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Bezze A, Mattioda C, Ciardelli G, Mattu C. Harnessing cells to improve transport of nanomedicines. Eur J Pharm Biopharm 2024; 203:114446. [PMID: 39122052 DOI: 10.1016/j.ejpb.2024.114446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/18/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Efficient tumour treatment is hampered by the poor selectivity of anticancer drugs, resulting in scarce tumour accumulation and undesired off-target effects. Nano-sized drug-delivery systems in the form of nanoparticles (NPs) have been proposed to improve drug distribution to solid tumours, by virtue of their ability of passive and active tumour targeting. Despite these advantages, literature studies indicated that less than 1% of the administered NPs can successfully reach the tumour mass, highlighting the necessity for more efficient drug transporters in cancer treatment. Living cells, such as blood cells, circulating immune cells, platelets, and stem cells, are often found as an infiltrating component in most solid tumours, because of their ability to naturally circumvent immune recognition, bypass biological barriers, and reach inaccessible tissues through innate tropism and active motility. Therefore, the tumour-homing ability of these cells can be harnessed to design living cell carriers able to improve the transport of drugs and NPs to tumours. Albeit promising, this approach is still in its beginnings and suffers from difficult scalability, high cost, and poor reproducibility. In this review, we present an overview of the most common cell transporters of drugs and NPs, and we discuss how different cell types interact with biological barriers to deliver cargoes of various natures to tumours. Finally, we analyse the different techniques used to load drugs or NPs in living cells and discuss their advantages and disadvantages.
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Affiliation(s)
- Andrea Bezze
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy
| | - Carlotta Mattioda
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy
| | - Gianluca Ciardelli
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy
| | - Clara Mattu
- Politecnico di Torino - DIMEAS, C.so Duca degli Abruzzi 24, 10129 Torino, Italy.
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2
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Guo L, Zou D, Qiu W, Fei F, Chen L, Chen W, Xiong H, Li X, Wang Y, Gao M, Zhu J, Zhang J, He Y, Gao M, Xu R. Linc-NSC affects cell differentiation, apoptosis and proliferation in mouse neural stem cells and embryonic stem cells in vitro and in vivo. Cell Mol Life Sci 2024; 81:182. [PMID: 38615283 PMCID: PMC11016521 DOI: 10.1007/s00018-024-05224-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 12/12/2023] [Accepted: 03/18/2024] [Indexed: 04/15/2024]
Abstract
BACKGROUND Stem cell therapy is a promising therapeutic strategy. In a previous study, we evaluated tumorigenicity by the stereotactic transplantation of neural stem cells (NSCs) and embryonic stem cells (ESCs) from experimental mice. Twenty-eight days later, there was no evidence of tumor formation or long-term engraftment in the NSCs transplantation group. In contrast, the transplantation of ESCs caused tumor formation; this was due to their high proliferative capacity. Based on transcriptome sequencing, we found that a long intergenic non-coding RNA (named linc-NSC) with unknown structure and function was expressed at 1100-fold higher levels in NSCs than in ESCs. This finding suggested that linc-NSC is negatively correlated with stem cell pluripotency and tumor development, but positively correlated with neurogenesis. In the present study, we investigated the specific role of linc-NSC in NSCs/ESCs in tumor formation and neurogenesis. METHODS Whole transcriptome profiling by RNA sequencing and bioinformatics was used to predict lncRNAs that are widely associated with enhanced tumorigenicity. The expression of linc-NSC was assessed by quantitative real-time PCR. We also performed a number of in vitro methods, including cell proliferation assays, differentiation assays, immunofluorescence assays, flow cytometry, along with in vivo survival and immunofluorescence assays to investigate the impacts of linc-NSC on tumor formation and neurogenesis in NSCs and ESCs. RESULTS Following the knockdown of linc-NSC in NSCs, NSCs cultured in vitro and those transplanted into the cortex of mice showed stronger survival ability (P < 0.0001), enhanced proliferation(P < 0.001), and reduced apoptosis (P < 0.05); the opposite results were observed when linc-NSC was overexpressed in ESCs. Furthermore, the overexpression of linc-NSC in ECSs induced enhanced apoptosis (P < 0.001) and differentiation (P < 0.01), inhibited tumorigenesis (P < 0.05) in vivo, and led to a reduction in tumor weight (P < 0.0001). CONCLUSIONS Our analyses demonstrated that linc-NSC, a promising gene-edited target, may promote the differentiation of mouse NSCs and inhibit tumorigenesis in mouse ESCs. The knockdown of linc-NSC inhibited the apoptosis in NSCs both in vitro and in vivo, and prevented tumor formation, revealing a new dimension into the effect of lncRNA on low survival NSCs and providing a prospective gene manipulation target prior to transplantation. In parallel, the overexpression of linc-NSC induced apoptosis in ESCs both in vitro and in vivo and attenuated the tumorigenicity of ESCs in vivo, but did not completely prevent tumor formation.
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Affiliation(s)
- Lili Guo
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Dan Zou
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Wenqiao Qiu
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Fan Fei
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Lihua Chen
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Wenjin Chen
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Huan Xiong
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Xinda Li
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Yangyang Wang
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Mingjun Gao
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Jianwei Zhu
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Jin Zhang
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Yunsen He
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China
| | - Mou Gao
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Ruxiang Xu
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, 610072, China.
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3
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Lu Q, Liu T, Han Z, Zhao J, Fan X, Wang H, Song J, Ye H, Sun J. Revolutionizing cancer treatment: The power of cell-based drug delivery systems. J Control Release 2023; 361:604-620. [PMID: 37579974 DOI: 10.1016/j.jconrel.2023.08.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 07/30/2023] [Accepted: 08/11/2023] [Indexed: 08/16/2023]
Abstract
Intravenous administration of drugs is a widely used cancer therapy approach. However, the efficacy of these drugs is often hindered by various biological barriers, including circulation, accumulation, and penetration, resulting in poor delivery to solid tumors. Recently, cell-based drug delivery platforms have emerged as promising solutions to overcome these limitations. These platforms offer several advantages, including prolonged circulation time, active targeting, controlled release, and excellent biocompatibility. Cell-based delivery systems encompass cell membrane coating, intracellular loading, and extracellular backpacking. These innovative platforms hold the potential to revolutionize cancer diagnosis, monitoring, and treatment, presenting a plethora of opportunities for the advancement and integration of pharmaceuticals, medicine, and materials science. Nevertheless, several technological, ethical, and financial barriers must be addressed to facilitate the translation of these platforms into clinical practice. In this review, we explore the emerging strategies to overcome these challenges, focusing specifically on the functions and advantages of cell-mediated drug delivery in cancer treatment.
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Affiliation(s)
- Qi Lu
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Tian Liu
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Zeyu Han
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Jian Zhao
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Xiaoyuan Fan
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Helin Wang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Jiaxuan Song
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China
| | - Hao Ye
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China; Multi-Scale Robotics Lab (MSRL), Institute of Robotics & Intelligent Systems (IRIS), ETH Zurich, Zurich 8092, Switzerland.
| | - Jin Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, PR China.
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Kim JH, Ahn JS, Lee DS, Hong SH, Lee HJ. Anti-Cancer Effect of Neural Stem Cells Transfected with Carboxylesterase and sTRAIL Genes in Animals with Brain Lesions of Lung Cancer. Pharmaceuticals (Basel) 2023; 16:1156. [PMID: 37631070 PMCID: PMC10458428 DOI: 10.3390/ph16081156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
A metastatic brain tumor is the most common type of malignancy in the central nervous system, which is one of the leading causes of death in patients with lung cancer. The purpose of this study is to evaluate the efficacy of a novel treatment for metastatic brain tumors with lung cancer using neural stem cells (NSCs), which encode rabbit carboxylesterase (rCE) and the secretion form of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). rCE and/or sTRAIL were transduced in immortalized human fetal NSCs, HB1.F3. The cytotoxic effects of the therapeutic cells on human lung cancer cells were evaluated in vitro with the ligands and decoy receptor expression for sTRAIL in the presence of CPT-11. Human NSCs encoding rCE (F3.CE and F3.CE.sTRAIL) significantly inhibited the growth of lung cancer cells in the presence of CPT-11 in vitro. Lung cancer cells were inoculated in immune-deficient mice, and therapeutic cells were transplanted systematically through intracardiac arterial injection and then treated with CPT-11. In resting state, DR4 expression in lung cancer cells and DcR1 in NSCs increased to 70% and 90% after CPT-11 addition, respectively. The volumes of the tumors in immune-deficient mice were reduced significantly in mice with F3.CE.sTRAIL transplantation and CPT-11 treatment. The survival was also significantly prolonged with treatment with F3.sTRAIL and F3.CE plus CPT-11 as well as F3.CE.sTRAIL plus CPT-11. NSCs transduced with rCE and sTRAIL genes showed a significant anti-cancer effect on brain metastatic lung cancer in vivo and in vitro, and the effect may be synergistic when rCE/CPT-11 and sTRAIL are combined. This stem-cell-based study using two therapeutic genes of different biological effects can be translatable to clinical application.
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Affiliation(s)
- Jung Hak Kim
- Research Institute, Humetacell Inc., Bucheon-si 14786, Republic of Korea
| | - Jae Sung Ahn
- Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Dong-Seok Lee
- School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Seok Ho Hong
- Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Hong J. Lee
- Research Institute, Humetacell Inc., Bucheon-si 14786, Republic of Korea
- College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju-si 28644, Republic of Korea
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Nadesh R, Menon KN, Biswas L, Mony U, Subramania Iyer K, Vijayaraghavan S, Nambiar A, Nair S. Adipose derived mesenchymal stem cell secretome formulation as a biotherapeutic to inhibit growth of drug resistant triple negative breast cancer. Sci Rep 2021; 11:23435. [PMID: 34873206 PMCID: PMC8648896 DOI: 10.1038/s41598-021-01878-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 10/22/2021] [Indexed: 12/30/2022] Open
Abstract
In the present study, a protocol was developed for processing of human adipose derived mesenchymal stem cell secretome formulation of varying concentration. Its molecular composition was evaluated, and its effectiveness in vitro using breast cancer cell lines, and in vivo in a nude mice breast cancer model was studied to determine its role in suppressing triple negative breast cancer in a dose dependent manner. Because the secretome could have value as an add-on therapy along with a current drug, the effectiveness of the secretome both in monotherapy and in combination therapy along with paclitaxel was evaluated. The results showed significant cell kill when exposed to the secretome above 20 mg/ml at which concentration there was no toxicity to normal cells. 70 mg/ml of SF showed 90 ± 10% apoptosis and significant decrease in CD44+/CD24−, MDR1+ and PDL-1+ cancer cells. In vivo, the tumor showed no growth after daily intra tumor injections at 50 mg/ml and 100 mg/ml doses whereas substantial tumor growth occurred after saline intra tumor injection. The study concludes that SF is a potential biotherapeutic for breast cancer and could be used initially as an add-on therapy to other standard of care to provide improved efficacy without other adverse effects.
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Affiliation(s)
- Ragima Nadesh
- Amrita Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Krishnakumar N Menon
- Amrita Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Lalitha Biswas
- Amrita Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Ullas Mony
- Amrita Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - K Subramania Iyer
- Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Sundeep Vijayaraghavan
- Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Ajit Nambiar
- Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Shantikumar Nair
- Amrita Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India.
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6
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Mercer-Smith AR, Jiang W, Bago JR, Valdivia A, Thang M, Woodell AS, Montgomery SA, Sheets KT, Anders CK, Hingtgen SD. Cytotoxic Engineered Induced Neural Stem Cells as an Intravenous Therapy for Primary Non-Small Cell Lung Cancer and Triple-Negative Breast Cancer. Mol Cancer Ther 2021; 20:2291-2301. [PMID: 34433662 DOI: 10.1158/1535-7163.mct-21-0109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 06/30/2021] [Accepted: 08/16/2021] [Indexed: 11/16/2022]
Abstract
Converting human fibroblasts into personalized induced neural stem cells (hiNSC) that actively seek out tumors and deliver cytotoxic agents is a promising approach for treating cancer. Herein, we provide the first evidence that intravenously-infused hiNSCs secreting cytotoxic agent home to and suppress the growth of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Migration of hiNSCs to NSCLC and TNBC in vitro was investigated using time-lapse motion analysis, which showed directional movement of hiNSCs to both tumor cell lines. In vivo, migration of intravenous hiNSCs to orthotopic NSCLC or TNBC tumors was determined using bioluminescent imaging (BLI) and immunofluorescent post-mortem tissue analysis, which indicated that hiNSCs colocalized with tumors within 3 days of intravenous administration and persisted through 14 days. In vitro, efficacy of hiNSCs releasing cytotoxic TRAIL (hiNSC-TRAIL) was monitored using kinetic imaging of co-cultures, in which hiNSC-TRAIL therapy induced rapid killing of both NSCLC and TNBC. Efficacy was determined in vivo by infusing hiNSC-TRAIL or control cells intravenously into mice bearing orthotopic NSCLC or TNBC and tracking changes in tumor volume using BLI. Mice treated with intravenous hiNSC-TRAIL showed a 70% or 72% reduction in NSCLC or TNBC tumor volume compared with controls within 14 or 21 days, respectively. Safety was assessed by hematology, blood chemistry, and histology, and no significant changes in these safety parameters was observed through 28 days. These results indicate that intravenous hiNSCs-TRAIL seek out and kill NSCLC and TNBC tumors, suggesting a potential new strategy for treating aggressive peripheral cancers.
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Affiliation(s)
- Alison R Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Wulin Jiang
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Juli R Bago
- Department of Hemato-Oncology, University of Ostrava, Ostrava, Czech Republic
| | - Alain Valdivia
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Morrent Thang
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Alex S Woodell
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Stephanie A Montgomery
- Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kevin T Sheets
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Carey K Anders
- Department of Medicine, Duke University, Durham, North Carolina
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
- Department of Neurosurgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Mercer-Smith AR, Findlay IA, Bomba HN, Hingtgen SD. Intravenously Infused Stem Cells for Cancer Treatment. Stem Cell Rev Rep 2021; 17:2025-2041. [PMID: 34138421 DOI: 10.1007/s12015-021-10192-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2021] [Indexed: 01/14/2023]
Abstract
Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be engineered to secrete cytotoxic products, loaded with oncolytic viruses or nanoparticles containing small molecule drugs, or conjugated with immunotherapies. Herein we describe these preclinical and clinical studies, discuss the distribution and migration of stem cells following intravenous infusion, and examine both the limitations of and the methods to improve the migration and therapeutic efficacy of tumoritropic, therapeutic stem cells.
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Affiliation(s)
- Alison R Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Ingrid A Findlay
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Hunter N Bomba
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA. .,Department of Neurosurgery, The University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, 27599, USA.
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8
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Jiang W, Yang Y, Mercer-Smith AR, Valdivia A, Bago JR, Woodell AS, Buckley AA, Marand MH, Qian L, Anders CK, Hingtgen SD. Development of next-generation tumor-homing induced neural stem cells to enhance treatment of metastatic cancers. SCIENCE ADVANCES 2021; 7:eabf1526. [PMID: 34108203 PMCID: PMC8189583 DOI: 10.1126/sciadv.abf1526] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 04/23/2021] [Indexed: 05/08/2023]
Abstract
Engineered tumor-homing neural stem cells (NSCs) have shown promise in treating cancer. Recently, we transdifferentiated skin fibroblasts into human-induced NSCs (hiNSC) as personalized NSC drug carriers. Here, using a SOX2 and spheroidal culture-based reprogramming strategy, we generated a new hiNSC variant, hiNeuroS, that was genetically distinct from fibroblasts and first-generation hiNSCs and had significantly enhanced tumor-homing and antitumor properties. In vitro, hiNeuroSs demonstrated superior migration to human triple-negative breast cancer (TNBC) cells and in vivo rapidly homed to TNBC tumor foci following intracerebroventricular (ICV) infusion. In TNBC parenchymal metastasis models, ICV infusion of hiNeuroSs secreting the proapoptotic agent TRAIL (hiNeuroS-TRAIL) significantly reduced tumor burden and extended median survival. In models of TNBC leptomeningeal carcinomatosis, ICV dosing of hiNeuroS-TRAIL therapy significantly delayed the onset of tumor formation and extended survival when administered as a prophylactic treatment, as well as reduced tumor volume while prolonging survival when delivered as established tumor therapy.
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Affiliation(s)
- Wulin Jiang
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Yuchen Yang
- Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
- McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Alison R Mercer-Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Alain Valdivia
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Juli R Bago
- Department of Hemato-Oncology, University Hospital of Ostrava, 708 52 Ostrava, Czech Republic
- Faculty of Medicine, University of Ostrava, 703 00 Ostrava, Czech Republic
| | - Alex S Woodell
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Andrew A Buckley
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Michael H Marand
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Li Qian
- Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
- McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
| | - Carey K Anders
- Department of Medicine, Duke University, North Carolina, 27710, USA
| | - Shawn D Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA.
- Department of Neurosurgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27588, USA
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9
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Kumar S, Mongia A, Gulati S, Singh P, Diwan A, Shukla S. Emerging theranostic gold nanostructures to combat cancer: Novel probes for Combinatorial Immunotherapy and Photothermal Therapy. Cancer Treat Res Commun 2020; 25:100258. [PMID: 33307507 DOI: 10.1016/j.ctarc.2020.100258] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 11/16/2020] [Accepted: 11/28/2020] [Indexed: 12/21/2022]
Abstract
The application of gold nanoparticles in immunotherapy has emerged as one of the most effective therapeutic strategy for eradicating cancer by releasing antigens, oligonucleotides, adjuvants, immune-stimulating agents into the body. Gold nanoparticles are found to be a superior choice, for generating attack on oncogenic cells, due to their low toxicity, better target specificity, diagnostic capabilities, and enhanced cellular uptake rate. This review focuses on the efficiency of several functionalized gold nanoparticles of diverse shapes and sizes as delivery vehicles to desired target cells through effective immunotherapy, along with a brief discussion about photothermal therapy.
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Affiliation(s)
- Sanjay Kumar
- Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, 110021
| | - Ayush Mongia
- Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, 110021
| | - Shikha Gulati
- Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, 110021
| | - Parinita Singh
- Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, 110021
| | - Anchita Diwan
- Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, 110021
| | - Shefali Shukla
- Department of Chemistry, Sri Venkateswara College, University of Delhi, Delhi, 110021
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10
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Romero-Trejo D, Mejía-Rodríguez R, Sierra-Mondragón E, Navarrete A, Pérez-Tapia M, González RO, Segovia J. The systemic administration of neural stem cells expressing an inducible and soluble form of growth arrest specific 1 inhibits mammary gland tumor growth and the formation of metastases. Cytotherapy 2020; 23:223-235. [PMID: 33168454 DOI: 10.1016/j.jcyt.2020.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/21/2020] [Accepted: 09/30/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND AIMS Metastasis to different organs is the major cause of death in breast cancer patients. The poor clinical prognosis and lack of successful treatments for metastatic breast cancer patients demand the development of new tumor-selective therapies. Thus, it is necessary to develop treatments capable of releasing therapeutic agents to both primary tumors and metastases that avoid toxic side effects in normal tissue, and neural stem cells are an attractive vehicle for tracking tumor cells and delivering anti-cancer agents. The authorspreviously demonstrated that a soluble form of growth arrest specific 1 (GAS1) inhibits the growth of triple-negative breast tumors and glioblastoma. METHODS In this study, the authors engineered ReNcell CX (EMD Millipore, Temecula, CA, USA) neural progenitor cells to express truncated GAS1 (tGAS1) under a tetracycline/on inducible system using lentiviral vectors. RESULTS Here the authors show that treatment with ReNcell-tGAS1 in combination with tetracycline decreased primary tumor growth and inhibited the formation of metastases in tumor-bearing mice by diminishing the phosphorylation of AKT and ERK1/2 in orthotopic mammary gland tumors. Moreover, the authors observed that ReNcell-tGAS1 prolonged the survival of 4T1 tumor-bearing mice. CONCLUSIONS These data suggest that the delivery of tGAS1 by ReNcell cells could be an effective adjuvant for the treatment of triple-negative breast cancer.
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Affiliation(s)
- Daniel Romero-Trejo
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México
| | - Rosalinda Mejía-Rodríguez
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México
| | - Edith Sierra-Mondragón
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México
| | - Araceli Navarrete
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México
| | - Mayra Pérez-Tapia
- Departamento de Inmunología Escuela Nacional de Ciencias Biológicas, del Instituto Politécnico Nacional, México
| | - Rosa O González
- Departamento de Matemáticas, Universidad Autónoma Metropolitana-Iztapalapa (UAM-I), México
| | - José Segovia
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México.
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11
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Carvalho LA, Teng J, Fleming RL, Tabet EI, Zinter M, de Melo Reis RA, Tannous BA. Olfactory Ensheathing Cells: A Trojan Horse for Glioma Gene Therapy. J Natl Cancer Inst 2020; 111:283-291. [PMID: 30257000 DOI: 10.1093/jnci/djy138] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/18/2018] [Accepted: 07/10/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The olfactory ensheathing cells (OECs) migrate from the peripheral nervous system to the central nervous system (CNS), a critical process for the development of the olfactory system and axonal extension after injury in neural regeneration. Because of their ability to migrate to the injury site and anti-inflammatory properties, OECs were tested against different neurological pathologies, but were never studied in the context of cancer. Here, we evaluated OEC tropism to gliomas and their potential as a "Trojan horse" to deliver therapeutic transgenes through the nasal pathway, their natural route to CNS. METHODS OECs were purified from the mouse olfactory bulb and engineered to express a fusion protein between cytosine deaminase and uracil phosphoribosyltransferase (CU), which convert the prodrug 5-fluorocytosine (5-FC) into cytotoxic metabolite 5-fluorouracil, leading to a bystander killing of tumor cells. These cells were injected into the nasal cavity of mice bearing glioblastoma tumors and OEC-mediated gene therapy was monitored by bioluminescence imaging and confirmed with survival and ex vivo histological analysis. All statistical tests were two-sided. RESULTS OECs migrated from the nasal pathway to the primary glioma site, tracked infiltrative glioma stemlike cells, and delivered therapeutic transgene, leading to a slower tumor growth and increased mice survival. At day 28, bioluminescence imaging revealed that mice treated with a single injection of OEC-expressing CU and 5-FC had tumor-associated photons (mean [SD]) of 1.08E + 08 [9.7E + 07] vs 4.1E + 08 [2.3E + 08] for control group (P < .001), with a median survival of 41 days vs 34 days, respectively (ratio = 0.8293, 95% confidence interval = 0.4323 to 1.226, P < .001) (n = 9 mice per group). CONCLUSIONS We show for the first time that autologous transplantation of OECs can target and deliver therapeutic transgenes to brain tumors upon intranasal delivery, the natural route of OECs to the CNS, which could be extended to other types of cancer.
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Affiliation(s)
- Litia A Carvalho
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, MA.,Neuroscience Program, Harvard Medical School, Boston, MA
| | - Jian Teng
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, MA.,Neuroscience Program, Harvard Medical School, Boston, MA
| | - Renata L Fleming
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, MA.,Neuroscience Program, Harvard Medical School, Boston, MA
| | - Elie I Tabet
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, MA.,Neuroscience Program, Harvard Medical School, Boston, MA
| | - Max Zinter
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, MA.,Neuroscience Program, Harvard Medical School, Boston, MA
| | - Ricardo A de Melo Reis
- Laboratory of Neurochemistry, Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Bakhos A Tannous
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Boston, MA.,Neuroscience Program, Harvard Medical School, Boston, MA
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12
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Lin YY, Wang CY, Phan NN, Chiao CC, Li CY, Sun Z, Hung JH, Chen YL, Yen MC, Weng TY, Hsu HP, Lai MD. PODXL2 maintains cellular stemness and promotes breast cancer development through the Rac1/Akt pathway. Int J Med Sci 2020; 17:1639-1651. [PMID: 32669966 PMCID: PMC7359396 DOI: 10.7150/ijms.46125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/21/2020] [Indexed: 12/13/2022] Open
Abstract
The cluster of differentiation 34 (CD34) family, which includes CD34, podocalyxin-like protein 1 (PODXL), and PODXL2, are type-I transmembrane sialomucins and markers of hematopoietic stem cells (HSCs) and vascular-associated tissues. CD34 family proteins are expressed by endothelial cells and hematopoietic precursors. PODXL is well known to be associated with invadopodia formation and to promote the epithelial-mesenchymal transition, tumor migration and invasion. PODXL expression was correlated with poor survival of cancer patients. However, the role of PODXL2 in cancer has been less fully explored. To reveal the novel role of PODXL2 in breast cancer, the present study evaluated PODXL2 levels in relation to clinical outcomes of cancer patients by performing a bioinformatics analysis using the Oncomine database, Kaplan-Meier plots, and the CCLE database. Empirical validation of bioinformatics predictions was conducted utilizing the short hairpin (sh)-RNA silencing method for PODXL2 in the BT474 invasive ductal breast carcinoma cell line. The bioinformatics analysis revealed that PODXL2 overexpression was correlated with poor survival of breast cancer patients, suggesting an oncogenic role of PODXL2 in breast carcinoma. In a validation experiment, knockdown of PODXL2 in BT474 cells slightly influenced cell proliferation, suppressed migration, and inhibited expressions of downstream molecules, including Ras-related C3 botulinum toxin substrate 1 (Rac1), phosphorylated (p)-Akt (S473), and p-paxillin (Y31) proteins. In addition, knockdown of PODXL2 reduced expression levels of cancer stem cell (CSC) markers, including Oct-4 and Nanog, and the breast CSC marker aldehyde dehydrogenase 1 (ALDH1). Collectively, our present study demonstrated that PODXL2 plays a crucial role in cancer development and could serve as a potential prognostic biomarker in breast cancer patients.
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Affiliation(s)
- Yi-Yi Lin
- Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan 70101, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chih-Yang Wang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Nam Nhut Phan
- NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam
| | - Chung-Chieh Chiao
- School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
| | - Chung-Yen Li
- Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan 70101, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Zhengda Sun
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA
| | - Jui-Hsiang Hung
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan
| | - Yi-Ling Chen
- Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan
| | - Meng-Chi Yen
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Tzu-Yang Weng
- Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan 70101, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.,Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan 70101, Taiwan
| | - Ming-Derg Lai
- Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan 70101, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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13
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Shin HJ, Hwang KA, Go RE, Kim SU, Choi KC. Antithyroid cancer effects of human neural stem cells expressing therapeutic genes on anaplastic thyroid cancer cells. J Cell Biochem 2019; 121:1586-1598. [PMID: 31512776 DOI: 10.1002/jcb.29393] [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: 04/19/2019] [Accepted: 05/31/2019] [Indexed: 11/07/2022]
Abstract
Stem cells that express therapeutic proteins have been identified to have an anticancer effects on various types of cancer. In the present study study, human neural stem cells (hNSCs) that were genetically engineered to express cytosine deaminase (CD) and human interferon-β (IFN-β) were used for anaplastic thyroid cancer (ATC) treatment owing to their tumor-tropic properties and therapeutic effects. CD is an enzyme that converts 5-fluorocytosine (5-FC), a prodrug, to 5-fluorouracil (5-FU) which is a medication to suppress tumor growth through DNA synthesis inhibition. Also, IFN-β suppresses tumor growth by the induction of apoptotic process. In water soluble tetrazolium salt (WST) assay, SNU-80 cells which are human female ATC cells were cocultured with three cell types including engineered hNSCs such as HB1.F3, HB1.F3.CD, and HB1.F3.CD.IFN-β cells on transwells and treated with 5-FC for 72 hours. Finally, the SNU-80 cell viability was reduced by the coculture with HB1.F3.CD and HB1.F3.CD.IFN-β cells. In dichlorofluorescein diacetate (DCF-DA) and TdT-mediated dUTP nick-end labeling (TUNEL) assays, the production of reactive oxygen species (ROS) and the number of apoptotic cells were increased by HB1.F3.CD and HB1.F3.CD.IFN-β cells in the presence of 5-FC. In Western blot assay, ROS, and apoptosis-related genes were increased in SNU-80 cells when they were cocultured with HB1.F3.CD and HB1.F3.CD.IFN-β cells. In transwell migration assay, hNSCs selectively migrated to SNU-80 cells because hNSCs interacted with chemoattractant factors like SDF-1α, uPAR, and CCR2 secreted by SNU-80 cells. Taken together, engineered hNSCs were revealed to selectively migrate to ATC cells and to inhibit growth as well as to induce apoptosis of ATC cells via ROS production through the actions of transgenes such as CD and IFN-β. Therefore, these engineered hNSCs can be promising candidates for the treatment of metastatic ATC.
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Affiliation(s)
- Hye-Ji Shin
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-A Hwang
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Ryeo-Eun Go
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Seung U Kim
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.,Institute of Life Science and Bio-Engineering, TheraCell Bio & Science, Cheongju, Chungbuk, Republic of Korea
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14
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Tiet P, Li J, Abidi W, Mooney R, Flores L, Aramburo S, Batalla-Covello J, Gonzaga J, Tsaturyan L, Kang Y, Cornejo YR, Dellinger T, Han E, Aboody KS, Berlin JM. Silica Coated Paclitaxel Nanocrystals Enable Neural Stem Cell Loading For Treatment of Ovarian Cancer. Bioconjug Chem 2019; 30:1415-1424. [PMID: 30835443 DOI: 10.1021/acs.bioconjchem.9b00160] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ovarian cancer is commonly diagnosed only after it has metastasized to the abdominal cavity (stage III). While the current standard of care of intraperitoneal (IP) administration of cisplatin and paclitaxel (PTX) combination chemotherapy has benefit, patient 5-year survival rates are low and have not significantly improved in the past decade. The ability to target chemotherapy selectively to ovarian tumors while sparing normal tissue would improve efficacy and decrease toxicities. We have previously shown that cisplatin-loaded nanoparticles (NPs) loaded within neural stem cells (NSCs) are selectively delivered to ovarian tumors in the abdominal cavity following IP injection, with no evidence of localization to normal tissue. Here we extended the capabilities of this system to also include PTX delivery. NPs that will be loaded into NSCs must contain a high amount of drug by weight but constrain the release of the drug such that the NSCs are viable after loading and can successfully migrate to tumors. We developed silica coated PTX nanocrystals (Si[PTX-NC]) meeting these requirements. Si[PTX-NC] were more effective than uncoated PTX-NC or Abraxane for loading NSCs with PTX. NSCs loaded with Si[PTX-NC] maintained their migratory ability and, for low dose PTX, were more effective than free PTX-NC or Si[PTX-NC] at killing ovarian tumors in vivo. This work demonstrates that NSC/NP delivery is a platform technology amenable to delivering different therapeutics and enables the pursuit of NSC/NP targeted delivery of the entire preferred chemotherapy regimen for ovarian cancer. It also describes efficient silica coating chemistry for PTX nanocrystals that may have applications beyond our focus on NSC transport.
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15
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Pirbhai M, Chandrasekar S, Zheng M, Ignatova T, Rotkin SV, Jedlicka SS. Augmentation of C17.2 Neural Stem Cell Differentiation via Uptake of Low Concentrations of ssDNA‐Wrapped Single‐Walled Carbon Nanotubes. ACTA ACUST UNITED AC 2019; 3:e1800321. [DOI: 10.1002/adbi.201800321] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Massooma Pirbhai
- Department of Physics Susquehanna University 514 University Ave. Selinsgrove PA 17870 USA
| | - Swetha Chandrasekar
- Department of Bioengineering Lehigh University 111 Research Drive Bethlehem PA 18015 USA
| | - Ming Zheng
- National Institute of Standards and Technology 1000 Bureau Drive, M/S 8542 Gaithersburg MD 20899 USA
| | - Tetyana Ignatova
- Department of Nanoscience Joint School of Nanoscience and Nanoengineering University of North Carolina at Greensboro 2907 East Gate City Blvd. Greensboro NC 27401 USA
| | - Slava V. Rotkin
- Department of Engineering Science and Mechanics Materials Research Institute The Pennsylvania State University N‐332 Millennium Science Complex University Park PA 16802 USA
| | - Sabrina S. Jedlicka
- Department of Materials Science and Engineering Department of Bioengineering Lehigh University 5 E. Packer Ave. Bethlehem PA 18015 USA
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16
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Tuazon JP, Castelli V, Lee JY, Desideri GB, Stuppia L, Cimini AM, Borlongan CV. Neural Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:79-91. [PMID: 31898782 DOI: 10.1007/978-3-030-31206-0_4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Neural stem cell (NSC) transplantation has provided the basis for the development of potentially powerful new therapeutic cell-based strategies for a broad spectrum of clinical diseases, including stroke, psychiatric illnesses such as fetal alcohol spectrum disorders, and cancer. Here, we discuss pertinent preclinical investigations involving NSCs, including how NSCs can ameliorate these diseases, the current barriers hindering NSC-based treatments, and future directions for NSC research. There are still many translational requirements to overcome before clinical therapeutic applications, such as establishing optimal dosing, route of delivery, and timing regimens and understanding the exact mechanism by which transplanted NSCs lead to enhanced recovery. Such critical lab-to-clinic investigations will be necessary in order to refine NSC-based therapies for debilitating human disorders.
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Affiliation(s)
- Julian P Tuazon
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - Vanessa Castelli
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - Jea-Young Lee
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | | | - Liborio Stuppia
- Department of Psychological, Humanistic and Territorial Sciences, University G. D'Annunzio, Chieti, Italy
| | - Anna Maria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, Philadelphia, PA, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA.
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17
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Mooney R, Hammad M, Batalla‐Covello J, Abdul Majid A, Aboody KS. Concise Review: Neural Stem Cell-Mediated Targeted Cancer Therapies. Stem Cells Transl Med 2018; 7:740-747. [PMID: 30133188 PMCID: PMC6186269 DOI: 10.1002/sctm.18-0003] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/28/2018] [Accepted: 04/24/2018] [Indexed: 12/27/2022] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide, with 1,688,780 new cancer cases and 600,920 cancer deaths projected to occur in 2017 in the U.S. alone. Conventional cancer treatments including surgical, chemo-, and radiation therapies can be effective, but are often limited by tumor invasion, off-target toxicities, and acquired resistance. To improve clinical outcomes and decrease toxic side effects, more targeted, tumor-specific therapies are being developed. Delivering anticancer payloads using tumor-tropic cells can greatly increase therapeutic distribution to tumor sites, while sparing non-tumor tissues therefore minimizing toxic side effects. Neural stem cells (NSCs) are tumor-tropic cells that can pass through normal organs quickly, localize to invasive and metastatic tumor foci throughout the body, and cross the blood-brain barrier to reach tumors in the brain. This review focuses on the potential use of NSCs as vehicles to deliver various anticancer payloads selectively to tumor sites. The use of NSCs in cancer treatment has been studied most extensively in the brain, but the findings are applicable to other metastatic solid tumors, which will be described in this review. Strategies include NSC-mediated enzyme/prodrug gene therapy, oncolytic virotherapy, and delivery of antibodies, nanoparticles, and extracellular vesicles containing oligonucleotides. Preclinical discovery and translational studies, as well as early clinical trials, will be discussed. Stem Cells Translational Medicine 2018;7:740-747.
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Affiliation(s)
- Rachael Mooney
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
- Irell and Manella Graduate, School of Biological SciencesBeckman Research InstituteCity of Hope DuarteCaliforniaUSA
| | - Mohamed Hammad
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
| | - Jennifer Batalla‐Covello
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
- Irell and Manella Graduate, School of Biological SciencesBeckman Research InstituteCity of Hope DuarteCaliforniaUSA
| | - Asma Abdul Majid
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
| | - Karen S. Aboody
- Department of Developmental and Stem Cell BiologyBeckman Research Institute City of Hope DuarteCaliforniaUSA
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18
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Lang T, Yin Q, Li Y. Progress of Cell-Derived Biomimetic Drug Delivery Systems for Cancer Therapy. ADVANCED THERAPEUTICS 2018. [DOI: 10.1002/adtp.201800053] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Tianqun Lang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica; Chinese Academy of Sciences; 501 Haike Road Shanghai 201203 China
- School of Pharmacy; University of Chinese Academy of Sciences; Beijing 100049 China
| | - Qi Yin
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica; Chinese Academy of Sciences; 501 Haike Road Shanghai 201203 China
- School of Pharmacy; University of Chinese Academy of Sciences; Beijing 100049 China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica; Chinese Academy of Sciences; 501 Haike Road Shanghai 201203 China
- School of Pharmacy; University of Chinese Academy of Sciences; Beijing 100049 China
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19
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Liu XY, Zhou CB, Fang C. Nanomaterial-involved neural stem cell research: Disease treatment, cell labeling, and growth regulation. Biomed Pharmacother 2018; 107:583-597. [PMID: 30114642 DOI: 10.1016/j.biopha.2018.08.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/19/2018] [Accepted: 08/06/2018] [Indexed: 12/21/2022] Open
Abstract
Neural stem cells (NSCs) have been widely investigated for their potential in the treatment of various diseases and transplantation therapy. However, NSC growth regulation, labeling, and its application to disease diagnosis and treatment are outstanding challenges. Recently, nanomaterials have shown promise for various applications including genetic modification, imaging, and controlled drug release. Here we summarize the recent progress in the use of nanomaterials in combination with NSCs for disease treatment and diagnosis, cell labeling, and NSC growth regulation. The toxicity of nanomaterials to NSCs is also discussed.
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Affiliation(s)
- Xiang-Yu Liu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China
| | - Cheng-Bin Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 China
| | - Chao Fang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
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20
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Park GT, Heo JR, Kim SU, Choi KC. The growth of K562 human leukemia cells was inhibited by therapeutic neural stem cells in cellular and xenograft mouse models. Cytotherapy 2018; 20:1191-1201. [PMID: 30078654 DOI: 10.1016/j.jcyt.2018.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 05/07/2018] [Accepted: 05/15/2018] [Indexed: 10/28/2022]
Abstract
To confirm the anti-tumor effect of engineered neural stem cells (NSCs) expressing cytosine deaminase (CD) and interferon-β (IFN-β) with prodrug 5-fluorocytosine (FC), K562 chronic myeloid leukemia (CML) cells were co-cultured with the neural stem cell lines HB1.F3.CD and HB1.F3.CD.IFN-β in 5-FC containing media. A significant decrease in the viability of K562 cells was observed by the treatment of the NSC lines, HB1.F3.CD and HB1.F3.CD.IFN-β, compared with the control. A modified trans-well assay showed that engineered human NSCs significantly migrated toward K562 CML cells more than human normal lung cells. In addition, the important chemoattractant factors involved in the specific migration ability of stem cells were found to be expressed in K562 CML cells. In a xenograft mouse model, NSC treatments via subcutaneous and intravenous injections resulted in significant inhibitions of tumor mass growth and extended survival dates of the mice. Taken together, these results suggest that gene therapy using genetically engineered stem cells expressing CD and IFN-β may be effective for treating CML in these mouse models.
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Affiliation(s)
- Geon-Tae Park
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Jae-Rim Heo
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Seung U Kim
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea; Institute of Life Science and Bio-Engineering, TheraCell Bio & Science, Cheongju, Chungbuk, Republic of Korea.
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21
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Joshi BP, Hardie J, Farkas ME. Harnessing Biology to Deliver Therapeutic and Imaging Entities via Cell-Based Methods. Chemistry 2018; 24:8717-8726. [PMID: 29543990 PMCID: PMC6174085 DOI: 10.1002/chem.201706180] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 03/12/2018] [Indexed: 01/21/2023]
Abstract
The accumulation of therapeutic and imaging agents at sites of interest is critical to their efficacy. Similarly, off-target effects (especially toxicity) are a major liability for these entities. For this reason, the use of delivery vehicles to improve the distribution characteristics of bio-active agents has become ubiquitous in the field. However, the majority of traditionally employed, cargo-bearing platforms rely on passive accumulation. Even in cases where "targeting" functionalities are used, the agents must first reach the site in order for the ligand-receptor interaction to occur. The next stage of vehicle development is the use of "recruited" entities, which respond to biological signals produced in the tissues to be targeted, resulting in improved specificities. Recently, many advances have been made in the utilization of cells as delivery agents. They are biocompatible, exhibit excellent circulation lifetimes and tissue penetration capabilities, and respond to chemotactic signals. In this Minireview, we will explore various cell types, modifications, and applications where cell-based delivery agents are used.
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Affiliation(s)
- Bishnu P Joshi
- Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA, 01002, USA
| | - Joseph Hardie
- Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA, 01002, USA
| | - Michelle E Farkas
- Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA, 01002, USA
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22
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Li X, Meng Y, Xie C, Zhu J, Wang X, Li Y, Geng S, Wu J, Zhong C, Li M. Diallyl Trisulfide inhibits breast cancer stem cells via suppression of Wnt/β-catenin pathway. J Cell Biochem 2018; 119:4134-4141. [PMID: 29243835 DOI: 10.1002/jcb.26613] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 12/07/2017] [Indexed: 12/16/2022]
Abstract
Cancer stem cells (CSCs) play a central role in the development of breast cancer. The canonical Wnt/β-catenin signal pathway is critical for maintaining CSCs characteristics. Diallyl trisulfide (DATS), a natural organosulfur compound from the garlic, exhibits effective antitumor properties. However, the role of DATS in regulating breast CSCs activity and the underlying molecular mechanisms remain obscure. In the present study, we reported that DATS efficiently inhibited the viability of breast CSCs as evidenced by reducing turmorspheres formation, decreasing the expression of breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Furthermore, we showed that DATS downregulated the activity of Wnt/β-catenin pathway, while LiCl-triggered Wnt/β-catenin activation diminished DATS inhibition on breast CSCs. Taken together, our results illustrated that DATS suppressed breast CSCs through inhibiting Wnt/β-catenin pathway activation. These novel findings could provide new insights into the molecular mechanisms of breast CSCs regulation as well as its target intervention and might provide new strategies for preventing and treating breast cancers.
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Affiliation(s)
- Xiaoting Li
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yu Meng
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chunfeng Xie
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jianyun Zhu
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xiaoqian Wang
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yuan Li
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Shanshan Geng
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jieshu Wu
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Caiyun Zhong
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Min Li
- Department of Anatomy, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
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23
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Choi SS, Yoon K, Choi SA, Yoon SB, Kim SU, Lee HJ. Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase. Oncotarget 2018; 7:75319-75327. [PMID: 27659534 PMCID: PMC5342743 DOI: 10.18632/oncotarget.12173] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 09/13/2016] [Indexed: 01/14/2023] Open
Abstract
Advanced pancreatic cancer is one of the most lethal malignant human diseases lacking effective treatment. Its extremely low survival rate necessitates development of novel therapeutic approach. Human neural stem cells (NSCs) are known to have tumor-tropic effect. We genetically engineered them to express rabbit carboxyl esterase (F3.CE), which activates prodrug CPT-11(irinotecan) into potent metabolite SN-38. We found significant inhibition of the growth of BxPC3 human pancreatic cancer cell line in vitro by F3.CE in presence of CPT-11. Apoptosis was also markedly increased in BxPC3 cells treated with F3.CE and CPT-11. The ligand VEGF and receptor VEGF-1(Flt1) were identified to be the relevant tumor-tropic chemoattractant. We confirmed in vivo that in mice injected with BxPC3 on their skin, there was significant reduction of tumor size in those treated with both F3.CE and BxPC3 adjacent to the cancer mass. Administration of F3.CE in conjunction with CPT-11 could be a new possibility as an effective treatment regimen for patients suffering from advanced pancreatic cancer.
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Affiliation(s)
- Sung S Choi
- Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
| | - Kichul Yoon
- Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea.,Seoul Adventist Hospital, Seoul, Korea.,Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Seon-A Choi
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
| | - Seung-Bin Yoon
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
| | - Seung U Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Hong J Lee
- Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
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24
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Park GT, Choi KC. Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy. Oncotarget 2018; 7:58684-58695. [PMID: 27494901 PMCID: PMC5295462 DOI: 10.18632/oncotarget.11017] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/29/2016] [Indexed: 01/14/2023] Open
Abstract
The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field.
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Affiliation(s)
- Geon-Tae Park
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.,TheraCell Bio & Science, Cheongju, Chungbuk, Republic of Korea
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25
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Li Z, Yu XF, Chu PK. Recent advances in cell-mediated nanomaterial delivery systems for photothermal therapy. J Mater Chem B 2018; 6:1296-1311. [DOI: 10.1039/c7tb03166a] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cell-mediated “Trojan Horse” delivery vehicles overcome the drug delivery barriers to transport nano-agents enhancing the efficiency of photothermal therapy.
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Affiliation(s)
- Zhibin Li
- Department of Physics and Department of Materials Science and Engineering
- City University of Hong Kong
- Kowloon
- China
- Center for Biomedical Materials and Interfaces
| | - Xue-Feng Yu
- Center for Biomedical Materials and Interfaces
- Shenzhen Institutes of Advanced Technology
- Chinese Academy of Sciences
- Shenzhen 518055
- P. R. China
| | - Paul K. Chu
- Department of Physics and Department of Materials Science and Engineering
- City University of Hong Kong
- Kowloon
- China
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26
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Jeng KS, Jeng CJ, Jeng WJ, Sheen IS, Li SY, Lu SJ, Chang CF. Tropism of liver epithelial cells toward hepatocellular carcinoma in vitro and in vivo with altering gene expression of cancer stem cells. Am J Surg 2017; 215:735-743. [PMID: 29246405 DOI: 10.1016/j.amjsurg.2017.11.041] [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: 04/07/2017] [Revised: 11/02/2017] [Accepted: 11/28/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Rat liver epithelial (RLE) cells could inhibit the proliferation and invasiveness of hepatoma cells in vitro. This study is to understand the tropism and the effect of RLE cells on mouse hepatoma cells both in vitro and in vivo. METHODS RLE cells were isolated from new-born rats and characterized their stem cell markers. Co-culture and HCC mouse model was established to detect therapeutic effect of RLE cells. RESULTS RLE cells (including Thy-1+ RLE cells, Thy-1- RLE cells, RLE cells) displayed a selective tropism toward ML-1 hepatoma cells both in vitro and in vivo. They altered the gene expression of some cancer stem cell markers in the liver tumor. CONCLUSION Liver epithelial cells have a selective tropism toward HCC in vitro and in vivo. They could alter the gene expression of cancer stem cells.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, Chang-Gung University, Taiwan
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, Chang-Gung University, Taiwan
| | - Shih-Yun Li
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Ssu-Jung Lu
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
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27
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Qin Y, Zhuo L, Cai J, He X, Liu B, Feng C, Zhang L. In vivo monitoring of magnetically labeled mesenchymal stem cells homing to rabbit hepatic VX2 tumors using magnetic resonance imaging. Mol Med Rep 2017; 17:452-458. [PMID: 29115453 DOI: 10.3892/mmr.2017.7902] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 07/20/2017] [Indexed: 11/05/2022] Open
Abstract
Although mesenchymal stem cells (MSCs) have been demonstrated to possess a tumor‑homing feature, their tropism to liver tumors has not been delineated in a visible manner. The aim of the present study was to evaluate the tumor‑homing capacity of MSCs and to investigate the spatial and temporal distributions of MSCs in liver tumors using magnetic resonance imaging (MRI). MSCs were colabeled with superparamagnetic iron oxide (SPIO) particles and 4',6‑diamidino‑2‑phenylindole (DAPI), and then transplanted into rabbits with VX2 liver tumors through intravenous injections. The rabbits were subjected to MRI before and at 3, 7 and 14 days after cell transplantation using a clinical 1.5‑T MRI system. Immediately after the MRI examination, histological analyses were performed using fluorescence and Prussian blue staining. At 3 days after injection with labeled MSCs, heterogeneous hypointensity was detected on the MRI images of the tumor. At 7 days after transplantation, the tumor exhibited anisointense MRI signal, whereas a hypointense ring was detected at the border of the tumor. At 14 days after transplantation, the MRI signal recovered the hyperintensity. As demonstrated in the histological analyses, the distribution of the iron particles visualized with Prussian blue staining was consistent with the DAPI‑stained bright fluorescent nuclei, and the particles corresponded to the hypointense region on the MR images. Thus, systemically administered MSCs could localize to liver tumors with high specificity and possessed a migration feature with active tumor growth. These results demonstrated that the targeting and distribution of the magnetically labeled stem cells in the tumor could be tracked for 7 days in vivo using a clinical 1.5‑T MRI scanner.
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Affiliation(s)
- Yong Qin
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Lisha Zhuo
- Outpatient Department, 77100 Troops, Chinese People's Liberation Army, Chongqing 400020, P.R. China
| | - Jinhua Cai
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Xiaoya He
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Bo Liu
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Chuan Feng
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Lin Zhang
- Department of Radiology, Xinan Hospital of Third Military Medical University, Chongqing 400038, P.R. China
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28
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Mooney R, Abdul Majid A, Batalla J, Annala AJ, Aboody KS. Cell-mediated enzyme prodrug cancer therapies. Adv Drug Deliv Rev 2017; 118:35-51. [PMID: 28916493 DOI: 10.1016/j.addr.2017.09.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 08/15/2017] [Accepted: 09/06/2017] [Indexed: 02/08/2023]
Abstract
Cell-directed gene therapy is a promising new frontier for the field of targeted cancer therapies. Here we discuss the current pre-clinical and clinical use of cell-mediated enzyme prodrug therapy (EPT) directed against solid tumors and avenues for further development. We also discuss some of the challenges encountered upon translating these therapies to clinical trials. Upon sufficient development, cell-mediated enzyme prodrug therapy has the potential to maximize the distribution of therapeutic enzymes within the tumor environment, localizing conversion of prodrug to active drug at the tumor sites thereby decreasing off-target toxicities. New combinatorial possibilities are also promising. For example, when combined with viral gene-delivery vehicles, this may result in new hybrid vehicles that attain heretofore unmatched levels of therapeutic gene expression within the tumor.
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29
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Asad AS, Moreno Ayala MA, Gottardo MF, Zuccato C, Nicola Candia AJ, Zanetti FA, Seilicovich A, Candolfi M. Viral gene therapy for breast cancer: progress and challenges. Expert Opin Biol Ther 2017; 17:945-959. [DOI: 10.1080/14712598.2017.1338684] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Antonela S. Asad
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mariela A. Moreno Ayala
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - M. Florencia Gottardo
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Camila Zuccato
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Alejandro Javier Nicola Candia
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Flavia A. Zanetti
- Instituto de Ciencia y Tecnología César Milstein (ICT Milstein), Unidad Ejecutora del Consejo Nacional de Investigaciones Científicas y Técnicas, Fundación Pablo Cassará, Buenos Aires, Argentina
| | - Adriana Seilicovich
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marianela Candolfi
- Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas (INBIOMED-CONICET/UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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30
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Cao P, Mooney R, Tirughana R, Abidi W, Aramburo S, Flores L, Gilchrist M, Nwokafor U, Haber T, Tiet P, Annala AJ, Han E, Dellinger T, Aboody KS, Berlin JM. Intraperitoneal Administration of Neural Stem Cell-Nanoparticle Conjugates Targets Chemotherapy to Ovarian Tumors. Bioconjug Chem 2017; 28:1767-1776. [PMID: 28453256 DOI: 10.1021/acs.bioconjchem.7b00237] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Ovarian cancer is particularly aggressive once it has metastasized to the abdominal cavity (stage III). Intraperitoneal (IP) as compared to intravenous (IV) administration of chemotherapy improves survival for stage III ovarian cancer, demonstrating that concentrating chemotherapy at tumor sites has therapeutic benefit; unfortunately, IP therapy also increases toxic side effects, thus preventing its completion in many patients. The ability to target chemotherapy selectively to ovarian tumors while sparing normal tissue would improve efficacy and decrease toxicities. We have previously shown that tumor-tropic neural stem cells (NSCs) dramatically improve the intratumoral distribution of nanoparticles (NPs) when given intracerebrally near an orthotopic brain tumor or into a flank xenograft tumor. Here, we show that NPs either conjugated to the surface of NSCs or loaded within the cells are selectively delivered to and distributed within ovarian tumors in the abdominal cavity following IP injection, with no evidence of localization to normal tissue. IP administration is significantly more effective than IV administration, and NPs carried by NSCs show substantially deeper penetration into tumors than free NPs. The NSCs and NPs target and localize to ovarian tumors within 1 h of administration. Pt-loaded silica NPs (SiNP[Pt]) were developed that can be transported in NSCs, and it was found that the NSC delivery of SiNP[Pt] (NSC-SiNP[Pt]) results in higher levels of Pt in tumors as compared to free drug or SiNP[Pt]. To the best of our knowledge, this work represents the first demonstration that cells given IP can target the delivery of drug-loaded NPs.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Ernest Han
- Department of Surgery, City of Hope , 1500 East Duarte Road, Duarte, California 91010, United States
| | - Thanh Dellinger
- Department of Surgery, City of Hope , 1500 East Duarte Road, Duarte, California 91010, United States
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31
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Barish ME, Herrmann K, Tang Y, Argalian Herculian S, Metz M, Aramburo S, Tirughana R, Gutova M, Annala A, Moats RA, Goldstein L, Rockne RC, Gutierrez J, Brown CE, Ghoda L, Aboody KS. Human Neural Stem Cell Biodistribution and Predicted Tumor Coverage by a Diffusible Therapeutic in a Mouse Glioma Model. Stem Cells Transl Med 2017; 6:1522-1532. [PMID: 28481046 PMCID: PMC5689763 DOI: 10.1002/sctm.16-0397] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 02/20/2017] [Indexed: 12/20/2022] Open
Abstract
Engineered neural stem cells (NSCs) intrinsically migrating to brain tumors offer a promising mechanism for local therapeutic delivery. However, difficulties in quantitative assessments of NSC migration and in estimates of tumor coverage by diffusible therapeutics have impeded development and refinement of NSC-based therapies. To address this need, we developed techniques by which conventional serial-sectioned formalin-fixed paraffin-embedded (FFPE) brains can be analyzed in their entirety across multiple test animals. We considered a conventional human glioblastoma model: U251 glioma cells orthotopically engrafted in immunodeficient mice receiving intracerebral (i.c.) or intravenous (i.v.) administrations of NSCs expressing a diffusible enzyme to locally catalyze chemotherapeutic formation. NSC migration to tumor sites was dose-dependent, reaching 50%-60% of total administered NSCs for the i.c route and 1.5% for the i.v. route. Curiously, the most efficient NSC homing was seen with smaller NSC doses, implying existence of rate-limiting process active during administration and/or migration. Predicted tumor exposure to a diffusing therapeutic (assuming a 50 µm radius of action) could reach greater than 50% of the entire tumor volume for i.c. and 25% for i.v. administration. Within individual sections, coverage of tumor area could be as high as 100% for i.c. and 70% for i.v. routes. Greater estimated therapeutic coverage was observed for larger tumors and for larger tumor regions in individual sections. Overall, we have demonstrated a framework within which investigators may rationally evaluate NSC migration to, and integration into, brain tumors, and therefore enhance understanding of mechanisms that both promote and limit this therapeutic modality. Stem Cells Translational Medicine 2017;6:1522-1532.
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Affiliation(s)
- Michael E Barish
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Kelsey Herrmann
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Yang Tang
- Department of Radiology, University of Southern California, Los Angeles, California, USA
| | - Siranush Argalian Herculian
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Marianne Metz
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Soraya Aramburo
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Revathiswari Tirughana
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Margarita Gutova
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Alexander Annala
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Rex A Moats
- Department of Radiology, University of Southern California, Los Angeles, California, USA.,Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.,Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA
| | - Leanne Goldstein
- Department of Information Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Russell C Rockne
- Department of Information Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Jennifer Gutierrez
- Department of Information Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Christine E Brown
- Department of Hematology/HCT, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA.,Department of Immuno-Oncology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Lucy Ghoda
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
| | - Karen S Aboody
- Department of Developmental & Stem Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA.,Department of Division of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, California, USA
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32
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Cascales C, Paíno CL, Bazán E, Zaldo C. Ultrasmall, water dispersible, TWEEN80 modified Yb:Er:NaGd(WO 4) 2 nanoparticles with record upconversion ratiometric thermal sensitivity and their internalization by mesenchymal stem cells. NANOTECHNOLOGY 2017; 28:185101. [PMID: 28323636 DOI: 10.1088/1361-6528/aa6834] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
This work presents the synthesis by coprecipitation of diamond shaped Yb:Er:NaGd(WO4)2 crystalline nanoparticles (NPs) with diagonal dimensions in the 5-7 nm × 10-12 nm range which have been modified with TWEEN80 for their dispersion in water, and their interaction with mesenchymal stem cells (MSCs) proposed as cellular NP vehicles. These NPs belong to a large family of tetragonal Yb:Er:NaT(XO4)2 (T = Y, La, Gd, Lu; X = Mo, W) compounds with green (2H11/2 + 4S3/2 → 4I15/2) Er-related upconversion (UC) efficiency comparable to that of Yb:Er:β-NaYF4 reference compound, but with a ratiometric thermal sensitivity (S) 2.5-3.5 times larger than that of the fluoride. At the temperature range of interest for biomedical applications (∼293-317 K/20-44 °C) S = 108-118 × 10-4 K-1 for 20 at%Yb:5 at%Er:NaGd(WO4)2 NPs, being the largest values so far reported using the 2H11/2/4S3/2 Er intensity ratiometric method. Cultured MSCs, incubated with these water NP emulsions, internalize and accumulate the NPs enclosed in endosomes/lysosomes. Incubations with up to 10 μg of NPs per ml of culture medium maintain cellular metabolism at 72 h. A thermal assisted excitation path is discussed as responsible for the UC behavior of Yb:Er:NaT(XO4)2 compounds.
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Affiliation(s)
- Concepción Cascales
- Instituto de Ciencia de Materiales de Madrid, Consejo Superior de Investigaciones Científicas, c/Sor Juana Inés de la Cruz 3, E-28049 Madrid, Spain
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Yi BR, Kim SU, Choi KC. Synergistic effect of therapeutic stem cells expressing cytosine deaminase and interferon-beta via apoptotic pathway in the metastatic mouse model of breast cancer. Oncotarget 2017; 7:5985-99. [PMID: 26716512 PMCID: PMC4868735 DOI: 10.18632/oncotarget.6719] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 11/25/2015] [Indexed: 11/25/2022] Open
Abstract
As an approach to improve treatment of breast cancer metastasis to the brain, we employed genetically engineered stem cells (GESTECs, HB1.F3 cells) consisting of neural stem cells (NSCs) expressing cytosine deaminase and the interferon-beta genes, HB1.F3.CD and HB1.F3.CD.IFN-β. In this model, MDA-MB-231/Luc breast cancer cells were implanted in the right hemisphere of the mouse brain, while pre-stained GESTECs with redfluorescence were implanted in the contralateral brain. Two days after stem cells injection, 5-fluorocytosine (5-FC) was administrated via intraperitoneal injection. Histological analysis of extracted brain confirmed the therapeutic efficacy of GESTECs in the presence of 5-FC based on reductions in density and aggressive tendency of breast cancer cells, as well as pyknosis, karyorrhexis, and karyolysis relative to a negative control. Additionally, expression of PCNA decreased in the stem cells treated group. Treatment of breast cancer cells with 5-fluorouracil (5-FU) increased the expression of pro-apoptotic and anti-proliferative factor, BAX and p21 protein through phosphorylation of p53 and p38. Moreover, analysis of stem cell migratory ability revealed that MDA-MB-231 cells endogenously secreted VEGF, and stem cells expressed their receptor (VEGFR2). To confirm the role of VEGF/VEGFR2 signaling in tumor tropism of stem cells, samples were treated with the VEGFR2 inhibitor, KRN633. The number of migrated stem cells decreased significantly in response to KRN633 due to Erk1/2 activation and PI3K/Akt inhibition. Taken together, these results indicate that treatment with GESTECs, particularly HB1.F3.CD.IFN-β co-expressing CD.IFN-β, may be a useful strategy for treating breast cancer metastasis to the brain in the presence of a prodrug.
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Affiliation(s)
- Bo-Rim Yi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Seung U Kim
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.,TheraCell Bio and Science, Cheongju, Chungbuk, Republic of Korea
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Gutova M, Goldstein L, Metz M, Hovsepyan A, Tsurkan LG, Tirughana R, Tsaturyan L, Annala AJ, Synold TW, Wan Z, Seeger R, Anderson C, Moats RA, Potter PM, Aboody KS. Optimization of a Neural Stem-Cell-Mediated Carboxylesterase/Irinotecan Gene Therapy for Metastatic Neuroblastoma. MOLECULAR THERAPY-ONCOLYTICS 2016; 4:67-76. [PMID: 28345025 PMCID: PMC5363723 DOI: 10.1016/j.omto.2016.11.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 11/29/2016] [Indexed: 12/22/2022]
Abstract
Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, with treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing a modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs in mice and convert the prodrug irinotecan (CPT-11) to the 1,000-fold more toxic topoisomerase-1 inhibitor SN-38, resulting in significant therapeutic efficacy. We sought to extend these studies by using a clinically relevant NSC line expressing a modified human CE (hCE1m6-NSCs) to establish proof of concept and identify an intravenous dose and treatment schedule that gave maximal efficacy. Human-derived NB cell lines were significantly more sensitive to treatment with hCE1m6-NSCs and irinotecan as compared with drug alone. This was supported by pharmacokinetic studies in subcutaneous NB mouse models demonstrating tumor-specific conversion of irinotecan to SN-38. Furthermore, NB-bearing mice that received repeat treatment with intravenous hCE1m6-NSCs and irinotecan showed significantly lower tumor burden (1.4-fold, p = 0.0093) and increased long-term survival compared with mice treated with drug alone. These studies support the continued development of NSC-mediated gene therapy for improved clinical outcome in NB patients.
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Affiliation(s)
- Margarita Gutova
- Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Leanne Goldstein
- Information Sciences, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Marianne Metz
- Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Anahit Hovsepyan
- Departments of Radiology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Lyudmila G Tsurkan
- Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38101, USA
| | - Revathiswari Tirughana
- Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Lusine Tsaturyan
- Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Alexander J Annala
- Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Timothy W Synold
- Department of Cancer Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Zesheng Wan
- Children's Center for Cancer and Blood Diseases, CHLA/Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Robert Seeger
- Children's Center for Cancer and Blood Diseases, CHLA/Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Clarke Anderson
- Department of Pediatric Oncology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Rex A Moats
- Departments of Radiology and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Philip M Potter
- Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38101, USA
| | - Karen S Aboody
- Departments of Developmental and Stem Cell Biology, City of Hope National Medical Center and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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Banskota S, Yousefpour P, Chilkoti A. Cell-Based Biohybrid Drug Delivery Systems: The Best of the Synthetic and Natural Worlds. Macromol Biosci 2016; 17. [DOI: 10.1002/mabi.201600361] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 10/18/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Samagya Banskota
- Department of Biomedical Engineering; Duke University; Durham NC 27708 USA
| | - Parisa Yousefpour
- Department of Biomedical Engineering; Duke University; Durham NC 27708 USA
| | - Ashutosh Chilkoti
- Department of Biomedical Engineering; Duke University; Durham NC 27708 USA
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Abstract
Stem cell-based drug delivery for cancer therapy has steadily gained momentum in the past decade as several studies have reported stem cells' inherent tropism towards tumors. Since this science is still in its early stages and there are many factors that could significantly impact tumor tropism of stem cells, some contradictory results have been observed. This review starts by examining a number of proof-of-concept studies that demonstrate the potential application of stem cells in cancer therapy. Studies that illustrate stem cells' tumor tropism and discuss the technical difficulties that could impact the therapeutic outcome are also highlighted. The discussion also emphasizes stem cell imaging/tracking, as it plays a crucial role in performing reliable dose-response studies and evaluating the therapeutic outcome of treatment protocols. In each section, the pros and cons associated with each method are highlighted, limitations are underlined, and potential solutions are discussed. The overall intention is to familiarize the reader with important practical issues related to stem cell cancer tropism and in vivo tracking, underline the shortcomings, and emphasize critical factors that need to be considered for effective translation of this science into the clinic.
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Kida K, Ishikawa T, Yamada A, Shimada K, Narui K, Sugae S, Shimizu D, Tanabe M, Sasaki T, Ichikawa Y, Endo I. Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype. Breast Cancer Res Treat 2016; 156:261-9. [PMID: 26975188 DOI: 10.1007/s10549-016-3738-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 02/27/2016] [Indexed: 01/08/2023]
Abstract
Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker, but its value as a predictor of prognosis and chemoresistance is controversial. This study investigated the effect of ALDH1 on prognosis and chemoresponse by breast cancer subtype. We immunohistochemically analyzed 653 invasive breast cancer specimens and evaluated correlations among clinicopathological factors, survival status, response to neoadjuvant chemotherapy, and ALDH1 expression. Of 653 specimens, 139 (21.3 %) expressed ALDH1 in tumor cells. ALDH1 expression was correlated significantly with larger tumor size, node metastasis, higher nuclear grade, and with HER2(+) and progesterone/estrogen receptor (HR)(-) subtypes. ALDH1 expression was significantly observed in HER2 type and triple-negative breast cancer (TNBC). Patients with ALDH1(+) cancers had significantly shorter disease-free survival (P < 0001) and overall survival (P = 0.044). ALDH1 expression significantly affected prognosis of luminal types, but not TNBC and HER2-enriched types. For the 234 patients treated with neoadjuvant chemotherapy, pathological complete response (pCR) rate was significantly lower in ALDH1(+) cases (13.5 vs. 30.3 %, P = 0.003). pCR and ALDH1 expression were significantly correlated in TNBC patients (P = 0.003). ALDH1(+) breast cancers tended to be aggressive, with poor prognoses. Although ALDH1(+) TNBC showed higher chemoresistance, ALDH1 had significant impact on prognosis in the luminal type but not in TNBC.
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Affiliation(s)
- Kumiko Kida
- Department of Gastroenterological Surgery and Surgical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, Japan.
| | - Akimitsu Yamada
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan
| | - Kazuhiro Shimada
- Department of Gastroenterological Surgery and Surgical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kazutaka Narui
- Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan
| | - Sadatoshi Sugae
- Department of Gastroenterological Surgery and Surgical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Daisuke Shimizu
- Department of Gastroenterological Surgery and Surgical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Mikiko Tanabe
- Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Takeshi Sasaki
- Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Yasushi Ichikawa
- Department of Gastroenterological Surgery and Surgical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery and Surgical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Kim J, Hall RR, Lesniak MS, Ahmed AU. Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions. Viruses 2015; 7:6200-17. [PMID: 26633462 PMCID: PMC4690850 DOI: 10.3390/v7122921] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 10/28/2015] [Accepted: 11/03/2015] [Indexed: 12/22/2022] Open
Abstract
Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis—all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.
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Affiliation(s)
- Janice Kim
- The Department of Surgery and the Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA.
| | - Robert R Hall
- The Department of Surgery and the Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA.
| | - Maciej S Lesniak
- The Department of Surgery and the Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA.
| | - Atique U Ahmed
- The Department of Surgery and the Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA.
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Li C, Ruan J, Yang M, Pan F, Gao G, Qu S, Shen YL, Dang YJ, Wang K, Jin WL, Cui DX. Human induced pluripotent stem cells labeled with fluorescent magnetic nanoparticles for targeted imaging and hyperthermia therapy for gastric cancer. Cancer Biol Med 2015; 12:163-74. [PMID: 26487961 PMCID: PMC4607817 DOI: 10.7497/j.issn.2095-3941.2015.0040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective Human induced pluripotent stem (iPS) cells exhibit great potential for generating functional human cells for medical therapies. In this paper, we report for use of human iPS cells labeled with fluorescent magnetic nanoparticles (FMNPs) for targeted imaging and synergistic therapy of gastric cancer cells in vivo. Methods Human iPS cells were prepared and cultured for 72 h. The culture medium was collected, and then was co-incubated with MGC803 cells. Cell viability was analyzed by the MTT method. FMNP-labeled human iPS cells were prepared and injected into gastric cancer-bearing nude mice. The mouse model was observed using a small-animal imaging system. The nude mice were irradiated under an external alternating magnetic field and evaluated using an infrared thermal mapping instrument. Tumor sizes were measured weekly. Results iPS cells and the collected culture medium inhibited the growth of MGC803 cells. FMNP-labeled human iPS cells targeted and imaged gastric cancer cells in vivo, as well as inhibited cancer growth in vivo through the external magnetic field. Conclusion FMNP-labeled human iPS cells exhibit considerable potential in applications such as targeted dual-mode imaging and synergistic therapy for early gastric cancer.
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Affiliation(s)
- Chao Li
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Jing Ruan
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Meng Yang
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Fei Pan
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Guo Gao
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Su Qu
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - You-Lan Shen
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Yong-Jun Dang
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Kan Wang
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Wei-Lin Jin
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
| | - Da-Xiang Cui
- 1 Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Instrument Science and Engineering, National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China ; 2 Basic Medical Sciences Department of Biochemistry & Molecular Biology Key Laboratory of Molecular Medicine, Fudan University, Shanghai 200032, China ; 3 Department of Imaging and Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai 20006, China
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Kanojia D, Balyasnikova IV, Morshed RA, Frank RT, Yu D, Zhang L, Spencer DA, Kim JW, Han Y, Yu D, Ahmed AU, Aboody KS, Lesniak MS. Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases. Stem Cells 2015; 33:2985-94. [PMID: 26260958 DOI: 10.1002/stem.2109] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 06/23/2015] [Indexed: 12/26/2022]
Abstract
The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that intracranial injection of HER2Ab-NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off-target side effects. Our results establish HER2Ab-NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation.
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Affiliation(s)
- Deepak Kanojia
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | | | - Ramin A Morshed
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | - Richard T Frank
- Department of Neurosciences and Division of Neurosurgery, Beckman Research Institute of the City of Hope, Duarte, California, USA
| | - Dou Yu
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | - Lingjiao Zhang
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | - Drew A Spencer
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | - Julius W Kim
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | - Yu Han
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The Univ. Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Atique U Ahmed
- Brain Tumor Center, The University of Chicago, Illinois, USA
| | - Karen S Aboody
- Department of Neurosciences and Division of Neurosurgery, Beckman Research Institute of the City of Hope, Duarte, California, USA
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Salgado AJ, Sousa JC, Costa BM, Pires AO, Mateus-Pinheiro A, Teixeira FG, Pinto L, Sousa N. Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities. Front Cell Neurosci 2015. [PMID: 26217178 PMCID: PMC4499760 DOI: 10.3389/fncel.2015.00249] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) share few characteristics apart from self-renewal and multipotency. In fact, the neurogenic and osteogenic stem cell niches derive from two distinct embryonary structures; while the later originates from the mesoderm, as all the connective tissues do, the first derives from the ectoderm. Therefore, it is highly unlikely that stem cells isolated from one niche could form terminally differentiated cells from the other. Additionally, these two niches are associated to tissues/systems (e.g., bone and central nervous system) that have markedly different needs and display diverse functions within the human body. Nevertheless they do share common features. For instance, the differentiation of both NSCs and MSCs is intimately associated with the bone morphogenetic protein family. Moreover, both NSCs and MSCs secrete a panel of common growth factors, such as nerve growth factor (NGF), glial derived neurotrophic factor (GDNF), and brain derived neurotrophic factor (BDNF), among others. But it is not the features they share but the interaction between them that seem most important, and worth exploring; namely, it has already been shown that there are mutually beneficially effects when these cell types are co-cultured in vitro. In fact the use of MSCs, and their secretome, become a strong candidate to be used as a therapeutic tool for CNS applications, namely by triggering the endogenous proliferation and differentiation of neural progenitors, among other mechanisms. Quite interestingly it was recently revealed that MSCs could be found in the human brain, in the vicinity of capillaries. In the present review we highlight how MSCs and NSCs in the neurogenic niches interact. Furthermore, we propose directions on this field and explore the future therapeutic possibilities that may arise from the combination/interaction of MSCs and NSCs.
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Affiliation(s)
- Antonio J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
| | - Joao C Sousa
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
| | - Bruno M Costa
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
| | - Ana O Pires
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
| | - António Mateus-Pinheiro
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
| | - F G Teixeira
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
| | - Luisa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho Braga, Portugal ; ICVS/3B's, PT Government Associate Laboratory Braga/Guimarães, Portugal
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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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Bryukhovetskiy IS, Mischenko PV, Tolok EV, Zaitcev SV, Khotimchenko YS, Bryukhovetskiy AS. Directional migration of adult hematopoeitic progenitors to C6 glioma in vitro. Oncol Lett 2015; 9:1839-1844. [PMID: 25789053 PMCID: PMC4356383 DOI: 10.3892/ol.2015.2952] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 11/25/2014] [Indexed: 11/26/2022] Open
Abstract
Multiform glioblastoma is the most common primary, highly invasive, malignant tumor of the central nervous system, with an extremely poor prognosis. The median survival of patients following surgical resection, radiation therapy and chemotherapy does not exceed 12–15 months and thus, novel approaches for the treatment of the disease are required. The phenomenon of the directed migration of stem cells in tumor tissue presents a novel approach for the development of technologies that facilitate the targeted delivery of drugs and other therapeutic agents to the tumor foci. Hematopoietic cluster of differentiation (CD)34+/CD133+ stem cells possess significant reparative potential and are inert with respect to normal neural tissue. The aim of the present study was to investigate the substantiation ability of adult hematopoietic progenitors to the directed migration of glioma cells. A C6 glioma cell line, a culture of hematopoietic CD34+/CD133+ stem cells and primary cultures of rat astrocytes and fibroblasts were used. The cells were co-cultured for five days. The results revealed the formation of cell shaft hematopoietic stem cells on the perimeter of the culture inserts containing the glioma culture. However, this was not observed in the wells with fibroblast and astrocyte cultures. The results indicated that hematopoietic stem cells exhibit a high potential for the directional migration of C6 glioma cells, which allows them to be considered as a promising cell line for the development of novel anticancer biomedical technologies and increases our understanding with regard to previously unclear aspects of glial tumor carcinogenesis.
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Affiliation(s)
- Igor Stepanovich Bryukhovetskiy
- Laboratory of Molecular and Cellular Neurobiology, School of Biomedicine, Far Eastern Federal University, Vladivostok 690091, Russia ; Laboratory of Pharmacology, A.V. Zhirmunski Institute of Marine Biology, Far Eastern Branch of the Russian Academy of Sciences, Vladivostok 690041, Russia
| | - Polina Viktorovna Mischenko
- Laboratory of Molecular and Cellular Neurobiology, School of Biomedicine, Far Eastern Federal University, Vladivostok 690091, Russia ; Laboratory of Pharmacology, A.V. Zhirmunski Institute of Marine Biology, Far Eastern Branch of the Russian Academy of Sciences, Vladivostok 690041, Russia
| | - Elena Vadimovna Tolok
- Laboratory of Molecular and Cellular Neurobiology, School of Biomedicine, Far Eastern Federal University, Vladivostok 690091, Russia ; Laboratory of Pharmacology, A.V. Zhirmunski Institute of Marine Biology, Far Eastern Branch of the Russian Academy of Sciences, Vladivostok 690041, Russia
| | - Sergei Victorovich Zaitcev
- Laboratory of Molecular and Cellular Neurobiology, School of Biomedicine, Far Eastern Federal University, Vladivostok 690091, Russia
| | - Yuri Stepanovich Khotimchenko
- Laboratory of Molecular and Cellular Neurobiology, School of Biomedicine, Far Eastern Federal University, Vladivostok 690091, Russia ; Laboratory of Pharmacology, A.V. Zhirmunski Institute of Marine Biology, Far Eastern Branch of the Russian Academy of Sciences, Vladivostok 690041, Russia
| | - Andrei Stepanovich Bryukhovetskiy
- Laboratory of Molecular and Cellular Neurobiology, School of Biomedicine, Far Eastern Federal University, Vladivostok 690091, Russia ; NeuroVita Clinic of Interventional and Restorative Neurology and Therapy, Moscow 115478, Russia
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Perrigue PM, Silva ME, Warden CD, Feng NL, Reid MA, Mota DJ, Joseph LP, Tian YI, Glackin CA, Gutova M, Najbauer J, Aboody KS, Barish ME. The histone demethylase jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines. Mol Cancer Res 2015; 13:636-50. [PMID: 25652587 DOI: 10.1158/1541-7786.mcr-13-0268] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 01/12/2015] [Indexed: 01/09/2023]
Abstract
UNLABELLED Jumonji domain-containing protein 3 (JMJD3/KDM6B) demethylates lysine 27 on histone H3 (H3K27me3), a repressive epigenetic mark controlling chromatin organization and cellular senescence. To better understand the functional consequences of JMJD3 its expression was investigated in brain tumor cells. Querying patient expression profile databases confirmed JMJD3 overexpression in high-grade glioma. Immunochemical staining of two glioma cell lines, U251 and U87, indicated intrinsic differences in JMJD3 expression levels that were reflected in changes in cell phenotype and variations associated with cellular senescence, including senescence-associated β-galactosidase (SA-β-gal) activity and the senescence-associated secretory phenotype (SASP). Overexpressing wild-type JMJD3 (JMJD3wt) activated SASP-associated genes, enhanced SA-β-gal activity, and induced nuclear blebbing. Conversely, overexpression of a catalytically inactive dominant negative mutant JMJD3 (JMJD3mut) increased proliferation. In addition, a large number of transcripts were identified by RNA-seq as altered in JMJD3 overexpressing cells, including cancer- and inflammation-related transcripts as defined by Ingenuity Pathway Analysis. These results suggest that expression of the SASP in the context of cancer undermines normal tissue homeostasis and contributes to tumorigenesis and tumor progression. These studies are therapeutically relevant because inflammatory cytokines have been linked to homing of neural stem cells and other stem cells to tumor loci. IMPLICATIONS This glioma study brings together actions of a normal epigenetic mechanism (JMJD3 activity) with dysfunctional activation of senescence-related processes, including secretion of SASP proinflammatory cytokines and stem cell tropism toward tumors.
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Affiliation(s)
- Patrick M Perrigue
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Michael E Silva
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Charles D Warden
- Bioinformatics Core Facility, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Nathan L Feng
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Michael A Reid
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Daniel J Mota
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Lauren P Joseph
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Yangzi Isabel Tian
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Carlotta A Glackin
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Margarita Gutova
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Joseph Najbauer
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Karen S Aboody
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Division of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Michael E Barish
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Mooney R, Roma L, Zhao D, Van Haute D, Garcia E, Kim SU, Annala AJ, Aboody KS, Berlin JM. Neural stem cell-mediated intratumoral delivery of gold nanorods improves photothermal therapy. ACS NANO 2014; 8:12450-60. [PMID: 25375246 PMCID: PMC4278682 DOI: 10.1021/nn505147w] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 11/06/2014] [Indexed: 05/19/2023]
Abstract
Plasmonic photothermal therapy utilizes biologically inert gold nanorods (AuNRs) as tumor-localized antennas that convert light into heat capable of eliminating cancerous tissue. This approach has lower morbidity than surgical resection and can potentially synergize with other treatment modalities including chemotherapy and immunotherapy. Despite these advantages, it is still challenging to obtain heating of the entire tumor mass while avoiding unnecessary collateral damage to surrounding healthy tissue. It is therefore critical to identify innovative methods to distribute an effective concentration of AuNRs throughout tumors without depositing them in surrounding healthy tissue. Here we demonstrate that AuNR-loaded, tumor-tropic neural stem cells (NSCs) can be used to improve the intratumoral distribution of AuNRs. A simple UV-vis technique for measuring AuNR loading within NSCs was established. It was then confirmed that NSC viability is unimpaired following AuNR loading and that NSCs retain AuNRs long enough to migrate throughout tumors. We then demonstrate that intratumoral injections of AuNR-loaded NSCs are more efficacious than free AuNR injections, as evidenced by reduced recurrence rates of triple-negative breast cancer (MDA-MB-231) xenografts following NIR exposure. Finally, we demonstrate that the distribution of AuNRs throughout the tumors is improved when transported by NSCs, likely resulting in the improved efficacy of AuNR-loaded NSCs as compared to free AuNRs. These findings highlight the advantage of combining cellular therapies and nanotechnology to generate more effective cancer treatments.
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Affiliation(s)
- Rachael Mooney
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
- Address correspondence to ,
| | - Luella Roma
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
| | - Donghong Zhao
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
| | - Desiree Van Haute
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
| | - Elizabeth Garcia
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
| | - Seung U. Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia V6T2B5, Canada
| | - Alexander J. Annala
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
| | - Karen S. Aboody
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
| | - Jacob M. Berlin
- Department of Neurosciences, Department of Molecular Medicine, and Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States
- Address correspondence to ,
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Mooney R, Weng Y, Garcia E, Bhojane S, Smith-Powell L, Kim SU, Annala AJ, Aboody KS, Berlin JM. Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy. J Control Release 2014; 191:82-9. [PMID: 24952368 PMCID: PMC4156897 DOI: 10.1016/j.jconrel.2014.06.015] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 06/06/2014] [Accepted: 06/11/2014] [Indexed: 12/31/2022]
Abstract
Intratumoral drug delivery is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. This mode of administration is currently used in a number of clinical treatments such as neoadjuvant, adjuvant, and even standalone therapies when radiation and surgery are not possible. However, even when injected locally, it is difficult to achieve efficient distribution of chemotherapeutics throughout the tumor. This is primarily attributed to the high interstitial pressure which results in gradients that drive fluid away from the tumor center. The stiff extracellular matrix also limits drug penetration throughout the tumor. We have previously shown that neural stem cells can penetrate tumor interstitium, actively migrating even to hypoxic tumor cores. When used to deliver therapeutics, these migratory neural stem cells result in dramatically enhanced tumor coverage relative to conventional delivery approaches. We recently showed that neural stem cells maintain their tumor tropic properties when surface-conjugated to nanoparticles. Here we demonstrate that this hybrid delivery system can be used to improve the efficacy of docetaxel-loaded nanoparticles when administered intratumorally. This was achieved by conjugating drug-loaded nanoparticles to the surface of neural stem cells using a bond that allows the stem cells to efficiently distribute nanoparticles throughout the tumor before releasing the drug for uptake by tumor cells. The modular nature of this system suggests that it could be used to improve the efficacy of many chemotherapy drugs after intratumoral administration.
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Affiliation(s)
- Rachael Mooney
- Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
| | - Yiming Weng
- Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Elizabeth Garcia
- Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Sukhada Bhojane
- Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Leslie Smith-Powell
- Department of Analytical Pharmacology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Seung U Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia V6T2B5, Canada
| | - Alexander J Annala
- Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Karen S Aboody
- Department of Neurosciences, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA; Division of Neurosurgery, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Jacob M Berlin
- Department of Molecular Medicine, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
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Zhu D, Chen C, Purwanti YI, Du S, Lam DH, Wu C, Zeng J, Toh HC, Wang S. Induced Pluripotent Stem Cell-Derived Neural Stem Cells Transduced with Baculovirus Encoding CD40 Ligand for Immunogene Therapy in Mouse Models of Breast Cancer. Hum Gene Ther 2014; 25:747-58. [DOI: 10.1089/hum.2013.160] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Detu Zhu
- Department of Biological Sciences, National University of Singapore, Singapore 117543
- Institute of Bioengineering and Nanotechnology, Singapore 138669
| | - Can Chen
- Department of Biological Sciences, National University of Singapore, Singapore 117543
| | - Yovita Ida Purwanti
- Department of Biological Sciences, National University of Singapore, Singapore 117543
- Institute of Bioengineering and Nanotechnology, Singapore 138669
| | - Shouhui Du
- Department of Biological Sciences, National University of Singapore, Singapore 117543
| | - Dang Hoang Lam
- Department of Biological Sciences, National University of Singapore, Singapore 117543
- Institute of Bioengineering and Nanotechnology, Singapore 138669
| | - Chunxiao Wu
- Institute of Bioengineering and Nanotechnology, Singapore 138669
| | - Jieming Zeng
- Institute of Bioengineering and Nanotechnology, Singapore 138669
| | | | - Shu Wang
- Department of Biological Sciences, National University of Singapore, Singapore 117543
- Institute of Bioengineering and Nanotechnology, Singapore 138669
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Liu Y, Lv DL, Duan JJ, Xu SL, Zhang JF, Yang XJ, Zhang X, Cui YH, Bian XW, Yu SC. ALDH1A1 expression correlates with clinicopathologic features and poor prognosis of breast cancer patients: a systematic review and meta-analysis. BMC Cancer 2014; 14:444. [PMID: 24938375 PMCID: PMC4070403 DOI: 10.1186/1471-2407-14-444] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 06/06/2014] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) has been identified as a putative cancer stem cell (CSC) marker in breast cancer. However, the clinicopathological and prognostic significance of this protein in breast cancer patients remains controversial. METHODS This meta-analysis was conducted to address the above issues using 15 publications covering 921 ALDH1A1(+) cases and 2353 controls. The overall and subcategory analyses were performed to detect the association between ALDH1A1 expression and clinicopathological/prognostic parameters in breast cancer patients. RESULTS The overall analysis showed that higher expression of ALDH1A1 is associated with larger tumor size, higher histological grade, greater possibility of lymph node metastasis (LNM), higher level expression of epidermal growth factor receptor 2 (HER2), and lower level expression of estrogen receptor (ER)/progesterone receptor (PR). The prognosis of breast cancer patients with ALDH1A1(+) tumors was poorer than that of the ALDH1A1(-) patients. Although the relationships between ALDH1A1 expression and some clinicopathological parameters (tumor size, LNM, and the expression of HER2) was not definitive to some degree when we performed a subcategory analysis, the predictive values of ALDH1A1 expression for histological grade and survival of breast cancer patients were significant regardless of the different cutoff values of ALDH1A1 expression, the different districts where the patients were located, the different clinical stages of the patients, the difference in antibodies used in the studies, and the surgery status. CONCLUSIONS Our results indicate that ALDH1A1 is a biomarker to predict tumor progression and poor survival of breast cancer patients. This marker should be taken into consideration in the development of new diagnostic and therapeutic program for breast cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xiu-wu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400037, China.
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Combinatorial control of transgene expression by hypoxia-responsive promoter and microrna regulation for neural stem cell-based cancer therapy. BIOMED RESEARCH INTERNATIONAL 2014; 2014:751397. [PMID: 24864258 PMCID: PMC4016878 DOI: 10.1155/2014/751397] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 03/19/2014] [Indexed: 12/20/2022]
Abstract
Owing to their strong migratory capacity, tumor tropism, and tumor inhibitory effect, neural stem cells (NSCs) have recently emerged as one of the most attractive gene delivery vectors for cancer therapy. However, further animal studies found that proportional NSC vectors were distributed to nontarget organs after intravenous injection and the nonspecific transgene expression led to significant cytotoxic effects in these organs. Hence, an expression cassette that controls the transgene expression within NSC vectors in a tumor site-specific manner is desired. Considering hypoxia as a hallmark of tumor microenvironment, we have developed a novel NSC vector platform coupling transcriptional targeting with microRNA (miRNA) regulation for tumor hypoxia targeting. This combinatorial vector employed a hypoxia-responsive promoter and repeated targeting sequences of an miRNA that is enriched in NSCs but downregulated upon hypoxia induction to control the transgene expression. This resulted in significantly improved hypoxic selectivity over the use of a control vector without miRNA regulation. Thus, incorporating miRNA regulation into a transcriptional targeting vector adds an extra layer of security to prevent off-target transgene expression and should be useful for the development of NSC vectors with high targeting specifcity for cancer therapy.
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A pilot microdialysis study in brain tumor patients to assess changes in intracerebral cytokine levels after craniotomy and in response to treatment with a targeted anti-cancer agent. J Neurooncol 2014; 118:169-77. [PMID: 24634191 DOI: 10.1007/s11060-014-1415-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 02/21/2014] [Indexed: 12/24/2022]
Abstract
Intracerebral microdialysis enables continuous measurement of changes in brain biochemistry. In this study intracerebral microdialysis was used to assess changes in cytokine levels after tumor resection and in response to treatment with temsirolimus. Brain tumor patients undergoing craniotomy participated in this non-therapeutic study. A 100 kDa molecular weight cut-off microdialysis catheter was placed in peritumoral tissue at the time of resection. Cohort 1 underwent craniotomy only. Cohort 2 received a 200 mg dose of intravenous temsirolimus 48 h after surgery. Dialysate samples were collected continuously for 96 h and analyzed for the presence of 30 cytokines. Serial blood samples were collected to measure systemic cytokine levels. Dialysate samples were obtained from six patients in cohort 1 and 4 in cohort 2. Seventeen cytokines could be recovered in dialysate samples from at least 8 of 10 patients. Concentrations of interleukins and chemokines were markedly elevated in peritumoral tissue, and most declined over time, with IL-8, IP-10, MCP-1, MIP1β, IL-6, IL-12p40/p70, MIP1α, IFN-α, G-CSF, IL-2R, and vascular endothelial growth factor significantly (p < 0.05) decreasing over 96 h following surgery. No qualitative changes in intracerebral or serum cytokine concentrations were detected after temsirolimus administration. This is the first intracerebral microdialysis study to evaluate the time course of changes in macromolecule levels in the peritumoral microenvironment after a debulking craniotomy. Initial elevations of peritumoral interleukins and chemokines most likely reflected an inflammatory response to both tumor and surgical trauma. These findings have implications for development of cellular therapies that are administered intracranially at the time of surgery.
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