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Yang Y, Wang J, Zhong Y, Tian M, Zhang H. Advances in Radionuclide-Labeled Biological Carriers for Tumor Imaging and Treatment. ACS APPLIED MATERIALS & INTERFACES 2025; 17:4316-4336. [PMID: 39792777 DOI: 10.1021/acsami.4c19059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Biological carriers have emerged as significant tools to deliver radionuclides in nuclear medicine, providing a meaningful perspective for tumor imaging and treatment. Various radionuclide-labeled biological carriers have been developed to meet the needs of biomedical applications. This review introduces the principles of radionuclide-mediated imaging and therapy and the selected criteria of them, as well as a comprehensive description of the characteristics and functions of representative biological carriers including bacteria, cells, viruses, and their biological derivatives, emphasizing the labeled strategies of biological carriers combined with radionuclides. Subsequently, we in-depth introduce the application of radionuclide-labeled biological carriers in tumor imaging and treatment, including the imaging of the behaviors of biological carriers in vivo and tumor metastasis and the tumor treatment by radionuclide therapy, plus other strategies and radiation-induced photodynamic therapy. Finally, the challenges and prospects of radionuclide-labeled biological carriers are discussed to improve the shortcomings of this innovative platform and promote clinical transformation in the field of medical imaging.
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Affiliation(s)
- Yaozhang Yang
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, Zhejiang 310009, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, Zhejiang 310009, China
| | - Jing Wang
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, Zhejiang 310009, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, Zhejiang 310009, China
| | - Yan Zhong
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, Zhejiang 310009, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, Zhejiang 310009, China
| | - Mei Tian
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, Zhejiang 310009, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, Zhejiang 310009, China
- Human Phenome Institute, Fudan University, Shanghai 201203, China
| | - Hong Zhang
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, Zhejiang 310009, China
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, Zhejiang 310009, China
- College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, Zhejiang 310014, China
- Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, Zhejiang 310014, China
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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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Shah S, Lucke-Wold B. Image-Guided Mesenchymal Stem Cell Sodium Iodide Symporter (NIS) Radionuclide Therapy for Glioblastoma. Cancers (Basel) 2024; 16:2892. [PMID: 39199662 PMCID: PMC11352884 DOI: 10.3390/cancers16162892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/12/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
BACKGROUND Glioblastoma (GBM) is a highly aggressive, invasive, and growth factor-independent grade IV glioma. Survival following the diagnosis is generally poor, with a median survival of approximately 15 months, and it is considered the most aggressive and lethal central nervous system tumor. Conventional treatments based on surgery, chemotherapy, and radiation therapy only delay progression, and death is inevitable. Malignant glioma cells are resistant to traditional therapies, potentially due to a subpopulation of glioma stem cells that are invasive and capable of rapid regrowth. METHODS This is a literature review. The systematic retrieval of information was performed on PubMed, Embase, and Google Scholar. Specified keywords were used in PubMed and the articles retrieved were published in peer-reviewed scientific journals and were associated with brain GBM cancer and the sodium iodide symporter (NIS). Additionally, the words 'radionuclide therapy OR mesenchyma, OR radioiodine OR iodine-131 OR molecular imaging OR gene therapy OR translational imaging OR targeted OR theranostic OR symporter OR virus OR solid tumor OR combined therapy OR pituitary OR plasmid AND glioblastoma OR GBM OR GB OR glioma' were also used in the appropriate literature databases of PubMed and Google Scholar. A total of 68,244 articles were found in this search on Mesenchymal Stem Cell Sodium Iodide Symporter and GBM. These articles were found till 2024. To study recent advances, a filter was added to include articles only from 2014 to 2024, duplicates were removed, and articles not related to the title were excluded. These came out to be 78 articles. From these, nine were not retrieved and only seven were selected after the removal of keyword mismatched articles. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. RESULTS As a result of their natural capacity to identify malignancies, MSCs are employed as tumor therapy vehicles. Because MSCs may be transplanted using several methods, they have been proposed as the ideal vehicles for NIS gene transfer. MSCs have been used as a delivery vector for anticancer drugs in many tumor models due to their capacity to move precisely to malignancies. Also, by directly injecting radiolabeled MSCs into malignant tumors, a therapeutic dosage of beta radiation may be deposited, with the added benefit that the tumor would only localize and not spread to the surrounding healthy tissues. CONCLUSION The non-invasive imaging-based detection of glioma stem cells presents an alternate means to monitor the tumor and diagnose and evaluate recurrence. The sodium iodide symporter gene is a specific gene in a variety of human thyroid diseases that functions to move iodine into the cell. In recent years, an increasing number of studies related to the sodium iodide symporter gene have been reported in a variety of tumors and as therapeutic vectors for imaging and therapy. Gene therapy and nuclear medicine therapy for GBM provide a new direction. In all the preclinical studies reviewed, image-guided cell therapy led to greater survival benefits and, therefore, has the potential to be translated into techniques in glioblastoma treatment trials.
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Affiliation(s)
- Siddharth Shah
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA;
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Hong S, Lee DS, Bae GW, Jeon J, Kim HK, Rhee S, Jung KO. In Vivo Stem Cell Imaging Principles and Applications. Int J Stem Cells 2023; 16:363-375. [PMID: 37643761 PMCID: PMC10686800 DOI: 10.15283/ijsc23045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/13/2023] [Accepted: 07/21/2023] [Indexed: 08/31/2023] Open
Abstract
Stem cells are the foundational cells for every organ and tissue in our body. Cell-based therapeutics using stem cells in regenerative medicine have received attracting attention as a possible treatment for various diseases caused by congenital defects. Stem cells such as induced pluripotent stem cells (iPSCs) as well as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and neuroprogenitors stem cells (NSCs) have recently been studied in various ways as a cell-based therapeutic agent. When various stem cells are transplanted into a living body, they can differentiate and perform complex functions. For stem cell transplantation, it is essential to determine the suitability of the stem cell-based treatment by evaluating the origin of stem, the route of administration, in vivo bio-distribution, transplanted cell survival, function, and mobility. Currently, these various stem cells are being imaged in vivo through various molecular imaging methods. Various imaging modalities such as optical imaging, magnetic resonance imaging (MRI), ultrasound (US), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) have been introduced for the application of various stem cell imaging. In this review, we discuss the principles and recent advances of in vivo molecular imaging for application of stem cell research.
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Affiliation(s)
- Seongje Hong
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Dong-Sung Lee
- Department of Life Sciences, University of Seoul, Seoul, Korea
| | - Geun-Woo Bae
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Juhyeong Jeon
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Hak Kyun Kim
- Department of Life Science, Chung-Ang University, Seoul, Korea
| | - Siyeon Rhee
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Kyung Oh Jung
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Korea
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Wang H, Zhou Z, Lin W, Qian Y, He S, Wang J. MicroRNA-21 promotes head and neck squamous cell carcinoma (HNSCC) induced transition of bone marrow mesenchymal stem cells to cancer-associated fibroblasts. BMC Cancer 2023; 23:1135. [PMID: 37993769 PMCID: PMC10666302 DOI: 10.1186/s12885-023-11630-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Most patients diagnosed with head and neck tumor will present with locally advanced disease, requiring multimodality therapy. Bone marrow-derived mesenchymal stromal cells (BMSCs) respond to a variety of tumor cell-derived signals, such as inflammatory cytokines and growth factors. As a result, the inflammatory tumor microenvironment may lead to the recruitment of BMSCs. Whether BMSCs in the tumor environment are more likely to promote tumor growth or tumor suppression is still controversial. We aimed to determine whether microRNA-21(miR-21) would play a vital role in HNSCC induced transition of human bone marrow mesenchymal stem cells (hBMSCs) to cancer-associated fibroblasts (CAFs). METHODS In this study, we used electron microscope to observed exosomes collected from human tissue and two cell lines. We co-cultured hBMSCs with exosomes from FaDu and Cal-27 cells with miR-21 inhibited or not, then assessed cell cycle changes of hBMSCs with flow cytometry and determined expression level of α-SMA and FAP through qRT-PCR and Western blot. RESULTS We observed an up-regulation of miR-21 expression in HNSCC tissue and FaDu and Cal-27 cells. Importantly, the exosomes derived from both cells induced CAFs-like characteristics in hBMSCs. while treatment with a miR-21 inhibitor effectively suppressed the transition of hBMSCs to CAFs and reversed the changes in the cell cycle distribution. This suggests that miR-21 plays a crucial role in facilitating the transition of hBMSCs to CAFs and modulating the cell cycle dynamics. CONCLUSION Our findings highlight the significance of miR-21 in mediating the communication between HNSCC cells and hBMSCs through exosomes, leading to the promotion of CAFs-like features and alterations in the cell cycle of hBMSCs.
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Affiliation(s)
- Hao Wang
- Department of Otorhinolaryngology, Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China
| | - Zhengyu Zhou
- Department of Laboratory Diagnostics, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Wenchao Lin
- Department of Otorhinolaryngology, Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China
| | - Yechun Qian
- Department of Otorhinolaryngology, Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China
| | - Shifang He
- Department of Otorhinolaryngology, Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China.
| | - Jun Wang
- Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China.
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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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Li Q, Zhang L, Lang J, Tan Z, Feng Q, Zhu F, Liu G, Ying Z, Yu X, Feng H, Yi H, Wen Q, Jin T, Cheng K, Zhao X, Ge M. Lipid-Peptide-mRNA Nanoparticles Augment Radioiodine Uptake in Anaplastic Thyroid Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204334. [PMID: 36453580 PMCID: PMC9875617 DOI: 10.1002/advs.202204334] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 11/09/2022] [Indexed: 06/17/2023]
Abstract
Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid-peptide-mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase-free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10-fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 (131 I) accumulation in the tumor, thereby significantly inhibiting tumor growth. Overall, this work designs three arginine-rich peptide nanoparticles, contributing to the choice of liposome cores for gene delivery. LPm NP can serve as a promising adjunctive therapy for patients with ATC by restoring iodine affinity and enhancing the therapeutic efficacy of radioactive iodine.
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Affiliation(s)
- Qinglin Li
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiang310022China
| | - Lizhuo Zhang
- Department of Head and Neck SurgeryCenter of Otolaryngology-head and neck surgeryZhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College)Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiang310014China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing100190China
| | - Jiayan Lang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing100190China
| | - Zhuo Tan
- Department of Head and Neck SurgeryCenter of Otolaryngology-head and neck surgeryZhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College)Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiang310014China
| | - Qingqing Feng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing100190China
| | - Fei Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing100190China
| | - Guangna Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing100190China
| | - Zhangguo Ying
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiang310022China
| | - Xuefei Yu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiang310022China
| | - He Feng
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiang310022China
| | - Heqing Yi
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiang310022China
| | - Qingliang Wen
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiang310022China
| | - Tiefeng Jin
- Department of Head and Neck SurgeryCenter of Otolaryngology-head and neck surgeryZhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College)Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiang310014China
| | - Keman Cheng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing100190China
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing100190China
- Center of Materials Science and Optoelectronics EngineeringUniversity of Chinese Academy of SciencesBeijing100049China
| | - Minghua Ge
- Department of Head and Neck SurgeryCenter of Otolaryngology-head and neck surgeryZhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College)Key Laboratory of Endocrine Gland Diseases of Zhejiang ProvinceHangzhouZhejiang310014China
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Kitzberger C, Spellerberg R, Morath V, Schwenk N, Schmohl KA, Schug C, Urnauer S, Tutter M, Eiber M, Schilling F, Weber WA, Ziegler S, Bartenstein P, Wagner E, Nelson PJ, Spitzweg C. The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy. EJNMMI Res 2022; 12:25. [PMID: 35503582 PMCID: PMC9065223 DOI: 10.1186/s13550-022-00888-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 03/11/2022] [Indexed: 01/14/2023] Open
Abstract
Cloning of the sodium iodide symporter (NIS) in 1996 has provided an opportunity to use NIS as a powerful theranostic transgene. Novel gene therapy strategies rely on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of therapeutic radionuclides. This review highlights the remarkable progress during the last two decades in the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and genetically engineered mesenchymal stem cells. In addition, NIS is a sensitive reporter gene and can be monitored by high resolution PET imaging using the radiotracers sodium [124I]iodide ([124I]NaI) or [18F]tetrafluoroborate ([18F]TFB). We performed a small preclinical PET imaging study comparing sodium [124I]iodide and in-house synthesized [18F]TFB in an orthotopic NIS-expressing glioblastoma model. The results demonstrated an improved image quality using [18F]TFB. Building upon these results, we will be able to expand the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumor models with low volume disease, such as glioblastoma. Trial registration not applicable.
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Affiliation(s)
- Carolin Kitzberger
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Rebekka Spellerberg
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Volker Morath
- Department of Nuclear Medicine, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Christina Schug
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Sarah Urnauer
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Mariella Tutter
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, 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
| | - Wolfgang A Weber
- Department of Nuclear Medicine, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Sibylle Ziegler
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital, LMU 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, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany. .,Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA.
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Belmar-López C, Vassaux G, Medel-Martinez A, Burnet J, Quintanilla M, Ramón y Cajal S, Hernandez-Losa J, De la Vieja A, Martin-Duque P. Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications. Int J Mol Sci 2022; 23:ijms23031682. [PMID: 35163605 PMCID: PMC8835939 DOI: 10.3390/ijms23031682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 02/05/2023] Open
Abstract
Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenoviruses, including the interaction between tumor microenvironment and MSCs on their arrival. Mechanisms such as transdifferentiation, MSC fusion with cells, or paracrine processes after MSCs homing were studied, increasing the knowledge and safety of this new therapy for cancer.
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Affiliation(s)
- Carolina Belmar-López
- Instituto Aragonés de Ciencias de la Salud/IIS Aragón, 50009 Zaragoza, Spain; (C.B.-L.); (A.M.-M.)
| | - Georges Vassaux
- Institut de Pharmacologie Moléculaire et Cellulaire, INSERM, CNRS, Université Côte d’Azur, 06560 Valbonne, France;
| | - Ana Medel-Martinez
- Instituto Aragonés de Ciencias de la Salud/IIS Aragón, 50009 Zaragoza, Spain; (C.B.-L.); (A.M.-M.)
| | - Jerome Burnet
- Cancer Research UK, Queen Mary University of London, London E1 4NS, UK;
| | - Miguel Quintanilla
- Instituto de Investigaciones Biomedicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain;
| | - Santiago Ramón y Cajal
- Pathology Department, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain; (S.R.y.C.); (J.H.-L.)
| | - Javier Hernandez-Losa
- Pathology Department, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain; (S.R.y.C.); (J.H.-L.)
| | - Antonio De la Vieja
- Endocrine Tumors Unit, Unidad Funcional de Investigación en Enfermedades Endocrinas (UFIEC), Instituto de Salud Carlos III (ISCIII), 28222 Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Correspondence: (A.D.l.V.); (P.M.-D.)
| | - Pilar Martin-Duque
- Instituto Aragonés de Ciencias de la Salud/IIS Aragón, 50009 Zaragoza, Spain; (C.B.-L.); (A.M.-M.)
- Fundación ARAID, 50018 Zaragoza, Spain
- Networking Research Center in Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (A.D.l.V.); (P.M.-D.)
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10
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Spellerberg R, Benli-Hoppe T, Kitzberger C, Berger S, Schmohl KA, Schwenk N, Yen HY, Zach C, Schilling F, Weber WA, Kälin RE, Glass R, Nelson PJ, Wagner E, Spitzweg C. Selective sodium iodide symporter ( NIS) genetherapy of glioblastoma mediatedby EGFR-targeted lipopolyplexes. Mol Ther Oncolytics 2021; 23:432-446. [PMID: 34853814 PMCID: PMC8604759 DOI: 10.1016/j.omto.2021.10.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 10/11/2021] [Accepted: 10/26/2021] [Indexed: 12/18/2022] Open
Abstract
Lipo-oligomers, post-functionalized with ligands to enhance targeting, represent promising new vehicles for the tumor-specific delivery of therapeutic genes such as the sodium iodide symporter (NIS). Due to its iodide trapping activity, NIS is a powerful theranostic tool for diagnostic imaging and the application of therapeutic radionuclides. 124I PET imaging allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression, and application of 131I enables cytoreduction. In our experimental design, we used epidermal growth factor receptor (EGFR)-targeted polyplexes (GE11) initially characterized in vitro using 125I uptake assays. Mice bearing an orthotopic glioblastoma were treated subsequently with mono-dibenzocyclooctyne (DBCO)-PEG24-GE11/NIS or bisDBCO-PEG24-GE11/NIS, and 24-48 h later, 124I uptake was assessed by positron emission tomography (PET) imaging. The best-performing polyplex in the imaging studies was then selected for 131I therapy studies. The in vitro studies showed EGFR-dependent and NIS-specific transfection efficiency of the polyplexes. The injection of monoDBCO-PEG24-GE11/NIS polyplexes 48 h before 124I application was characterized to be the optimal regime in the imaging studies and was therefore used for an 131I therapy study, showing a significant decrease in tumor growth and a significant extension of survival in the therapy group. These studies demonstrate the potential of EGFR-targeted polyplex-mediated NIS gene therapy as a new strategy for the therapy of glioblastoma.
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Affiliation(s)
- Rebekka Spellerberg
- Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Teoman Benli-Hoppe
- Pharmaceutical Biotechnology, Department of Pharmacy, LMU Munich, 81377 Munich, Germany
| | - Carolin Kitzberger
- Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Simone Berger
- Pharmaceutical Biotechnology, Department of Pharmacy, LMU Munich, 81377 Munich, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Hsi-Yu Yen
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Christian Zach
- Department of Nuclear Medicine, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Franz Schilling
- Department of Nuclear Medicine, School of Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
| | - Wolfgang A Weber
- Department of Nuclear Medicine, School of Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
| | - Roland E Kälin
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, 81377 Munich, Germany.,Walter Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, 81377 Munich, Germany
| | - Rainer Glass
- Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, 81377 Munich, Germany.,Walter Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, 81377 Munich, Germany.,German Cancer Consortium (DKTK), partner site 80336 Munich and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Peter J Nelson
- Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, LMU Munich, 81377 Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany.,Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
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11
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Moody AS, Dayton PA, Zamboni WC. Imaging methods to evaluate tumor microenvironment factors affecting nanoparticle drug delivery and antitumor response. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:382-413. [PMID: 34796317 PMCID: PMC8597952 DOI: 10.20517/cdr.2020.94] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/07/2021] [Accepted: 01/28/2021] [Indexed: 11/24/2022]
Abstract
Standard small molecule and nanoparticulate chemotherapies are used for cancer treatment; however, their effectiveness remains highly variable. One reason for this variable response is hypothesized to be due to nonspecific drug distribution and heterogeneity of the tumor microenvironment, which affect tumor delivery of the agents. Nanoparticle drugs have many theoretical advantages, but due to variability in tumor microenvironment (TME) factors, the overall drug delivery to tumors and associated antitumor response are low. The nanotechnology field would greatly benefit from a thorough analysis of the TME factors that create these physiological barriers to tumor delivery and treatment in preclinical models and in patients. Thus, there is a need to develop methods that can be used to reveal the content of the TME, determine how these TME factors affect drug delivery, and modulate TME factors to increase the tumor delivery and efficacy of nanoparticles. In this review, we will discuss TME factors involved in drug delivery, and how biomedical imaging tools can be used to evaluate tumor barriers and predict drug delivery to tumors and antitumor response.
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Affiliation(s)
- Amber S. Moody
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
- UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA
- Carolina Institute for Nanomedicine, Chapel Hill, NC 27599, USA
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA
| | - Paul A. Dayton
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
- UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA
| | - William C. Zamboni
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
- UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA
- Carolina Institute for Nanomedicine, Chapel Hill, NC 27599, USA
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12
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Rajendran RL, Jogalekar MP, Gangadaran P, Ahn BC. Noninvasive in vivo cell tracking using molecular imaging: A useful tool for developing mesenchymal stem cell-based cancer treatment. World J Stem Cells 2020; 12:1492-1510. [PMID: 33505597 PMCID: PMC7789123 DOI: 10.4252/wjsc.v12.i12.1492] [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: 06/29/2020] [Revised: 10/05/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023] Open
Abstract
Mounting evidence has emphasized the potential of cell therapies in treating various diseases by restoring damaged tissues or replacing defective cells in the body. Cell therapies have become a strong therapeutic modality by applying noninvasive in vivo molecular imaging for examining complex cellular processes, understanding pathophysiological mechanisms of diseases, and evaluating the kinetics/dynamics of cell therapies. In particular, mesenchymal stem cells (MSCs) have shown promise in recent years as drug carriers for cancer treatment. They can also be labeled with different probes and tracked in vivo to assess the in vivo effect of administered cells, and to optimize therapy. The exact role of MSCs in oncologic diseases is not clear as MSCs have been shown to be involved in tumor progression and inhibition, and the exact interactions between MSCs and specific cancer microenvironments are not clear. In this review, a multitude of labeling approaches, imaging modalities, and the merits/demerits of each strategy are outlined. In addition, specific examples of the use of MSCs and in vivo imaging in cancer therapy are provided. Finally, present limitations and future outlooks in terms of the translation of different imaging approaches in clinics are discussed.
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Affiliation(s)
| | | | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
| | - Byeong-Cheol Ahn
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, South Korea.
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13
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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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14
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Tutter M, Schug C, Schmohl KA, Urnauer S, Schwenk N, Petrini M, Lokerse WJM, Zach C, Ziegler S, Bartenstein P, Weber WA, Wagner E, Lindner LH, Nelson PJ, Spitzweg C. Effective control of tumor growth through spatial and temporal control of theranostic sodium iodide symporter ( NIS) gene expression using a heat-inducible gene promoter in engineered mesenchymal stem cells. Am J Cancer Res 2020; 10:4490-4506. [PMID: 32292510 PMCID: PMC7150485 DOI: 10.7150/thno.41489] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023] Open
Abstract
Purpose: The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of 131I. To gain local and temporal control of transgene expression, and thereby improve tumor selectivity, we engineered MSCs to express the NIS gene under control of a heat-inducible HSP70B promoter (HSP70B-NIS-MSCs). Experimental Design: NIS induction in heat-treated HSP70B-NIS-MSCs was verified by 125I uptake assay, RT-PCR, Western blot and immunofluorescence staining. HSP70B-NIS-MSCs were then injected i.v. into mice carrying subcutaneous hepatocellular carcinoma HuH7 xenografts, and hyperthermia (1 h at 41°C) was locally applied to the tumor. 0 - 72 h later radioiodine uptake was assessed by 123I-scintigraphy. The most effective uptake regime was then selected for 131I therapy. Results: The HSP70B promoter showed low basal activity in vitro and was significantly induced in response to heat. In vivo, the highest tumoral iodine accumulation was seen 12 h after application of hyperthermia. HSP70B-NIS-MSC-mediated 131I therapy combined with hyperthermia resulted in a significantly reduced tumor growth with prolonged survival as compared to control groups. Conclusions: The heat-inducible HSP70B promoter allows hyperthermia-induced spatial and temporal control of MSC-mediated theranostic NIS gene radiotherapy with efficient tumor-selective and temperature-dependent accumulation of radioiodine in heat-treated tumors.
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15
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Schmohl KA, Mueller AM, Dohmann M, Spellerberg R, Urnauer S, Schwenk N, Ziegler SI, Bartenstein P, Nelson PJ, Spitzweg C. Integrin αvβ3-Mediated Effects of Thyroid Hormones on Mesenchymal Stem Cells in Tumor Angiogenesis. Thyroid 2019; 29:1843-1857. [PMID: 31816265 DOI: 10.1089/thy.2019.0413] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background: Several clinical and experimental studies have implicated thyroid hormones in cancer progression. Cancer-relevant effects, including stimulation of tumor growth and new blood vessel formation by angiogenesis, are thought to be mediated by a nonclassical signaling pathway initiated through integrin αvβ3 expressed on cancer cells and proliferating endothelium. In an earlier study, we established mesenchymal stem cells (MSCs), important contributors to the fibrovascular network of tumors, as new thyroid hormone-dependent targets. Here, we evaluated the effects of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) versus Tetrac, an integrin-specific inhibitor of thyroid hormone action, on MSCs in tumor angiogenesis. Methods: Modulation of the expression and secretion of angiogenesis-relevant factors by thyroid hormones in primary human MSCs and their effect on endothelial cell tube formation were tested in vitro. We further engineered MSCs to express the sodium iodide symporter (NIS) reporter gene under control of a hypoxia-responsive promoter and the vascular endothelial growth factor (VEGF) promoter to test effects on these pathways in vitro and, for VEGF, in vivo in an orthotopic hepatocellular carcinoma (HCC) xenograft mouse model by positron emission tomography imaging. Results: T3 and T4 increased the expression of pro-angiogenic genes in MSCs and NIS-mediated radioiodide uptake in both NIS reporter MSC lines in the presence of HCC cell-conditioned medium. Supernatant from thyroid hormone-treated MSCs significantly enhanced endothelial cell tube formation. Tetrac and/or inhibitors of signaling pathways downstream of the integrin reversed all these effects. Tumoral radioiodide uptake in vivo demonstrated successful recruitment of MSCs to tumors and VEGF promoter-driven NIS expression. Hyperthyroid mice showed an increased radioiodide uptake compared with euthyroid mice, while tracer uptake was markedly reduced in hypothyroid and Tetrac-treated mice. Conclusions: Our data suggest that thyroid hormones influence angiogenic signaling in MSCs via integrin αvβ3 and further substantiate the anti-angiogenic activity of Tetrac in the tumor microenvironment.
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Affiliation(s)
- Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Andrea M Mueller
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Maike Dohmann
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Rebekka Spellerberg
- 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
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Sibylle I Ziegler
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Peter J 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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16
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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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17
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Schug C, Kitzberger C, Sievert W, Spellerberg R, Tutter M, Schmohl KA, Eberlein B, Biedermann T, Steiger K, Zach C, Schwaiger M, Multhoff G, Wagner E, Nelson PJ, Spitzweg C. Radiation-Induced Amplification of TGFB1-Induced Mesenchymal Stem Cell-Mediated Sodium Iodide Symporter ( NIS) Gene 131I Therapy. Clin Cancer Res 2019; 25:5997-6008. [PMID: 31196853 DOI: 10.1158/1078-0432.ccr-18-4092] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/10/2019] [Accepted: 06/10/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE The innate tumor homing potential of mesenchymal stem cells (MSCs) has been used for a targeted delivery of the theranostic sodium iodide symporter (NIS) transgene into solid tumors. We have previously shown that external beam radiotherapy (EBRT) results in the enhanced recruitment of NIS-expressing MSCs into human hepatocellular carcinoma (HuH7). In parallel, the tumor-associated cytokine TGFB1 becomes strongly upregulated in HuH7 tumors in response to EBRT. EXPERIMENTAL DESIGN We therefore evaluated the effects of combining focused EBRT (5 Gy) with MSC-mediated systemic delivery of the theranostic NIS transgene under control of a synthetic TGFB1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) using 123I-scintigraphy followed by 131I therapy in CD1 nu/nu mice harboring subcutaneous human hepatocellular carcinoma (HuH7). RESULTS Following tumor irradiation and SMAD-NIS-MSC application, tumoral iodide uptake monitored in vivo by 123I-scintigraphy was enhanced as compared with nonirradiated tumors. Combination of EBRT and SMAD-NIS-MSC-mediated 131I therapy resulted in a significantly improved delay in tumor growth and prolonged survival in therapy mice as compared with the combined therapy using CMV-NIS-MSCs or to control groups receiving EBRT or saline only, or EBRT together with SMAD-NIS-MSCs and saline applications. CONCLUSIONS MSC-based NIS-mediated 131I therapy after EBRT treatment dramatically enhanced therapeutic efficacy when a TGFB1-inducible SMAD-responsive promoter was used to drive NIS expression in adoptively applied MSCs. The remarkable therapeutic effect seen is thought to be linked in large part to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based NIS expression within the tumor milieu.
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Affiliation(s)
- Christina Schug
- Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Carolin Kitzberger
- Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Wolfgang Sievert
- Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar der Technischen Universität München, Radiation Immuno-Oncology group, Munich, Germany
| | - Rebekka Spellerberg
- Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Mariella Tutter
- Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Kathrin A Schmohl
- Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Bernadette Eberlein
- Department of Dermatology and Allergy Biederstein, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Tilo Biedermann
- Department of Dermatology and Allergy Biederstein, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Katja Steiger
- Department of Pathology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Christian Zach
- Department of Nuclear Medicine, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Markus Schwaiger
- Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Gabriele Multhoff
- Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar der Technischen Universität München, Radiation Immuno-Oncology group, Munich, Germany
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Peter J Nelson
- Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Christine Spitzweg
- Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
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18
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Schmohl KA, Nelson PJ, Spitzweg C. Tetrac as an anti-angiogenic agent in cancer. Endocr Relat Cancer 2019; 26:R287-R304. [PMID: 31063970 DOI: 10.1530/erc-19-0058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 04/04/2019] [Indexed: 12/24/2022]
Abstract
The thyroid hormones T3 and T4 have emerged as pro-angiogenic hormones with important implications for cancer management. Endogenous circulating hormone levels may help stimulate cancer progression and limit the effectiveness of anticancer therapy, though clinical data remain inconclusive. The capacity of thyroid hormones to modulate angiogenesis is mediated through non-canonical mechanisms initiated at the cell surface receptor integrin αvβ3. This integrin is predominantly expressed on tumour cells, proliferating endothelial cells and tumour stroma-associated cells, emphasising its potential relevance in angiogenesis and tumour biology. Thyroid hormone/integrin αvβ3 signalling results in the activation of intracellular pathways that are commonly associated with angiogenesis and are mediated through classical pro-angiogenic molecules such as vascular endothelial growth factor. The naturally occurring T4 analogue tetrac blocks the pro-angiogenic actions of thyroid hormones at the integrin receptor, in addition to agonist-independent anti-angiogenic effects. Tetrac reduces endothelial cell proliferation, migration and tube formation through a reduction in the transcription of vascular growth factors/growth factor receptors, hypoxia-inducible factor-1α, pro-angiogenic cytokines and a number of other pro-angiogenic genes, while at the same time stimulating the expression of endogenous angiogenesis inhibitors. It further modulates vascular growth factor activity by disrupting the crosstalk between integrin αvβ3 and adjacent growth factor receptors. Moreover, tetrac disrupts thyroid hormone-stimulated tumour recruitment, differentiation and the pro-angiogenic signalling of tumour stroma-associated mesenchymal stem cells. Tetrac affects tumour-associated angiogenesis via multiple mechanisms and interferes with other cancer cell survival pathways. In conjunction with its low toxicity and high tissue selectivity, tetrac is a promising candidate for clinical application.
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Affiliation(s)
- Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Peter J 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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19
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Urnauer S, Schmohl KA, Tutter M, Schug C, Schwenk N, Morys S, Ziegler S, Bartenstein P, Clevert DA, Wagner E, Spitzweg C. Dual-targeted NIS polyplexes-a theranostic strategy toward tumors with heterogeneous receptor expression. Gene Ther 2019; 26:93-108. [PMID: 30683895 DOI: 10.1038/s41434-019-0059-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 12/20/2018] [Accepted: 12/26/2018] [Indexed: 12/12/2022]
Abstract
Tumor heterogeneity, within and between tumors, may have severe implications for tumor therapy, especially for targeted gene therapy, where single-targeted approaches often result in limited efficacy and therapy resistance. Polymer-formulated nonviral vectors provide a potent delivery platform for cancer therapy. To improve applicability for future clinical use in a broad range of patients and cancer types, a dual-targeting approach was performed. Synthetic LPEI-PEG2kDa-based polymer backbones were coupled to two tumor-specific peptide ligands GE11 (EGFR-targeting) and cMBP (cMET-targeting). The dual-targeting approach was used to deliver the theranostic sodium iodide symporter (NIS) gene to hepatocellular cancer. NIS as auspicious theranostic gene allows noninvasive imaging of functional NIS gene expression and effective anticancer radioiodide therapy. Enhanced tumor-specific transduction efficiency of dual-targeted polyplexes compared to single-targeted polyplexes was demonstrated in vitro using tumor cell lines with different EGFR and cMET expression and in vivo by 124I-PET-imaging. Therapeutic efficacy of the bispecific concept was mirrored by significantly reduced tumor growth and perfusion, which was associated with prolonged animal survival. In conclusion, the dual-targeting approach highlights the benefits of a bifunctional strategy for a future clinical translation of the bioimaging-based NIS-mediated radiotherapy allowing efficient targeting of heterogeneic tumors with variable receptor expression levels.
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Affiliation(s)
- Sarah Urnauer
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Mariella Tutter
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Christina Schug
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Stephan Morys
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Germany
| | - Sibylle Ziegler
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Germany
| | - Dirk-André Clevert
- Department of Clinical Radiology, University Hospital of Munich, LMU Munich, Germany
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany.
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20
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Wang J, Zhu L, Chen X, Huang R, Wang S, Dong P. Human Bone Marrow Mesenchymal Stem Cells Functionalized by Hybrid Baculovirus-Adeno-Associated Viral Vectors for Targeting Hypopharyngeal Carcinoma. Stem Cells Dev 2019; 28:543-553. [PMID: 30747033 DOI: 10.1089/scd.2018.0252] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hypopharyngeal carcinoma is a common malignant tumor of the head and neck with a very poor prognosis; the median survival time for curatively treated patients was 17.2 months in India. However, cell-based gene therapy holds promise to improve patient outcomes. In this study, we investigated whether human bone marrow mesenchymal stem cells (BMSCs) possess potential homing capacity for hypopharyngeal carcinoma. To monitor the efficiency of BMSC transplantation therapy through reporter gene imaging, we employed a hybrid baculovirus vector containing the Luc-P2A-eGFP fusion or sodium iodide symporter (NIS) sequence under the control of the cytomegalovirus promoter. To enhance the transfection efficiency, baculovirus vectors (Bac-CMV-Luc-P2A-eGFP-ITR and Bac-CMV-NIS-ITR) were flanked by inverted terminal repeats (ITRs), which are key elements of adeno-associated viruses. The infection efficiency of Bac-CMV-Luc-P2A-eGFP-ITR in BMSCs was as high as 92.84 ± 1.14% with no obvious toxic effects at a multiplicity of infection of 400. Moreover, Bac-CMV-NIS-ITR-infected BMSCs showed highly efficient radioactive iodide (125I) uptake; these high uptake levels were maintained for at least 2 h. Transwell migration assays further demonstrated the chemotaxis of BMSCs to hypopharyngeal carcinoma cells (FaDu cells) in vitro. BMSCs modified by firefly luciferase report gene or NIS were injected into nude mice with hypopharyngeal carcinoma, and changes in the localization of the BMSCs were successfully tracked with bioluminescent imaging and micro-single-photon emission computed tomography imaging. These data indicate the potential utility of BMSCs as a promising targeted-delivery vehicle for hypopharyngeal carcinoma gene therapy. Importantly, BMSCs may represent a promising targeting vector for general tumor radionuclide therapy.
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Affiliation(s)
- Jun Wang
- 1 Department of Otolaryngology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,2 Department of Otolaryngology and Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liying Zhu
- 3 Department of Nuclear Medicine, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinwei Chen
- 1 Department of Otolaryngology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruofei Huang
- 1 Department of Otolaryngology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shili Wang
- 2 Department of Otolaryngology and Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pin Dong
- 1 Department of Otolaryngology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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21
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Abstract
Mesenchymal stromal cell (MSC) therapy has produced very promising results for multiple diseases in animal models, with over 780 clinical trials on going or completed. However, most of the human clinical trials have not been as successful as trials using preclinical models. To improve the therapeutic potential of MSCs, different research groups have used gene transfer vectors to express factors involved in migration, survival, differentiation, and immunomodulation. The ideal gene transfer vector for most applications should achieve long-term, stable (constitutive or inducible) transgene expression in MSCs and their progeny. Given their efficiency and low impact on transduced cells, lentiviral vectors (LVs) are the vectors of choice. In this chapter we will describe a detailed protocol for the generation of genetically modified MSCs using lentiviral vectors (LVs). Although this protocol has been optimized for MSC lentiviral transduction, it can be easily adapted to other stem cells by changing culture conditions while maintaining volumes and incubation times.
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22
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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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23
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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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24
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Shi S, Zhang M, Guo R, Miao Y, Li B. Bone Marrow-Derived Mesenchymal Stem Cell-Mediated Dual-Gene Therapy for Glioblastoma. Hum Gene Ther 2018; 30:106-117. [PMID: 29993289 DOI: 10.1089/hum.2018.092] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Bone-marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. However, the optimal treatment time post-BMSC implantation and the assessment of the long-term fate of therapeutic BMSCs post-tumor treatment are critical if such promising therapies are to be translated into clinical practice. An efficient BMSC-based therapeutic strategy has been developed that simultaneously allows killing of tumor cells, inhibiting of tumor angiogenesis, and assessment and eradication of implanted BMSCs after treatment of glioblastoma. BMSCs were engineered to co-express the angiogenesis inhibitor kringle 5 (K5) of human plasminogen, under the control of the cytomegalovirus promoter (CMV) and the human sodium-iodide symporter (NIS), involved in uptake of radioisotopes, under the control of early growth response factor 1 (Egr1), a radiation-activated promoter. A significant decrease in tumor growth and tumor angiogenesis and a subsequent increase in survival were observed when mice bearing glioblastoma were treated with 188Re post-therapeutic intravenous BMSC implantation. Furthermore, the systemic administration of 188Re post-tumor treatment selectively eliminated therapeutic BMSCs expressing NIS, which was monitored in real time by 125I micro single photon emission computed tomography/computed tomography imaging. Meanwhile, the Egr1 promoter induced a 188Re radiation positive feedback effect absorbed by NIS. After intravenous BMSC implantation, BMSCs levels in the tumor and lung both peaked on day 10 and decreased to the lowest levels on days 24 and 17, respectively. These findings suggest that day 17 post-BMSC implantation could be an optimal time for 188Re treatment. These results provide a new adjuvant therapy mediated by BMSCs for glioblastoma treatment.
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Affiliation(s)
- Shuo Shi
- Department of Nuclear Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Min Zhang
- Department of Nuclear Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Rui Guo
- Department of Nuclear Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ying Miao
- Department of Nuclear Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Biao Li
- Department of Nuclear Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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25
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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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26
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Krueger TEG, Thorek DLJ, Denmeade SR, Isaacs JT, Brennen WN. Concise Review: Mesenchymal Stem Cell-Based Drug Delivery: The Good, the Bad, the Ugly, and the Promise. Stem Cells Transl Med 2018; 7:651-663. [PMID: 30070053 PMCID: PMC6127224 DOI: 10.1002/sctm.18-0024] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/15/2018] [Accepted: 05/30/2018] [Indexed: 12/12/2022] Open
Abstract
The development of mesenchymal stem cells (MSCs) as cell‐based drug delivery vectors for numerous clinical indications, including cancer, has significant promise. However, a considerable challenge for effective translation of these approaches is the limited tumor tropism and broad biodistribution observed using conventional MSCs, which raises concerns for toxicity to nontarget peripheral tissues (i.e., the bad). Consequently, there are a variety of synthetic engineering platforms in active development to improve tumor‐selective targeting via increased homing efficiency and/or specificity of drug activation, some of which are already being evaluated clinically (i.e., the good). Unfortunately, the lack of robust quantification and widespread adoption of standardized methodologies with high sensitivity and resolution has made accurate comparisons across studies difficult, which has significantly impeded progress (i.e., the ugly). Herein, we provide a concise review of active and passive MSC homing mechanisms and biodistribution postinfusion; in addition to in vivo cell tracking methodologies and strategies to enhance tumor targeting with a focus on MSC‐based drug delivery strategies for cancer therapy. Stem Cells Translational Medicine2018;1–13
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Affiliation(s)
- Timothy E G Krueger
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Daniel L J Thorek
- Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, Maryland, USA
| | - Samuel R Denmeade
- Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, Maryland, USA.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - John T Isaacs
- Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, Maryland, USA.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - W Nathaniel Brennen
- Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, Maryland, USA
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27
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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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28
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De la Vieja A, Santisteban P. Role of iodide metabolism in physiology and cancer. Endocr Relat Cancer 2018; 25:R225-R245. [PMID: 29437784 DOI: 10.1530/erc-17-0515] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 02/01/2018] [Indexed: 12/28/2022]
Abstract
Iodide (I-) metabolism is crucial for the synthesis of thyroid hormones (THs) in the thyroid and the subsequent action of these hormones in the organism. I- is principally transported by the sodium iodide symporter (NIS) and by the anion exchanger PENDRIN, and recent studies have demonstrated the direct participation of new transporters including anoctamin 1 (ANO1), cystic fibrosis transmembrane conductance regulator (CFTR) and sodium multivitamin transporter (SMVT). Several of these transporters have been found expressed in various tissues, implicating them in I- recycling. New research supports the exciting idea that I- participates as a protective antioxidant and can be oxidized to hypoiodite, a potent oxidant involved in the host defense against microorganisms. This was possibly the original role of I- in biological systems, before the appearance of TH in evolution. I- per se participates in its own regulation, and new evidence indicates that it may be antineoplastic, anti-proliferative and cytotoxic in human cancer. Alterations in the expression of I- transporters are associated with tumor development in a cancer-type-dependent manner and, accordingly, NIS, CFTR and ANO1 have been proposed as tumor markers. Radioactive iodide has been the mainstay adjuvant treatment for thyroid cancer for the last seven decades by virtue of its active transport by NIS. The rapid advancement of techniques that detect radioisotopes, in particular I-, has made NIS a preferred target-specific theranostic agent.
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Affiliation(s)
- Antonio De la Vieja
- Tumor Endocrine Unit, Chronic Disease Program (UFIEC), Instituto de Salud Carlos III, Madrid, Spain
- CiberOnc, Instituto de Salud Carlos III, Madrid, Spain
| | - Pilar Santisteban
- CiberOnc, Instituto de Salud Carlos III, Madrid, Spain
- Department of Physiopathology of Endocrine a Nervous System, Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain
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Urnauer S, Klutz K, Grünwald GK, Morys S, Schwenk N, Zach C, Gildehaus FJ, Rödl W, Ogris M, Wagner E, Spitzweg C. Systemic tumor-targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes. J Gene Med 2018; 19. [PMID: 28423213 DOI: 10.1002/jgm.2957] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 04/03/2017] [Accepted: 04/16/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Nonviral polymer-based gene transfer represents an adaptable system for tumor-targeted gene therapy because various design strategies of shuttle systems, together with the mechanistic concept of active tumor targeting, lead to improved gene delivery vectors resulting in higher tumor specificity, efficacy and safety. METHODS Using the sodium iodide symporter (NIS) as a theranostic gene, nonviral gene delivery vehicles based on linear polyethylenimine (LPEI), polyethylene glycol (PEG) and coupled to the synthetic peptide B6 (LPEI-PEG-B6), which specifically binds to tumor cells, were investigated in a hepatocellular carcinoma xenograft model for tumor selectivity and transduction efficiency. RESULTS In vitro incubation of three different tumor cell lines with LPEI-PEG-B6/NIS resulted in significant increase in iodide uptake activity compared to untargeted and empty vectors. After establishment of subcutaneous HuH7 tumors, NIS-conjugated nanoparticles were injected intravenously followed by analysis of radioiodide biodistribution using 123 I-scintigraphy showing significant perchlorate-sensitive iodide accumulation in tumors of LPEI-PEG-B6/NIS-treated mice (8.0 ± 1.5% ID/g 123 I; biological half-life of 4 h). After four cycles of repetitive polyplex/131 I applications, a significant delay of tumor growth was observed, which was associated with markedly improved survival in the therapy group. CONCLUSIONS These results clearly demonstrate that systemic in vivo NIS gene transfer using nanoparticle vectors coupled to B6 tumor targeting ligand is capable of inducing tumor-specific radioiodide uptake. This promising gene therapy approach opens the exciting prospect of NIS-mediated radionuclide therapy in metastatic cancer, together with the possibility of combining several targeting ligands to enhance selective therapeutic efficacy in a broad field of cancer types with various receptor expression profiles.
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Affiliation(s)
- Sarah Urnauer
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Kathrin Klutz
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Geoffrey K Grünwald
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Stephan Morys
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
| | - Christian Zach
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Germany
| | | | - Wolfgang Rödl
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany
| | - Manfred Ogris
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany.,Division of Clinical Pharmacy and Diagnostics, University of Vienna, Austria
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany
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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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Schmohl KA, Dolp P, Schug C, Knoop K, Klutz K, Schwenk N, Bartenstein P, Nelson PJ, Ogris M, Wagner E, Spitzweg C. Reintroducing the Sodium-Iodide Symporter to Anaplastic Thyroid Carcinoma. Thyroid 2017; 27:1534-1543. [PMID: 29032724 DOI: 10.1089/thy.2017.0290] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Anaplastic thyroid carcinoma (ATC), the most aggressive form of thyroid cancer, is unresponsive to radioiodine therapy. The current study aimed to extend the diagnostic and therapeutic application of radioiodine beyond the treatment of differentiated thyroid cancer by targeting the functional sodium-iodide symporter (NIS) to ATC. METHODS The study employed nanoparticle vectors (polyplexes) based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG) and coupled to the synthetic peptide GE11 as an epidermal growth factor receptor (EGFR)-specific ligand in order to target a NIS-expressing plasmid (LPEI-PEG-GE11/NIS) to EGFR overexpressing human thyroid carcinoma cell lines. Using ATC xenograft mouse models, transfection efficiency by 123I scintigraphy and potential for systemic radioiodine therapy after systemic polyplex application were evaluated. RESULTS In vitro iodide uptake studies in SW1736 and Hth74 ATC cells, and, for comparison, in more differentiated follicular (FTC-133) and papillary (BCPAP) thyroid carcinoma cells demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS that correlated well with EGFR expression levels. After systemic polyplex injection, in vivo 123I gamma camera imaging revealed significant tumor-specific accumulation of radioiodine in an SW1736 and an Hth74 xenograft mouse model. Radioiodine accumulation was found to be higher in SW1736 tumors, reflecting in vitro results, EGFR expression levels, and results from ex vivo analysis of NIS staining. Administration of 131I in LPEI-PEG-GE11/NIS-treated SW1736 xenograft mice resulted in significantly reduced tumor growth associated with prolonged survival compared to control animals. CONCLUSIONS The data open the exciting prospect of NIS-mediated radionuclide imaging and therapy of ATC after non-viral reintroduction of the NIS gene. The high tumor specificity after systemic application makes the strategy an attractive alternative for the treatment of highly metastatic ATC.
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Affiliation(s)
- Kathrin A Schmohl
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Patrick Dolp
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Christina Schug
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Kerstin Knoop
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Kathrin Klutz
- 1 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
| | - Peter Bartenstein
- 2 Department of Nuclear Medicine, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Peter J Nelson
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
| | - Manfred Ogris
- 3 Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna , Vienna, Austria
| | - Ernst Wagner
- 4 Department of Pharmaceutical Biotechnology, Department of Pharmacy, Center for System-Based Drug Research and Center for Nanoscience , LMU Munich, Munich, Germany
| | - Christine Spitzweg
- 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany
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Urnauer S, Müller AM, Schug C, Schmohl KA, Tutter M, Schwenk N, Rödl W, Morys S, Ingrisch M, Bertram J, Bartenstein P, Clevert DA, Wagner E, Spitzweg C. EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases. Oncotarget 2017; 8:92195-92208. [PMID: 29190908 PMCID: PMC5696174 DOI: 10.18632/oncotarget.21028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 08/04/2017] [Indexed: 02/06/2023] Open
Abstract
Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases. The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of 131I. For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)-specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using 18F-tetrafluoroborate (18F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18F-TFB application showed high tumoral levels (4.8±0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq 131I resulted in marked delay in metastases spread, which was associated with improved animal survival. In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease.
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Affiliation(s)
- Sarah Urnauer
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Andrea M Müller
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Christina Schug
- 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
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Wolfgang Rödl
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
| | - Stephan Morys
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
| | - Michael Ingrisch
- Department of Clinical Radiology, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Jens Bertram
- Department of Nuclear Medicine, Radiopharmacy, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Dirk-André Clevert
- Department of Clinical Radiology, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
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Morys S, Urnauer S, Spitzweg C, Wagner E. EGFR Targeting and Shielding of pDNA Lipopolyplexes via Bivalent Attachment of a Sequence-Defined PEG Agent. Macromol Biosci 2017; 18. [PMID: 28877405 DOI: 10.1002/mabi.201700203] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 07/18/2017] [Indexed: 12/20/2022]
Abstract
For successful nonviral gene delivery, cationic polymers are promising DNA carrier, which need to comprise several functionalities. The current work focuses on the postincorporation of epidermal growth factor receptor (EGFR) targeted PEGylation agents onto lipopolyplexes for pDNA delivery. T-shaped lipo-oligomers are previously found to be effective sequence-defined carriers for pDNA and siRNA. Here, the bis-oleoyl-oligoaminoethanamide 454 containing tyrosine trimer-cysteine ends is applied for complex formation with pDNA coding for luciferase or sodium iodide symporter (NIS). In a second step, the lipopolyplexes are modified via disulfide formation with sequence-defined monovalent or bivalent PEGylation agents containing one or two 3-nitro-2-pyridinesulfenyl (NPys)-activated cysteines, respectively. For targeting, the polyethylene glycol (PEG) agents comprise the EGFR targeting peptide GE11. In comparison of all transfection complexes, 454 lipopolyplexes modified with the bidentate PEG-GE11 agent show the best, EGFR-dependent uptake as well as luciferase and NIS gene expression into receptor-positive tumor cells.
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Affiliation(s)
- Stephan Morys
- Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for Nanoscience (CeNS), LMU Munich, 81377, Munich, Germany
| | - Sarah Urnauer
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, 81377, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, 81377, Munich, Germany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for Nanoscience (CeNS), LMU Munich, 81377, Munich, Germany
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Schmohl KA, Gupta A, Grünwald GK, Trajkovic-Arsic M, Klutz K, Braren R, Schwaiger M, Nelson PJ, Ogris M, Wagner E, Siveke JT, Spitzweg C. Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene. Oncotarget 2017; 8:33393-33404. [PMID: 28380420 PMCID: PMC5464876 DOI: 10.18632/oncotarget.16499] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/27/2017] [Indexed: 12/18/2022] Open
Abstract
The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery.
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Affiliation(s)
- Kathrin A. Schmohl
- Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Aayush Gupta
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Geoffrey K. Grünwald
- Department of Internal Medicine II and IV, University Hospital of Munich, LMU 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
| | - Kathrin Klutz
- Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Rickmer Braren
- Department of Radiology, Klinikum rechts der Isar der Technischen Universität München, 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, LMU Munich, Munich, Germany
| | - Manfred Ogris
- Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna, Vienna, Austria
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for System-Based Drug Research and Center for Nanoscience, LMU 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 II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
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Ramamonjisoa N, Ackerstaff E. Characterization of the Tumor Microenvironment and Tumor-Stroma Interaction by Non-invasive Preclinical Imaging. Front Oncol 2017; 7:3. [PMID: 28197395 PMCID: PMC5281579 DOI: 10.3389/fonc.2017.00003] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 01/05/2017] [Indexed: 12/13/2022] Open
Abstract
Tumors are often characterized by hypoxia, vascular abnormalities, low extracellular pH, increased interstitial fluid pressure, altered choline-phospholipid metabolism, and aerobic glycolysis (Warburg effect). The impact of these tumor characteristics has been investigated extensively in the context of tumor development, progression, and treatment response, resulting in a number of non-invasive imaging biomarkers. More recent evidence suggests that cancer cells undergo metabolic reprograming, beyond aerobic glycolysis, in the course of tumor development and progression. The resulting altered metabolic content in tumors has the ability to affect cell signaling and block cellular differentiation. Additional emerging evidence reveals that the interaction between tumor and stroma cells can alter tumor metabolism (leading to metabolic reprograming) as well as tumor growth and vascular features. This review will summarize previous and current preclinical, non-invasive, multimodal imaging efforts to characterize the tumor microenvironment, including its stromal components and understand tumor-stroma interaction in cancer development, progression, and treatment response.
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Affiliation(s)
- Nirilanto Ramamonjisoa
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ellen Ackerstaff
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Cen P, Chen J, Hu C, Fan L, Wang J, Li L. Noninvasive in-vivo tracing and imaging of transplanted stem cells for liver regeneration. Stem Cell Res Ther 2016; 7:143. [PMID: 27664081 PMCID: PMC5035504 DOI: 10.1186/s13287-016-0396-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Terminal liver disease is a major cause of death globally. The only ultimate therapeutic approach is orthotopic liver transplant. Because of the innate defects of organ transplantation, stem cell-based therapy has emerged as an effective alternative, based on the capacity of stem cells for multilineage differentiation and their homing to injured sites. However, the disease etiology, cell type, timing of cellular graft, therapeutic dose, delivery route, and choice of endpoints have varied between studies, leading to different, even divergent, results. In-vivo cell imaging could therefore help us better understand the fate and behaviors of stem cells to optimize cell-based therapy for liver regeneration. The primary imaging techniques in preclinical or clinical studies have consisted of optical imaging, magnetic resonance imaging, radionuclide imaging, reporter gene imaging, and Y chromosome-based fluorescence in-situ hybridization imaging. More attention has been focused on developing new or modified imaging methods for longitudinal and high-efficiency tracing. Herein, we provide a descriptive overview of imaging modalities and discuss recent advances in the field of molecular imaging of intrahepatic stem cell grafts.
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Affiliation(s)
- Panpan Cen
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine; First Affiliated Hospital; Zhejiang University, Hangzhou, 310006, China
| | - Jiajia Chen
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine; First Affiliated Hospital; Zhejiang University, Hangzhou, 310006, China
| | - Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine; First Affiliated Hospital; Zhejiang University, Hangzhou, 310006, China
| | - Linxiao Fan
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine; First Affiliated Hospital; Zhejiang University, Hangzhou, 310006, China
| | - Jie Wang
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine; First Affiliated Hospital; Zhejiang University, Hangzhou, 310006, China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine; First Affiliated Hospital; Zhejiang University, Hangzhou, 310006, China.
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Niess H, Thomas MN, Schiergens TS, Kleespies A, Jauch KW, Bruns C, Werner J, Nelson PJ, Angele MK. Genetic engineering of mesenchymal stromal cells for cancer therapy: turning partners in crime into Trojan horses. Innov Surg Sci 2016; 1:19-32. [PMID: 31579715 PMCID: PMC6753982 DOI: 10.1515/iss-2016-0005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/03/2016] [Indexed: 12/26/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are adult progenitor cells with a high migratory and differentiation potential, which influence a broad range of biological functions in almost every tissue of the body. Among other mechanisms, MSCs do so by the secretion of molecular cues, differentiation toward more specialized cell types, or influence on the immune system. Expanding tumors also depend on the contribution of MSCs to building a supporting stroma, but the effects of MSCs appear to go beyond the mere supply of connective tissues. MSCs show targeted "homing" toward growing tumors, which is then followed by exerting direct and indirect effects on cancer cells. Several research groups have developed novel strategies that make use of the tumor tropism of MSCs by engineering them to express a transgene that enables an attack on cancer growth. This review aims to familiarize the reader with the current knowledge about MSC biology, the existing evidence for MSC contribution to tumor growth with its underlying mechanisms, and the strategies that have been developed using MSCs to deploy an anticancer therapy.
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Affiliation(s)
- Hanno Niess
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the University of Munich, Munich, Germany
| | - Michael N Thomas
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the University of Munich, Munich, Germany
| | - Tobias S Schiergens
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the University of Munich, Munich, Germany
| | - Axel Kleespies
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the University of Munich, Munich, Germany
| | - Karl-Walter Jauch
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the University of Munich, Munich, Germany
| | - Christiane Bruns
- Department of General, Visceral and Cancer Surgery, Hospital of the University of Cologne, Cologne, Germany
| | - Jens Werner
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the University of Munich, Munich, Germany
| | - Peter J Nelson
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universitaet Muenchen, Arbeitsgruppe Klinische Biochemie, Munich, Germany
| | - Martin K Angele
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the University of Munich, Munich, Germany
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Hagenhoff A, Bruns CJ, Zhao Y, von Lüttichau I, Niess H, Spitzweg C, Nelson PJ. Harnessing mesenchymal stem cell homing as an anticancer therapy. Expert Opin Biol Ther 2016; 16:1079-92. [PMID: 27270211 DOI: 10.1080/14712598.2016.1196179] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Mesenchymal stromal cells (MSCs) are non-hematopoietic progenitor cells that have been exploited as vehicles for cell-based cancer therapy. The general approach is based on the innate potential of adoptively applied MSC to undergo facilitated recruitment to malignant tissue. MSC from different tissue sources have been engineered using a variety of therapy genes that have shown efficacy in solid tumor models. AREAS COVERED In this review we will focus on the current developments of MSC-based gene therapy, in particular the diverse approaches that have been used for MSCs-targeted tumor therapy. We also discuss some outstanding issues and general prospects for their clinical application. EXPERT OPINION The use of modified mesenchymal stem cells as therapy vehicles for the treatment of solid tumors has progressed to the first generation of clinical trials, but the general field is still in its infancy. There are many questions that need to be addressed if this very complex therapy approach is widely applied in clinical settings. More must be understood about the mechanisms underlying tumor tropism and we need to identify the optimal source of the cells used. Outstanding issues also include the therapy transgenes used, and which tumor types represent viable targets for this therapy.
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Affiliation(s)
- Anna Hagenhoff
- a Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar , Technical University , Munich , Germany
| | - Christiane J Bruns
- b Department of Surgery , Otto-von-Guericke University , Magdeburg , Germany
| | - Yue Zhao
- b Department of Surgery , Otto-von-Guericke University , Magdeburg , Germany
| | - Irene von Lüttichau
- a Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar , Technical University , Munich , Germany
| | - Hanno Niess
- c Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery , University of Munich , Munich , Germany
| | - Christine Spitzweg
- d Department of Internal Medicine II , University of Munich , Munich , Germany
| | - Peter J Nelson
- e Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV , University of Munich , Munich , Germany
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Urnauer S, Morys S, Krhac Levacic A, Müller AM, Schug C, Schmohl KA, Schwenk N, Zach C, Carlsen J, Bartenstein P, Wagner E, Spitzweg C. Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene. Mol Ther 2016; 24:1395-404. [PMID: 27157666 DOI: 10.1038/mt.2016.95] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/29/2016] [Indexed: 12/18/2022] Open
Abstract
The sodium iodide symporter (NIS) as well-characterized theranostic gene represents an outstanding tool to target different cancer types allowing noninvasive imaging of functional NIS expression and therapeutic radioiodide application. Based on its overexpression on the surface of most cancer types, the cMET/hepatocyte growth factor receptor serves as ideal target for tumor-selective gene delivery. Sequence-defined polymers as nonviral gene delivery vehicles comprising polyethylene glycol (PEG) and cationic (oligoethanoamino) amide cores coupled with a cMET-binding peptide (cMBP2) were complexed with NIS-DNA and tested for receptor-specificity, transduction efficiency, and therapeutic efficacy in hepatocellular cancer cells HuH7. In vitro iodide uptake studies demonstrated high transduction efficiency and cMET-specificity of NIS-encoding polyplexes (cMBP2-PEG-Stp/NIS) compared to polyplexes without targeting ligand (Ala-PEG-Stp/NIS) and without coding DNA (cMBP2-PEG-Stp/Antisense-NIS). Tumor recruitment and vector biodistribution were investigated in vivo in a subcutaneous xenograft mouse model showing high tumor-selective iodide accumulation in cMBP2-PEG-Stp/NIS-treated mice (6.6 ± 1.6% ID/g (123)I, biological half-life 3 hours) by (123)I-scintigraphy. Therapy studies with three cycles of polyplexes and (131)I application resulted in significant delay in tumor growth and prolonged survival. These data demonstrate the enormous potential of cMET-targeted sequence-defined polymers combined with the unique theranostic function of NIS allowing for optimized transfection efficiency while eliminating toxicity.
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Affiliation(s)
- Sarah Urnauer
- Department of Internal Medicine II, LMU Munich, Munich, Germany
| | - Stephan Morys
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
| | - Ana Krhac Levacic
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
| | - Andrea M Müller
- Department of Internal Medicine II, LMU Munich, Munich, Germany
| | - Christina Schug
- Department of Internal Medicine II, LMU Munich, Munich, Germany
| | | | | | - Christian Zach
- Department of Nuclear Medicine, LMU Munich, Munich, Germany
| | | | | | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany
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Gao Y, Zhou Z, Lu S, Huang X, Zhang C, Jiang R, Yao A, Sun B, Wang X. Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma. Stem Cells 2016; 34:1112-22. [PMID: 26763650 DOI: 10.1002/stem.2275] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 11/12/2015] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC.
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MESH Headings
- Animals
- Bone Marrow Cells/cytology
- Bone Marrow Cells/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Cell Movement/genetics
- Chemokines, CC/biosynthesis
- Chemokines, CC/genetics
- Chemokines, CC/therapeutic use
- Chemotaxis/genetics
- Gene Expression Regulation, Neoplastic
- Gene Transfer Techniques
- Green Fluorescent Proteins/genetics
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/therapy
- Macrophage Inflammatory Proteins/biosynthesis
- Macrophage Inflammatory Proteins/genetics
- Macrophage Inflammatory Proteins/therapeutic use
- Mesenchymal Stem Cells/chemistry
- Mesenchymal Stem Cells/cytology
- Mesenchymal Stem Cells/metabolism
- Mice
- RNA, Small Interfering/genetics
- RNA, Small Interfering/therapeutic use
- Receptors, CCR1/biosynthesis
- Receptors, CCR1/genetics
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Yun Gao
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Zhong Zhou
- Department of Orthopaedics, Jiangsu Provincial Hospital of Integrated Chinese and Western Medicine, Nanjing, Jiangsu Province, People's Republic of China
| | - Sen Lu
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Xinli Huang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Chuanyong Zhang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Runqiu Jiang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Aihua Yao
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Beicheng Sun
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Xuehao Wang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
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Mansfield DC, Kyula JN, Rosenfelder N, Chao-Chu J, Kramer-Marek G, Khan AA, Roulstone V, McLaughlin M, Melcher AA, Vile RG, Pandha HS, Khoo V, Harrington KJ. Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer. Gene Ther 2016; 23:357-68. [PMID: 26814609 PMCID: PMC4827015 DOI: 10.1038/gt.2016.5] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 12/07/2015] [Accepted: 01/13/2016] [Indexed: 12/16/2022]
Abstract
Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice.
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Affiliation(s)
- D C Mansfield
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - J N Kyula
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - N Rosenfelder
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - J Chao-Chu
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - G Kramer-Marek
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - A A Khan
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - V Roulstone
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - M McLaughlin
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
| | - A A Melcher
- Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK
| | - R G Vile
- Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA
| | - H S Pandha
- Postgraduate Medical School, The University of Surrey, Guildford, UK
| | - V Khoo
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
- The Royal Marsden Hospital, London, UK
- University of Melbourne and Monash University, Victoria, Australia
| | - K J Harrington
- Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK
- The Royal Marsden Hospital, London, UK
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Guo XR, Hu QY, Yuan YH, Tang XJ, Yang ZS, Zou DD, Bian LJ, Dai LJ, Li DS. PTEN-mRNA engineered mesenchymal stem cell-mediated cytotoxic effects on U251 glioma cells. Oncol Lett 2016; 11:2733-2740. [PMID: 27073544 PMCID: PMC4812521 DOI: 10.3892/ol.2016.4297] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 01/11/2016] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been considered to have potential as ideal carriers for the delivery of anticancer agents since the capacity for tumor-oriented migration and integration was identified. In contrast to DNA-based vectors, mRNA synthesized in vitro may be readily transfected and is mutagenesis-free. The present study was performed in order to investigate the effects of phosphatase and tensin homolog (PTEN) mRNA-engineered MSCs on human glioma U251 cells under indirect co-culture conditions. PTEN-bearing mRNA was generated by in vitro transcription and was transfected into MSCs. The expression of PTEN in transfected MSCs was detected by immunoblotting, and the migration ability of MSCs following PTEN-bearing mRNA transfection was verified using Transwell co-cultures. The indirect co-culture was used to determine the effects of PTEN-engineered MSCs on the viability of U251 glioma cells by luminescence and fluorescence microscopy. The synthesized PTEN mRNA was expressed in MSCs, and the expression was highest at 24 h subsequent to transfection. An enhanced migration rate was observed in MSCs transfected with PTEN mRNA compared with non-transfected MSCs (P<0.05). A significant inhibition of U251 cells was observed when the cells were cultured with conditioned medium from PTEN mRNA-engineered MSCs (P<0.05). The results suggested that anticancer gene-bearing mRNA synthesized in vitro is capable of being applied to a MSC-mediated anticancer strategy for the treatment of glioblastoma patients.
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Affiliation(s)
- Xing Rong Guo
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Qin Yong Hu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ya Hong Yuan
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Xiang Jun Tang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Zhuo Shun Yang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Dan Dan Zou
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Liu Jiao Bian
- College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, P.R. China
| | - Long Jun Dai
- Department of Surgery, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| | - Dong Sheng Li
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
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Abstract
![]()
Development
of novel imaging probes for cancer diagnostics remains
critical for early detection of disease, yet most imaging agents are
hindered by suboptimal tumor accumulation. To overcome these limitations,
researchers have adapted antibodies for imaging purposes. As cancerous
malignancies express atypical patterns of cell surface proteins in
comparison to noncancerous tissues, novel antibody-based imaging agents
can be constructed to target individual cancer cells or surrounding
vasculature. Using molecular imaging techniques, these agents may
be utilized for detection of malignancies and monitoring of therapeutic
response. Currently, there are several imaging modalities commonly
employed for molecular imaging. These imaging modalities include positron
emission tomography (PET), single-photon emission computed tomography
(SPECT), magnetic resonance (MR) imaging, optical imaging (fluorescence
and bioluminescence), and photoacoustic (PA) imaging. While antibody-based
imaging agents may be employed for a broad range of diseases, this
review focuses on the molecular imaging of pancreatic cancer, as there
are limited resources for imaging and treatment of pancreatic malignancies.
Additionally, pancreatic cancer remains the most lethal cancer with
an overall 5-year survival rate of approximately 7%, despite significant
advances in the imaging and treatment of many other cancers. In this
review, we discuss recent advances in molecular imaging of pancreatic
cancer using antibody-based imaging agents. This task is accomplished
by summarizing the current progress in each type of molecular imaging
modality described above. Also, several considerations for designing
and synthesizing novel antibody-based imaging agents are discussed.
Lastly, the future directions of antibody-based imaging agents are
discussed, emphasizing the potential applications for personalized
medicine.
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Affiliation(s)
- Christopher G England
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Reinier Hernandez
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Savo Bou Zein Eddine
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Weibo Cai
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53792, United States.,University of Wisconsin Carbone Cancer Center , Madison, Wisconsin 53792, United States
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44
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Schmohl KA, Müller AM, Wechselberger A, Rühland S, Salb N, Schwenk N, Heuer H, Carlsen J, Göke B, Nelson PJ, Spitzweg C. Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3. Endocr Relat Cancer 2015; 22:941-52. [PMID: 26307023 DOI: 10.1530/erc-15-0245] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2015] [Indexed: 12/18/2022]
Abstract
To improve our understanding of non-genomic, integrin αvβ3-mediated thyroid hormone action in tumour stroma formation, we examined the effects of triiodo-l-thyronine (T3), l-thyroxine (T4) and integrin-specific inhibitor tetrac on differentiation, migration and invasion of mesenchymal stem cells (MSCs) that are an integral part of the tumour's fibrovascular network. Primary human bone marrow-derived MSCs were treated with T3 or T4 in the presence of hepatocellular carcinoma (HCC) cell-conditioned medium (CM), which resulted in stimulation of the expression of genes associated with cancer-associated fibroblast-like differentiation as determined by qPCR and ELISA. In addition, T3 and T4 increased migration of MSCs towards HCC cell-CM and invasion into the centre of three-dimensional HCC cell spheroids. All these effects were tetrac-dependent and therefore integrin αvβ3-mediated. In a subcutaneous HCC xenograft model, MSCs showed significantly increased recruitment and invasion into tumours of hyperthyroid mice compared to euthyroid and, in particular, hypothyroid mice, while treatment with tetrac almost completely eliminated MSC recruitment. These studies significantly improve our understanding of the anti-tumour activity of tetrac, as well as the mechanisms that regulate MSC differentiation and recruitment in the context of tumour stroma formation, as an important prerequisite for the utilisation of MSCs as gene delivery vehicles.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Differentiation/drug effects
- Cell Line, Tumor
- Cell Lineage
- Cell Movement
- Culture Media, Conditioned
- Heterografts
- Humans
- Hyperthyroidism/chemically induced
- Hyperthyroidism/complications
- Hypothyroidism/chemically induced
- Hypothyroidism/complications
- Integrin alphaVbeta3/physiology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/complications
- Liver Neoplasms, Experimental/pathology
- Male
- Mesenchymal Stem Cells/drug effects
- Mice
- Mice, Nude
- Neoplasm Invasiveness
- Neoplasm Proteins/physiology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/physiopathology
- Specific Pathogen-Free Organisms
- Spheroids, Cellular
- Stromal Cells/pathology
- Thyroxine/analogs & derivatives
- Thyroxine/pharmacology
- Thyroxine/therapeutic use
- Thyroxine/toxicity
- Triiodothyronine/pharmacology
- Triiodothyronine/therapeutic use
- Triiodothyronine/toxicity
- Tumor Microenvironment
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Kathrin A Schmohl
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Andrea M Müller
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Alexandra Wechselberger
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Svenja Rühland
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Nicole Salb
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Heike Heuer
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Janette Carlsen
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Burkhard Göke
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Peter J Nelson
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany
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45
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Schmohl KA, Müller AM, Schwenk N, Knoop K, Rijntjes E, Köhrle J, Heuer H, Bartenstein P, Göke B, Nelson PJ, Spitzweg C. Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice. Eur Thyroid J 2015; 4:74-80. [PMID: 26601076 PMCID: PMC4640294 DOI: 10.1159/000381019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 02/16/2015] [Indexed: 12/12/2022] Open
Abstract
Due to the high variance in available protocols on iodide-131 ((131)I) ablation in rodents, we set out to establish an effective method to generate a thyroid-ablated mouse model that allows the application of the sodium iodide symporter (NIS) as a reporter gene without interference with thyroidal NIS. We tested a range of (131)I doses with and without prestimulation of thyroidal radioiodide uptake by a low-iodine diet and thyroid-stimulating hormone (TSH) application. Efficacy of induction of hypothyroidism was tested by measurement of serum T4 concentrations, pituitary TSHβ and liver deiodinase type 1 (DIO1) mRNA expression, body weight analysis, and (99m)Tc-pertechnetate scintigraphy. While 200 µCi (7.4 MBq) (131)I alone was not sufficient to abolish thyroidal T4 production, 500 µCi (18.5 MBq) (131)I combined with 1 week of a low-iodine diet decreased serum concentrations below the detection limit. However, the high (131)I dose resulted in severe side effects. A combination of 1 week of a low-iodine diet followed by injection of bovine TSH before the application of 150 µCi (5.5 MBq) (131)I decreased serum T4 concentrations below the detection limit and significantly increased pituitary TSHβ concentrations. The systemic effects of induced hypothyroidism were shown by growth arrest and a decrease in liver DIO1 expression below the detection limit. (99m)Tc-pertechnetate scintigraphy revealed absence of thyroidal (99m)Tc-pertechnetate uptake in ablated mice. In summary, we report a revised protocol for radioiodide ablation of the thyroid gland in the mouse to generate an in vivo model that allows the study of thyroid hormone action using NIS as a reporter gene.
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Affiliation(s)
| | | | | | | | - Eddy Rijntjes
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Josef Köhrle
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Heike Heuer
- Leibniz Institute for Environmental Medicine, Düsseldorf, Germany
| | | | | | - Peter J. Nelson
- Medical Policlinic IV, University Hospital of Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine II, Munich, Germany
- *Christine Spitzweg, MD, Department of Internal Medicine II, University Hospital of Munich, Marchioninistrasse 15, DE-81377 Munich (Germany), E-Mail
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Knoop K, Schwenk N, Schmohl K, Müller A, Zach C, Cyran C, Carlsen J, Böning G, Bartenstein P, Göke B, Wagner E, Nelson PJ, Spitzweg C. Mesenchymal stem cell-mediated, tumor stroma-targeted radioiodine therapy of metastatic colon cancer using the sodium iodide symporter as theranostic gene. J Nucl Med 2015; 56:600-6. [PMID: 25745085 DOI: 10.2967/jnumed.114.146662] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 01/12/2015] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED The tumor-homing property of mesenchymal stem cells (MSCs) allows targeted delivery of therapeutic genes into the tumor microenvironment. The application of sodium iodide symporter (NIS) as a theranostic gene allows noninvasive imaging of MSC biodistribution and transgene expression before therapeutic radioiodine application. We have previously shown that linking therapeutic transgene expression to induction of the chemokine CCL5/RANTES allows a more focused expression within primary tumors, as the adoptively transferred MSC develop carcinoma-associated fibroblast-like characteristics. Although RANTES/CCL5-NIS targeting has shown efficacy in the treatment of primary tumors, it was not clear if it would also be effective in controlling the growth of metastatic disease. METHODS To expand the potential range of tumor targets, we investigated the biodistribution and tumor recruitment of MSCs transfected with NIS under control of the RANTES/CCL5 promoter (RANTES-NIS-MSC) in a colon cancer liver metastasis mouse model established by intrasplenic injection of the human colon cancer cell line LS174t. RANTES-NIS-MSCs were injected intravenously, followed by (123)I scintigraphy, (124)I PET imaging, and (131)I therapy. RESULTS Results show robust MSC recruitment with RANTES/CCL5-promoter activation within the stroma of liver metastases as evidenced by tumor-selective iodide accumulation, immunohistochemistry, and real-time polymerase chain reaction. Therapeutic application of (131)I in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved overall survival. CONCLUSION This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery.
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Affiliation(s)
- Kerstin Knoop
- Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany
| | - Kathrin Schmohl
- Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany
| | - Andrea Müller
- Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany
| | - Christian Zach
- Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Clemens Cyran
- Department of Clinical Radiology, Laboratory for Experimental Radiology, Ludwig-Maximilians-University, Munich, Germany
| | - Janette Carlsen
- Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Guido Böning
- Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Burkhard Göke
- Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Munich, Germany; and
| | - Peter J Nelson
- Clinical Biochemistry Group, Department of Internal Medicine and Policlinic IV, Ludwig-Maximilians-University, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany
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Lejmi E, Perriraz N, Clément S, Morel P, Baertschiger R, Christofilopoulos P, Meier R, Bosco D, Bühler LH, Gonelle-Gispert C. Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells. Stem Cells Dev 2015; 24:1223-35. [PMID: 25579056 DOI: 10.1089/scd.2014.0176] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In vivo, bone marrow-derived multipotent mesenchymal stromal cells (MSC) have been identified at sites of tumors, suggesting that specific signals mobilize and activate MSC to migrate to areas surrounding tumors. The signals and migratory mechanisms that guide MSC are not well understood. Here, we investigated the migration of human MSC induced by conditioned medium of Huh-7 hepatoma cells (Huh-7 CM). Using a transwell migration system, we showed that human MSC migration was increased in the presence of Huh-7 CM. Using a human cytokine antibody array, we detected increased levels of MIP-1δ and MIP-3α in Huh-7 CM. Recombinant chemokines MIP-1δ and MIP-3α induced MSC migration. Anti-MIP-1δ and anti-MIP-3α antibodies added to Huh-7 CM decreased MSC migration, further suggesting that MIP-1δ and MIP-3α were implicated in the Huh-7 CM-induced MSC migration. By real-time polymerase chain reaction, we observed an absence of chemokine receptors CCR2 and CXCR2 and low expression of CCR1, CCR5, and CCR6 in MSC. Expression of these chemokine receptors was not regulated by Huh-7 CM. Furthermore, matrix metalloproteinase 1 (MMP-1) expression was strongly increased in MSC after incubation with Huh-7 CM, suggesting that MSC migration depends on MMP-1 activity. The signaling pathway MAPK/ERK was activated by Huh-7 CM but its inhibition by PD98059 did not impair Huh-7 CM-induced MSC migration. Further, long-term incubation of MSC with MIP-1δ increased α-smooth muscle actin expression, suggesting its implication in the Huh-7 CM-induced evolvement of MSC into myofibroblasts. In conclusion, we report that two inflammatory cytokines, MIP-1δ and MIP-3α, are able to increase MSC migration in vitro. These cytokines might be responsible for migration and evolvement of MSC into myofibroblasts around tumors.
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Affiliation(s)
- Esma Lejmi
- 1 Surgical Research Unit, University Hospitals of Geneva , Geneva, Switzerland
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Barrett HH, Kupinski MA, Müeller S, Halpern HJ, Morris JC, Dwyer R. Objective assessment of image quality VI: imaging in radiation therapy. Phys Med Biol 2014; 58:8197-213. [PMID: 24200954 DOI: 10.1088/0031-9155/58/22/8197] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Earlier work on objective assessment of image quality (OAIQ) focused largely on estimation or classification tasks in which the desired outcome of imaging is accurate diagnosis. This paper develops a general framework for assessing imaging quality on the basis of therapeutic outcomes rather than diagnostic performance. By analogy to receiver operating characteristic (ROC) curves and their variants as used in diagnostic OAIQ, the method proposed here utilizes the therapy operating characteristic or TOC curves, which are plots of the probability of tumor control versus the probability of normal-tissue complications as the overall dose level of a radiotherapy treatment is varied. The proposed figure of merit is the area under the TOC curve, denoted AUTOC. This paper reviews an earlier exposition of the theory of TOC and AUTOC, which was specific to the assessment of image-segmentation algorithms, and extends it to other applications of imaging in external-beam radiation treatment as well as in treatment with internal radioactive sources. For each application, a methodology for computing the TOC is presented. A key difference between ROC and TOC is that the latter can be defined for a single patient rather than a population of patients.
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Micali S, Bulotta S, Puppin C, Territo A, Navarra M, Bianchi G, Damante G, Filetti S, Russo D. Sodium iodide symporter (NIS) in extrathyroidal malignancies: focus on breast and urological cancer. BMC Cancer 2014; 14:303. [PMID: 24884806 PMCID: PMC4019362 DOI: 10.1186/1471-2407-14-303] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 04/17/2014] [Indexed: 12/15/2022] Open
Abstract
Background Expression and function of sodium iodide symporter (NIS) is requisite for efficient iodide transport in thyrocytes, and its presence in cancer cells allows the use of radioiodine as a diagnostic and therapeutic tool in thyroid neoplasia. Discovery of NIS expression in extrathyroidal tissues, including transformed cells, has opened a novel field of research regarding NIS-expressing extrathyroidal neoplasia. Indeed, expression of NIS may be used as a biomarker for diagnostic, prognostic, and therapeutic purposes. Moreover, stimulation of endogenous NIS expression may permit the radioiodine treatment of extrathyroidal lesions by concentrating this radioisotope. Results This review describes recent findings in NIS research in extrathyroidal malignancies, focusing on breast and urological cancer, emphasizing the most relevant developments that may have clinical impact. Conclusions Given the recent progress in the study of NIS regulation as molecular basis for new therapeutic approaches in extrathyroidal cancers, particular attention is given to studies regarding the relationship between NIS and clinical-pathological aspects of the tumors and the regulation of NIS expression in the experimental models.
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Affiliation(s)
| | | | | | - Angelo Territo
- Department of Urology, University of Modena and Reggio Emilia, Via Largo del Pozzo, 71, Modena 41100, Italy.
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