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Lisha Zhuo
- Outpatient Department, 77100 Troops, Chinese People's Liberation Army, Chongqing 400020, P.R. China
| | - Jinhua Cai
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Xiaoya He
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Bo Liu
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Chuan Feng
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Lin Zhang
- Department of Radiology, Xinan Hospital of Third Military Medical University, Chongqing 400038, P.R. China
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Woodsworth DJ, Dreolini L, Abraham L, Holt RA. Targeted Cell-to-Cell Delivery of Protein Payloads via the Granzyme-Perforin Pathway. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2017; 7:132-145. [PMID: 29201936 PMCID: PMC5700818 DOI: 10.1016/j.omtm.2017.10.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 10/05/2017] [Indexed: 12/19/2022]
Abstract
There is great potential for engineering cellular therapeutics by repurposing biological systems. Here, we report utilization of the granzyme-perforin pathway of cytotoxic lymphocytes as a cell-to-cell protein delivery module. We designed and constructed granzyme B-derived chaperone molecules fused to a fluorescent protein payload and expressed these constructs in natural killer (NK) cells. Using confocal microscopy and flow cytometry, we investigated the co-localization of the chaperones with lytic granules and the chaperone-mediated transfer of the fluorescent protein payload from NK to target cells in co-culture experiments. A synthetic chaperone consisting of the granzyme B ER signal peptide and a domain encompassing putative N-linked glycosylation sites in granzyme B is insufficient for payload transfer to target cells, whereas full-length granzyme B is sufficient for payload delivery. Combining our functional data with an analysis of the crystal structure of granzyme B suggests that the necessary motifs for granzyme B loading into lytic granules are dispersed throughout the primary amino acid sequence and are only functional when contiguous in the tertiary structure. These results illustrate that by using granzyme B as a molecular chaperone the granzyme-perforin pathway can be exploited as a programmable molecular delivery system for cell-based therapies.
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Affiliation(s)
- Daniel J. Woodsworth
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Lisa Dreolini
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Libin Abraham
- Department of Microbiology & Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Robert A. Holt
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
- Corresponding author: Robert A. Holt, Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
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von Einem JC, Peter S, Günther C, Volk HD, Grütz G, Salat C, Stoetzer O, Nelson PJ, Michl M, Modest DP, Holch JW, Angele M, Bruns C, Niess H, Heinemann V. Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells - TREAT-ME-1 - a phase I, first in human, first in class trial. Oncotarget 2017; 8:80156-80166. [PMID: 29113291 PMCID: PMC5655186 DOI: 10.18632/oncotarget.20964] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 08/26/2017] [Indexed: 12/22/2022] Open
Abstract
PURPOSE This phase I, first in human, first in class clinical study aimed at evaluating the safety, tolerability and efficacy of treatment with genetically modified mesenchymal stromal cells (MSC) in combination with ganciclovir (GCV). MSC_apceth_101 are genetically modified autologous MSCs used as vehicles for a cell-based gene therapy in patients with advanced gastrointestinal adenocarcinoma. EXPERIMENTAL DESIGN The study design consisted of a dose-escalation 3 + 3 design. All patients (n = 6) were treated with up to three applications of MSC_apceth_101, followed by GCV infusions given on three consecutive days starting 48 hours after injection of MSC_apceth_101. Three of six patients received a total dose of 1.5 × 106 cells/kg. Two patients received three doses of 1 × 106 cells/kg, while one patient received only two doses of 1 × 106 cells/kg due to a SADR. RESULTS Six patients received MSC_apceth_101. No IMP-related serious adverse events occurred. Adverse-events related to IMP-injection were increased creatinine, cough, fever, and night sweat. TNF, IL-6, IL-8, IL-10 and sE-Selectin, showed that repeated application is immunologically safe, but induces a switch of the functional properties of monocytes to an inflammatory phenotype. Treatment induced stable disease in 4/6 patients, and progressive disease in 2/6 patients. CONCLUSION Treatment with MSC_apceth_101 in combination with GCV demonstrated acceptable safety and tolerability in patients with advanced gastrointestinal adenocarcinoma.
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Affiliation(s)
- Jobst C. von Einem
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | | | | | - Hans-Dieter Volk
- Institute for Medical Immunology and Berlin-Brandenburg Center for Regenerative Medicine, Charité-Universitätsmedizin, Berlin, Germany
| | - Gerald Grütz
- Institute for Medical Immunology and Berlin-Brandenburg Center for Regenerative Medicine, Charité-Universitätsmedizin, Berlin, Germany
| | - Christoph Salat
- Haemato-Onkologische Schwerpunktpraxis Prof. Salat, Dr. Stoetzer, Munich, Germany
| | - Oliver Stoetzer
- Haemato-Onkologische Schwerpunktpraxis Prof. Salat, Dr. Stoetzer, Munich, Germany
| | - Peter J. Nelson
- Department of Medicine IV, University Hospital of Munich, LMU, Munich, Germany
| | - Marlies Michl
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | - Dominik P. Modest
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | - Julian W. Holch
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
| | - Martin Angele
- Department of Surgery, University Hospital Grosshadern, LMU, Munich, Germany
| | - Christiane Bruns
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Hanno Niess
- Department of Surgery, University Hospital Grosshadern, LMU, Munich, Germany
| | - Volker Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany
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Bayo J, Real A, Fiore EJ, Malvicini M, Sganga L, Bolontrade M, Andriani O, Bizama C, Fresno C, Podhajcer O, Fernandez E, Gidekel M, Mazzolini GD, García MG. IL-8, GRO and MCP-1 produced by hepatocellular carcinoma microenvironment determine the migratory capacity of human bone marrow-derived mesenchymal stromal cells without affecting tumor aggressiveness. Oncotarget 2017; 8:80235-80248. [PMID: 29113298 PMCID: PMC5655193 DOI: 10.18632/oncotarget.10288] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 05/22/2016] [Indexed: 12/21/2022] Open
Abstract
New therapies are needed for advanced hepatocellular carcinoma (HCC) and the use of mesenchymal stromal cells (MSCs) carrying therapeutic genes is a promising strategy. HCC produce cytokines recruiting MSCs to the tumor milieu and modifying its biological properties. Our aim was to study changes generated on human MSCs exposed to conditioned media (CM) derived from human HCC fresh samples and xenografts. All CM shared similar cytokines expression pattern including CXCL1-2-3/GRO, CCL2/MCP-1 and CXCL8/IL-8 being the latter with the highest concentration. Neutralizing and knockdown experiments of CCL2/MCP-1, CXCL8/IL-8, CXCR1 and CXCR2 reduced in vitro MSC migration of ≥20%. Simultaneous CXCR1 and CXCR2 neutralization resulted in 50% of MSC migration inhibition. MSC stimulated with CM (sMSC) from HuH7 or HC-PT-5 showed a 2-fold increase of migration towards the CM compared with unstimulated MSC (usMSC). Gene expression profile of sMSC showed ~500 genes differentially expressed compared with usMSC, being 46 genes related with cell migration and invasion. sMSC increased fibroblasts and endothelial cells chemotaxis. Finally, sMSC with HuH7 CM and then inoculated in HCC tumor bearing-mice did not modify tumor growth. In this work we characterized factors produced by HCC responsible for the changes in MSC chemotactic capacity with would have an impact on therapeutic use of MSCs for human HCC.
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Affiliation(s)
- Juan Bayo
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Alejandrina Real
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Esteban J. Fiore
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Mariana Malvicini
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Leonardo Sganga
- Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina
| | | | - Oscar Andriani
- Liver Unit, Hospital Universitario Austral, Derqui-Pilar, Argentina
| | | | - Cristóbal Fresno
- BioScience Data Mining Group, Catholic University of Córdoba, Córdoba, Argentina
| | | | - Elmer Fernandez
- BioScience Data Mining Group, Catholic University of Córdoba, Córdoba, Argentina
| | - Manuel Gidekel
- Universidad de la Frontera, Temuco, Chile
- Universidad Autónoma de Chile, Santiago, Chile
| | - Guillermo D. Mazzolini
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
- Liver Unit, Hospital Universitario Austral, Derqui-Pilar, Argentina
| | - Mariana G. García
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
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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
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Kucerova L, Durinikova E, Toro L, Cihova M, Miklikova S, Poturnajova M, Kozovska Z, Matuskova M. Targeted antitumor therapy mediated by prodrug-activating mesenchymal stromal cells. Cancer Lett 2017; 408:1-9. [PMID: 28838843 DOI: 10.1016/j.canlet.2017.08.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 08/09/2017] [Accepted: 08/11/2017] [Indexed: 12/14/2022]
Abstract
Mesenchymal stromal cells (MSCs) were introduced as tumor-targeted vehicles suitable for delivery of the gene-directed enzyme/prodrug therapy more than 10 years ago. Over these years key properties of tumor cells and MSCs, which are crucial for the treatment efficiency, were examined; and there are some critical issues to be considered for the maximum antitumor effect. Moreover, engineered MSCs expressing enzymes capable of activating non-toxic prodrugs achieved long-term curative effect even in metastatic and hard-to-treat tumor types in pre-clinical scenario(s). These gene-modified MSCs are termed prodrug-activating MSCs throughout the text and represent promising approach for further clinical application. This review summarizes major determinants to be considered for the application of the prodrug-activating MSCs in antitumor therapy in order to maximize therapeutic efficiency.
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Affiliation(s)
- Lucia Kucerova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
| | - Erika Durinikova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Lenka Toro
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Marina Cihova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Svetlana Miklikova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Martina Poturnajova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Zuzana Kozovska
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
| | - Miroslava Matuskova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
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Sage EK, Thakrar RM, Janes SM. Genetically modified mesenchymal stromal cells in cancer therapy. Cytotherapy 2017; 18:1435-1445. [PMID: 27745603 PMCID: PMC5082580 DOI: 10.1016/j.jcyt.2016.09.003] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 08/31/2016] [Accepted: 09/02/2016] [Indexed: 12/14/2022]
Abstract
The cell therapy industry has grown rapidly over the past 3 decades, and multiple clinical trials have been performed to date covering a wide range of diseases. The most frequently used cell is mesenchymal stromal cells (MSCs), which have been used largely for their anti-inflammatory actions and in situations of tissue repair and although they have demonstrated a good safety profile, their therapeutic efficacy has been limited. In addition to these characteristics MSCs are being used for their homing and engraftment properties and have been genetically modified to enable targeted delivery of a variety of therapeutic agents in both malignant and nonmalignant conditions. This review discusses the science and technology behind genetically modified MSC therapy in malignant disease and how potential problems have been overcome to enable their use in two novel clinical trials in metastatic gastrointestinal and lung cancer.
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Affiliation(s)
- Elizabeth K Sage
- Lungs for Living Research Centre, UCL Respiratory, Rayne Institute, University College London, London, United Kingdom
| | - Ricky M Thakrar
- Lungs for Living Research Centre, UCL Respiratory, Rayne Institute, University College London, London, United Kingdom; Department of Thoracic Medicine, University College London Hospital, London, United Kingdom
| | - Sam M Janes
- Lungs for Living Research Centre, UCL Respiratory, Rayne Institute, University College London, London, United Kingdom; Department of Thoracic Medicine, University College London Hospital, London, United Kingdom.
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Woodsworth DJ, Holt RA. Cell-Based Therapeutics: Making a Faustian Pact with Biology. Trends Mol Med 2017; 23:104-115. [PMID: 28129958 DOI: 10.1016/j.molmed.2016.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/24/2016] [Accepted: 12/13/2016] [Indexed: 12/11/2022]
Abstract
The diversity and specialization found in biological molecules, pathways, and cells is staggering, and should be exploited for therapeutic use. Through evolution these biological systems have attained a level of functionality that would be impossible to recapitulate with de novo assembly. To adapt these systems for therapeutic applications it will be often necessary to re-engineer molecules and pathways to yield novel sensory, control, and effector modules for insertion into existing, specialized cellular chassis. However, these efforts will be greatly impeded and confounded by the noise, complexity, and context-dependency inherent in biological systems. Thus, we argue that repurposing biology for cell-based therapeutics will be an arduous process, but one that will yield great benefit, and is superior to any alternative.
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Affiliation(s)
- Daniel J Woodsworth
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Robert A Holt
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
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