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Liu Z, Wang Y, Peng Z, Li H, Wang H, Wu Y, Jiang X, Fu P. Fusion of tumor cells and mesenchymal stem/stroma cells: a source of tumor heterogeneity, evolution and recurrence. Med Oncol 2025; 42:52. [PMID: 39838167 DOI: 10.1007/s12032-024-02595-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 12/28/2024] [Indexed: 01/23/2025]
Abstract
The heterogeneity and evolution of tumors remain significant obstacles in cancer treatment, contributing to both therapy resistance and relapse. Mesenchymal stem/stromal cells (MSCs) are multipotent stromal cells within the tumor microenvironment that interact with tumor cells through various mechanisms, including cell fusion. While previous research has largely focused on the effects of MSC-tumor cell fusion on tumor proliferation, migration, and tumorigenicity, emerging evidence indicates that its role in tumor maintenance, evolution, and recurrence, particularly under stress conditions, may be even more pivotal. This review examines the connection between MSC-tumor cell fusion and several critical factors like tumor heterogeneity, cancer stem cells, and therapy resistance, highlighting the crucial role of cell fusion in tumor survival, evolution, and recurrence. Additionally, we explore potential therapeutic strategies aimed at targeting this process.
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Affiliation(s)
- Zhen Liu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yihao Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zesheng Peng
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hui Li
- Department of Cataract, Nanyang Eye Hospital, Nanyang, 473000, China
| | - Haofei Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuyi Wu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaobing Jiang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Peng Fu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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2
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Laplane L, Maley CC. The evolutionary theory of cancer: challenges and potential solutions. Nat Rev Cancer 2024; 24:718-733. [PMID: 39256635 PMCID: PMC11627115 DOI: 10.1038/s41568-024-00734-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 09/12/2024]
Abstract
The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer.
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Affiliation(s)
- Lucie Laplane
- UMR 8590 Institut d'Histoire et Philosophie des Sciences et des Techniques, CNRS, University Paris I Pantheon-Sorbonne, Paris, France
- UMR 1287 Hematopoietic Tissue Aging, Gustave Roussy Cancer Campus, Villejuif, France
| | - Carlo C Maley
- Arizona Cancer Evolution Center, Arizona State University, Tempe, AZ, USA.
- School of Life Sciences, Arizona State University, Tempe, AZ, USA.
- Biodesign Center for Biocomputing, Security and Society, Arizona State University, Tempe, AZ, USA.
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA.
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3
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Kaviani M, Soleimanian S, Keshtkar S, Azarpira N, Asvar Z, Pakbaz S. Molecular Prospective on Malignant Transformation of Mesenchymal Stem Cells: An Issue in Cell Therapy. Cell Reprogram 2024; 26:96-106. [PMID: 38917438 DOI: 10.1089/cell.2024.0026] [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] [Indexed: 06/27/2024] Open
Abstract
Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are multipotent stem cells that can be isolated from various tissues and could self-renew and differentiate. They secrete cytokines and trophic factors that create a regenerative microenvironment and have immunomodulatory properties. Although clinical trials have been conducted with MSCs in various diseases, concerns regarding the possibility of malignant transformation of these cells have been raised. The studies showed a higher rate of hematological malignancy and carcinogenesis in experimental models after MSC transplantation. The mechanisms underlying malignant transformation of MSCs are complex and not fully understood, but they are believed to involve the presence of special signaling molecules and alterations in cell behavior regulation pathways. Possible pathways that lead to MSCs' oncogenic transformation occur through two mechanisms: spontaneous and stimulated malignant transformation, including cell fusion, fusion proteins, and the tumor microenvironment. MSC-based therapies have the potential to revolutionize medicine, and addressing the issue of malignancy is crucial to ensure their safety and efficacy. Therefore, the purpose of the present review is to summarize the potential mechanisms of the malignant transformation of MSCs. [Figure: see text].
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Affiliation(s)
- Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeede Soleimanian
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Keshtkar
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Asvar
- Nanotechnology School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, Mount Sinai Hospital, Toronto, ON, Canada
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4
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Marzban H, Pedram N, Amini P, Gholampour Y, Saranjam N, Moradi S, Rahvarian J. Immunobiology of cancer stem cells and their immunoevasion mechanisms. Mol Biol Rep 2023; 50:9559-9573. [PMID: 37776412 DOI: 10.1007/s11033-023-08768-9] [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: 06/11/2023] [Accepted: 08/16/2023] [Indexed: 10/02/2023]
Abstract
Cancer stem cells (CSCs) defined as a small fraction of cells within malignancies have been isolated from tumors with different histological origins with stem related characteristics such as self-replicating potential, tumorigenesis, and therapy resistance. The dynamic communication between CSCs and tumor microenvironment particularly immune cells orchestrates their fate and plasticity as well as the patient outcome. According to recent evidence, it has been reported that they harness different immunological pathways to escape immunosurveillance and express aberrantly immunomodulatory agents or decreased levels of factors forming antigen presenting machinery (APM), subsequently followed by impaired antigen presentation and suppressed immune detection. As effective therapies are expected to be able to eradicate CSCs, mechanistic understanding of such interactions can provide insights into causes of therapy failure particularly in immunotherapy. Also, it can contribute to enhance the practical interventions against CSCs and their immunomodulatory features resulting in CSCs eradication and improving patient clinical outcome. The aim of this review is to explain the present knowledge regarding the immunobiology of CSCs and the immunoevasion mechanisms they use.
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Affiliation(s)
- Havva Marzban
- Department of Immunology, Mayo Clinic, Scottsdale, US.
| | - Nastaran Pedram
- Faculty of Veterinary Medicine, Department of Clinical Science, Shiraz University, Shiraz, Iran
| | - Parnian Amini
- Department of Veterinary Laboratory Science, Islamic Azad University, Rasht Branch, Rasht, Iran
| | - Yasaman Gholampour
- Faculty of Veterinary Medicine, Department of Clinical Sciences, Razi University, Kermanshah, Iran
| | | | - Samira Moradi
- Faculty of Medical Science, Department of Medicine, Hormozgan University, Bandar Abbas, Iran
| | - Jeiran Rahvarian
- Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
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5
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Erisik D, Ozdil B, Acikgoz E, Asker Abdikan CS, Yesin TK, Aktug H. Differences and Similarities between Colorectal Cancer Cells and Colorectal Cancer Stem Cells: Molecular Insights and Implications. ACS OMEGA 2023; 8:30145-30157. [PMID: 37636966 PMCID: PMC10448492 DOI: 10.1021/acsomega.3c02681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023]
Abstract
Malignant tumors are formed by diverse groups of cancer cells. Cancer stem cells (CSCs) are a subpopulation of heterogeneous cells identified in tumors that have the ability to self-renew and differentiate. Colorectal cancer (CRC), the third most frequent malignant tumor, is progressively being supported by evidence suggesting that CSCs are crucial in cancer development. We aim to identify molecular differences between CRC cells and CRC CSCs, as well as the effects of those differences on cell behavior in terms of migration, EMT, pluripotency, morphology, cell cycle/control, and epigenetic characteristics. The HT-29 cell line (human colorectal adenocarcinoma) and HT-29 CSCs (HT-29 CD133+/CD44+ cells) were cultured for 72 h. The levels of E-cadherin, KLF4, p53, p21, p16, cyclin D2, HDAC9, and P300 protein expression were determined using immunohistochemistry staining. The migration of cells was assessed by employing the scratch assay technique. Additionally, the scanning electron microscopy method was used to examine the morphological features of the cells, and their peripheral/central elemental ratios were compared with the help of EDS. Furthermore, a Muse cell cycle kit was utilized to determine the cell cycle analysis. The HT-29 CSC group exhibited high levels of expression for E-cadherin, p53, p21, p16, cyclin D2, HDAC9, and P300, whereas KLF4 was found to be high in the HT-29. The two groups did not exhibit any statistically significant differences in the percentages of cell cycle phases. The identification of specific CSC characteristics will allow for earlier cancer detection and the development of more effective precision oncology options.
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Affiliation(s)
- Derya Erisik
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Berrin Ozdil
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
- Department
of Histology and Embryology, Faculty of Medicine, Suleyman Demirel University, Isparta 32260, Turkey
| | - Eda Acikgoz
- Department
of Histology and Embryology, Faculty of Medicine, Yuzuncu Yil University, Van 65080, Turkey
| | | | - Taha Kadir Yesin
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Huseyin Aktug
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
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6
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Jing Y, Liang W, Zhang L, Tang J, Huang Z. The Role of Mesenchymal Stem Cells in the Induction of Cancer-Stem Cell Phenotype. Front Oncol 2022; 12:817971. [PMID: 35251985 PMCID: PMC8891610 DOI: 10.3389/fonc.2022.817971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) modify and form their microenvironment by recruiting and activating specific cell types such as mesenchymal stem cells (MSCs). Tumor-infiltrating MSCs help to establish a suitable tumor microenvironment for the restoration of CSCs and tumor progression. In addition, crosstalk between cancer cells and MSCs in the microenvironment induces a CSC phenotype in cancer cells. Many mechanisms are involved in crosstalk between CSCs/cancer cells and MSCs including cell-cell interaction, secretion of exosomes, and paracrine secretion of several molecules including inflammatory mediators, cytokines, and growth factors. Since this crosstalk may contribute to drug resistance, metastasis, and tumor growth, it is suggested that blockade of the crosstalk between MSCs and CSCs/cancer cells can provide a new avenue to improving the cancer therapeutic tools. In this review, we will discuss the role of MSCs in the induction of cancer stem cell phenotype and the restoration of CSCs. We also discuss targeting the crosstalk between MSCs and CSCs/cancer cells as a therapeutic strategy.
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Affiliation(s)
- Yuanming Jing
- Department of Gastrointestinal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Junjun Tang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
| | - Zongliang Huang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
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7
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Was H, Borkowska A, Olszewska A, Klemba A, Marciniak M, Synowiec A, Kieda C. Polyploidy formation in cancer cells: How a Trojan horse is born. Semin Cancer Biol 2021; 81:24-36. [PMID: 33727077 DOI: 10.1016/j.semcancer.2021.03.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/29/2021] [Accepted: 03/03/2021] [Indexed: 01/04/2023]
Abstract
Ploidy increase has been shown to occur in different type of tumors and participate in tumor initiation and resistance to the treatment. Polyploid giant cancer cells (PGCCs) are cells with multiple nuclei or a single giant nucleus containing multiple complete sets of chromosomes. The mechanism leading to formation of PGCCs may depend on: endoreplication, mitotic slippage, cytokinesis failure, cell fusion or cell cannibalism. Polyploidy formation might be triggered in response to various genotoxic stresses including: chemotherapeutics, radiation, hypoxia, oxidative stress or environmental factors like: air pollution, UV light or hyperthermia. A fundamental feature of polyploid cancer cells is the generation of progeny during the reversal of the polyploid state (depolyploidization) that may show high aggressiveness resulting in the formation of resistant disease and tumor recurrence. Therefore, we propose that modern anti-cancer therapies should be designed taking under consideration polyploidization/ depolyploidization processes, which confer the polyploidization a hidden potential similar to a Trojan horse delayed aggressiveness. Various mechanisms and stress factors leading to polyploidy formation in cancer cells are discussed in this review.
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Affiliation(s)
- Halina Was
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland.
| | - Agata Borkowska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61 Street, Warsaw, Poland
| | - Aleksandra Olszewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61 Street, Warsaw, Poland
| | - Aleksandra Klemba
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Banacha 2c Street, Warsaw, Poland
| | - Marta Marciniak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
| | - Agnieszka Synowiec
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
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8
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Zhou Y, Cheng JT, Feng ZX, Wang YY, Zhang Y, Cai WQ, Han ZW, Wang XW, Xiang Y, Yang HY, Liu BR, Peng XC, Cui SZ, Xin HW. Could gastrointestinal tumor-initiating cells originate from cell-cell fusion in vivo? World J Gastrointest Oncol 2021; 13:92-108. [PMID: 33643526 PMCID: PMC7896421 DOI: 10.4251/wjgo.v13.i2.92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/25/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor-initiating cells (TICs) or cancer stem cells are believed to be responsible for gastrointestinal tumor initiation, progression, metastasis, and drug resistance. It is hypothesized that gastrointestinal TICs (giTICs) might originate from cell-cell fusion. Here, we systemically evaluate the evidence that supports or opposes the hypothesis of giTIC generation from cell-cell fusion both in vitro and in vivo. We review giTICs that are capable of initiating tumors in vivo with 5000 or fewer in vivo fused cells. Under this restriction, there is currently little evidence demonstrating that giTICs originate from cell-cell fusion in vivo. However, there are many reports showing that tumor generation in vitro occurs with more than 5000 fused cells. In addition, the mechanisms of giTIC generation via cell-cell fusion are poorly understood, and thus, we propose its potential mechanisms of action. We suggest that future research should focus on giTIC origination from cell-cell fusion in vivo, isolation or enrichment of giTICs that have tumor-initiating capabilities with 5000 or less in vivo fused cells, and further clarification of the underlying mechanisms. Our review of the current advances in our understanding of giTIC origination from cell-cell fusion may have significant implications for the understanding of carcinogenesis and future cancer therapeutic strategies targeting giTICs.
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Affiliation(s)
- Yang Zhou
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Jun-Ting Cheng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Zi-Xian Feng
- Department of Oncology and Haematology, Lianjiang People's Hospital, Guangzhou 524400, Guangdong Province, China
| | - Ying-Ying Wang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Ying Zhang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wen-Qi Cai
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Zi-Wen Han
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Xian-Wang Wang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Ying Xiang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Hui-Yu Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Bing-Rong Liu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Xiao-Chun Peng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Shu-Zhong Cui
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong Province, China
| | - Hong-Wu Xin
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
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Cancer cells employ an evolutionarily conserved polyploidization program to resist therapy. Semin Cancer Biol 2020; 81:145-159. [PMID: 33276091 DOI: 10.1016/j.semcancer.2020.11.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022]
Abstract
Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.
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10
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Zhang LN, Zhang DD, Yang L, Gu YX, Zuo QP, Wang HY, Xu J, Liu DX. Roles of cell fusion between mesenchymal stromal/stem cells and malignant cells in tumor growth and metastasis. FEBS J 2020; 288:1447-1456. [PMID: 33070450 DOI: 10.1111/febs.15483] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/21/2020] [Accepted: 07/08/2020] [Indexed: 01/02/2023]
Abstract
Invasion and metastasis are the basic characteristics and important markers of malignant tumors, which are also the main cause of death in cancer patients. Epithelial-mesenchymal transition (EMT) is recognized as the first step of tumor invasion and metastasis. Many studies have demonstrated that cell fusion is a common phenomenon and plays a critical role in cancer development and progression. At present, cancer stem cell fusion has been considered as a new mechanism of cancer metastasis. Mesenchymal stromal/stem cell (MSC) is a kind of adult stem cells with high self-renewal ability and multidifferentiation potential, which is used as a very promising fusogenic candidate in the tumor microenvironment and has a crucial role in cancer progression. Many research results have shown that MSCs are involved in the regulation of tumor growth and metastasis through cell fusion. However, the role of cell fusion between MSCs and malignant cells in tumor growth and metastasis is still controversial. Several studies have demonstrated that MSCs can enhance malignant characteristics, promoting tumor growth and metastasis by fusing with malignant cells, while other conflicting reports believe that MSCs can reduce tumorigenicity upon fusion with malignant cells. In this review, we summarize the recent research on cell fusion events between MSCs and malignant cells in tumor growth and metastasis. The elucidation of the molecular mechanisms between MSC fusion and tumor metastasis may provide an effective strategy for tumor biotherapy.
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Affiliation(s)
- Li-Na Zhang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Di-Di Zhang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Lei Yang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Yu-Xuan Gu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Qiu-Ping Zuo
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Hao-Yi Wang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Jia Xu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Dian-Xin Liu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
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11
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Tal A, Tal R, Shaikh S, Gidicsin S, Mamillapalli R, Taylor HS. Characterization of cell fusion in an experimental mouse model of endometriosis†. Biol Reprod 2020; 100:390-397. [PMID: 30304517 DOI: 10.1093/biolre/ioy221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 09/29/2018] [Accepted: 10/08/2018] [Indexed: 02/01/2023] Open
Abstract
Cell fusion is involved in the development of some adult organs, is implicated in the pathogenesis of specific types of cancer, and is known to participate in repair/regeneration processes mediated by bone-marrow-derived cells (BMDCs). Endometriosis is a disease characterized by growth of functional endometrial tissue outside of the uterine cavity. Endometriosis shares some molecular properties with cancer and BMDCs home to endometriosis lesions in a mouse model. Our objective was to determine if cell fusion can occur in endometriosis and establish whether bone-marrow-derived cells participate in cell fusion events in lesions. We employed a Cre-Lox system to identify cell fusion events in a mouse model of endometriosis. Fused cells were detected in endometriotic lesions, albeit at a low frequency (∼1 in 400 cells), localized to the stromal compartment, and displayed restricted proliferation. Using 5-fluorouracil-based nongonadotoxic bone marrow transplantation model, we demonstrate that bone marrow cells represent a principal cell source for fusion events in lesions. Cell fusion progeny uniformly lacked expression of selected markers of hematopoietic, endothelial, and epithelial markers, though they expressed the mesenchymal/stromal markers Sca-1 and CD29. This study is the first to describe the phenomenon of cell fusion in endometriosis and points to a mesenchymal population derived from cell fusion events with limited proliferative activity, properties previously attributed to endometrial stem cells. Their putative role in the pathogenesis of the disease remains to be elucidated.
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Affiliation(s)
- A Tal
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - R Tal
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - S Shaikh
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - S Gidicsin
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - R Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - H S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
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Caglar HO, Biray Avci C. Alterations of cell cycle genes in cancer: unmasking the role of cancer stem cells. Mol Biol Rep 2020; 47:3065-3076. [DOI: 10.1007/s11033-020-05341-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/22/2020] [Indexed: 02/07/2023]
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Castagnoli L, De Santis F, Volpari T, Vernieri C, Tagliabue E, Di Nicola M, Pupa SM. Cancer Stem Cells: Devil or Savior-Looking behind the Scenes of Immunotherapy Failure. Cells 2020; 9:E555. [PMID: 32120774 PMCID: PMC7140486 DOI: 10.3390/cells9030555] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 12/12/2022] Open
Abstract
Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological mechanisms underlying cancer immune escape. Globally, tumor cells evade immune attack using two main strategies: avoiding recognition by immune cells and instigating an immunosuppressive tumor microenvironment. Emerging data suggest that the clinical efficacy of chemotherapy or molecularly targeted therapy is related to the ability of these therapies to target cancer stem cells (CSCs). However, little is known about the role of CSCs in mediating tumor resistance to immunotherapy. Due to their immunomodulating features and plasticity, CSCs can be especially proficient at evading immune surveillance, thus potentially representing the most prominent malignant cell component implicated in primary or acquired resistance to immunotherapy. The identification of immunomodulatory properties of CSCs that include mechanisms that regulate their interactions with immune cells, such as bidirectional release of particular cytokines/chemokines, fusion of CSCs with fusogenic stromal cells, and cell-to-cell communication exerted by extracellular vesicles, may significantly improve the efficacy of current immunotherapy strategies. The purpose of this review is to discuss the current scientific evidence linking CSC biological, immunological, and epigenetic features to tumor resistance to immunotherapy.
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Affiliation(s)
- Lorenzo Castagnoli
- Department of Research, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Amadeo 42, 20133 Milan, Italy; (L.C.); (E.T.)
| | - Francesca De Santis
- Department of Medical Oncology and Hematology, Unit of Immunotherapy and Anticancer Innovative Therapeutics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy; (F.D.S.); (T.V.); (M.D.N.)
| | - Tatiana Volpari
- Department of Medical Oncology and Hematology, Unit of Immunotherapy and Anticancer Innovative Therapeutics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy; (F.D.S.); (T.V.); (M.D.N.)
| | - Claudio Vernieri
- Department of Medical Oncology and Hematology, FIRC Institute of Molecular Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy;
- IFOM, FIRC Institute of Molecular Oncology, via Adamello 16, 20139 Milan, Italy
| | - Elda Tagliabue
- Department of Research, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Amadeo 42, 20133 Milan, Italy; (L.C.); (E.T.)
| | - Massimo Di Nicola
- Department of Medical Oncology and Hematology, Unit of Immunotherapy and Anticancer Innovative Therapeutics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy; (F.D.S.); (T.V.); (M.D.N.)
| | - Serenella M. Pupa
- Department of Research, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Amadeo 42, 20133 Milan, Italy; (L.C.); (E.T.)
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Tumor Microenvironment and Cell Fusion. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5013592. [PMID: 31380426 PMCID: PMC6657644 DOI: 10.1155/2019/5013592] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/06/2019] [Accepted: 06/16/2019] [Indexed: 12/14/2022]
Abstract
Cell fusion is a highly regulated biological process that occurs under both physiological and pathological conditions. The cellular and extracellular environment is critical for the induction of the cell-cell fusion. Aberrant cell fusion is initiated during tumor progression. Tumor microenvironment is a complex dynamic system formed by the interaction between tumor cells and their surrounding cells. Cell-cell fusion mediates direct interaction between tumor cells and their surrounding cells and is associated with tumor initiation and progression. Various microenvironmental factors affect cell fusion in tumor microenvironment and generate hybrids that acquire genomes of both parental cells and exhibit novel characteristics, such as tumor stem cell-like properties, radioresistance, drug resistance, immune evasion, and enhanced migration and invasion abilities, which are closely related to the initiation, invasion, and metastasis of tumor. The phenotypic characteristics of hybrids are based on the phenotypes of parental cells, and the fusion of tumor cells with diverse types of microenvironmental fusogenic cells is concomitant with phenotypic heterogeneity. This review highlights the types of fusogenic cells in tumor microenvironment that can fuse with tumor cells and their specific significance and summarizes the various microenvironmental factors affecting tumor cell fusion. This review may be used as a reference to develop strategies for future research on tumor cell fusion and the exploration of cell fusion-based antitumor therapies.
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Cancer cell fusion: a potential target to tackle drug-resistant and metastatic cancer cells. Drug Discov Today 2019; 24:1836-1844. [PMID: 31163272 DOI: 10.1016/j.drudis.2019.05.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/22/2019] [Accepted: 05/28/2019] [Indexed: 12/27/2022]
Abstract
Cell fusion is an integral, established phenomenon underlying various physiological processes in the cell cycle. Although research in cancer metastasis has hypothesised numerous molecular mechanisms and signalling pathways responsible for invasion and metastasis, the origin and progression of metastatic cells within primary tumours remains unclear. Recently, the role of cancer cell fusion in cancer metastasis and development of multidrug resistance (MDR) in tumours has gained prominence. However, evidence remains lacking to justify the role of cell fusion in cancer metastasis and drug resistance. Here, we highlight plausible mechanisms governing cell fusion with different cell types in the tumour microenvironment (TME), the clinical relevance of cancer cell fusion, its potential as a target for overcoming MDR and inhibiting metastasis, and putative modes of treatment.
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16
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Xie T, Liu B, Dai CG, Lu ZH, Dong J, Huang Q. Glioma stem cells reconstruct similar immunoinflammatory microenvironment in different transplant sites and induce malignant transformation of tumor microenvironment cells. J Cancer Res Clin Oncol 2019; 145:321-328. [PMID: 30415302 DOI: 10.1007/s00432-018-2786-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE This study aimed to examine whether the different tumor-transplanted sites could construct a similar immunoinflammatory microenvironment and to investigate the interactions between tumor microenvironment cells. METHODS The red fluorescent protein-SU3 (SU3-RFP) or SU3 glioma stem cells (GSC) were inoculated into the brain, liver, abdominal cavity, and subcutis of green fluorescent protein (GFP)-nude mice. The tumor tissues were taken to observe the tissue cell distribution. The single cell suspension of tumor tissues was prepared and cultured, while the SU3-RFP cells were co-cultured with the cells from GFP-transgenic mice. The RFP+, GFP+, and RFP+/GFP+ cells were traced by fluorescence microscope, and their protein expressions were determined by Western blot analysis. The markers of immunoinflammatory cells, including F4/80, CD11b, CD11c, CD80, CD47, and SIRP-α, were determined by RT-PCR and immunocytochemistry assays, respectively. RESULTS The xenograft models of all transplant sites were inducible, and the red tumor cells of tumor tissues were encircled by a great quantity of host-derived green cells, including immunoinflammatory cells with CD80, F4/80, CD11b, and CD11c expressions, which might generate the cell colonies and possess the pseudopodia. Additionally, the interactions between red tumor cells and green immunoinflammatory cells, including cell fusion process and yellow fusion cell formation, were observed in cultured cells. The fusion cells-derived B4 cells with expressions of CD47 and SIRP-α proteins had the strong proliferation ability and tumorigenic effect. CONCLUSIONS The similar tumor immunoinflammatory microenvironment was constructed by GSC in different transplant sites, and the cell fusion indicated a malignant transformation of the tumor microenvironment cells.
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Affiliation(s)
- Tao Xie
- The Experimental Center, Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Bing Liu
- The Experimental Center, Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Chun-Gang Dai
- The Experimental Center, Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Zhao-Hui Lu
- The Experimental Center, Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China.
| | - Jun Dong
- The Experimental Center, Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China.
| | - Qiang Huang
- The Experimental Center, Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
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17
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Zhang LN, Kong CF, Zhao D, Cong XL, Wang SS, Ma L, Huang YH. Fusion with mesenchymal stem cells differentially affects tumorigenic and metastatic abilities of lung cancer cells. J Cell Physiol 2018; 234:3570-3582. [PMID: 30417342 DOI: 10.1002/jcp.27011] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 06/25/2018] [Indexed: 12/13/2022]
Abstract
Cell fusion plays a crucial role in cancer progression and leads to massive aberrant changes in chromosome and gene expression involved in tumor metastasis. Cancer cells can fuse with many cell types, including stromal cells, epithelial cells, macrophages, and endothelial cells. Mesenchymal stem cells (MSCs) have been reported to migrate and incorporate into tumor sites during cancer progression. However, the underlying mechanism of stem cell fusion in tumor metastasis has not been fully deciphered. In this research, we established a cell fusion model between lung cancer cells and MSCs in vitro. We found that the hybrid cells showed enhanced metastatic capacity with increased expression of MMP-2 and MMP-9, whereas the proliferation ability was inhibited and cell cycle was blocked in the G0 /G1 phase with elevated expression of p21, p27, and p53. Moreover, the hybrid cells lost epithelial morphology and exhibited an epithelial-mesenchymal transition (EMT) change with downregulation of E-cadherin and upregulation of N-cadherin, Vimentin, α-SMA and Fibronectin1. Meanwhile, the expressions of EMT transcription factors, including Snail1, Slug, Twist1, Zeb1, and Zeb2, were also increased in hybrid cells. More important, the fusion hybrids acquired stem cell-like properties, which exhibited increased expression stem cell transcription factors Oct4, Sox2, Nanog, Kif4 as well as Bmi1. Taken together, our results suggested that cell fusion between lung cancer cells and MSCs offered enhanced metastatic capacity and characteristics of cancer stem cell by undergoing EMT. This study will contribute to explaning the origin of lung cancer stem cells and to elucidate the role of cell fusion in cancer metastasis.
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Affiliation(s)
- Li-Na Zhang
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Chen-Fei Kong
- China-Japan Union Hospital, Jilin University, Changchun, China
| | - Dan Zhao
- China-Japan Union Hospital, Jilin University, Changchun, China
| | - Xian-Ling Cong
- China-Japan Union Hospital, Jilin University, Changchun, China
| | - Shen-Sen Wang
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Ling Ma
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
| | - Ying-Hui Huang
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China
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18
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Chen T, Chen J, Zhu Y, Li Y, Wang Y, Chen H, Wang J, Li X, Liu Y, Li B, Sun X, Ke Y. CD163, a novel therapeutic target, regulates the proliferation and stemness of glioma cells via casein kinase 2. Oncogene 2018; 38:1183-1199. [PMID: 30258108 DOI: 10.1038/s41388-018-0515-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 09/01/2018] [Accepted: 09/01/2018] [Indexed: 01/08/2023]
Abstract
Glioma is a devastating cancer with a dismal prognosis and there is an urgent need to discover novel glioma-specific antigens for glioma therapy. Previous studies have identified CD163-positive tumour cells in certain solid tumours, but CD163 expression in glioma remains unknown. In this study, via an analysis of public datasets, we demonstrated that CD163 overexpression in glioma specimens correlated with an unfavourable patient prognosis. CD163 expression was increased in glioma cells, especially primary glioma cells. The loss of CD163 expression inhibited both cell cycle progression and the proliferation of glioblastoma multiforme (GBM) cell lines and primary glioma cells. CD163 interacted directly with casein kinase 2 (CK2) and CD163 silencing reduced AKT/GSK3β/β-catenin/cyclin D1 pathway activity via CK2. Moreover, CD163 was upregulated in CD133-positive glioma stem cells (GSCs), and CD163 downregulation decreased the expression of GSC markers, including CD133, ALDH1A1, NANOG and OCT4. The knockdown of CD163 impaired GSC stemness by inhibiting the CK2/AKT/GSK3β/β-catenin pathway. Finally, a CD163 antibody successfully induced complement-dependent cytotoxicity against glioma cells. Our findings indicate that CD163 contributes to gliomagenesis via CK2 and provides preclinical evidence that CD163 and the CD163 pathway might serve as a therapeutic target for glioma.
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Affiliation(s)
- Taoliang Chen
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Jiansheng Chen
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Yubo Zhu
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Yan Li
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Yun Wang
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.,Department of Neurosurgery, The First Hospital of Xinjiang Medical University, 830054, Urumqi, China
| | - Huajian Chen
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Jihui Wang
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Xiao Li
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Yang Liu
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China
| | - Baisheng Li
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.,Department of Neurosurgery, Huizhou Central People's Hospital, 516001, Huizhou, China
| | - Xinlin Sun
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
| | - Yiquan Ke
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, China.
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Amey CL, Karnoub AE. Targeting Cancer Stem Cells-A Renewed Therapeutic Paradigm. ONCOLOGY & HEMATOLOGY REVIEW 2017; 13:45-55. [PMID: 33959299 PMCID: PMC8098671 DOI: 10.17925/ohr.2017.13.01.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Metastasis is often accompanied by radio- and chemotherapeutic resistance to anticancer treatments and is the major cause of death in cancer patients. Better understanding of how cancer cells circumvent therapeutic insults and how disseminated cancer clones generate life-threatening metastases would therefore be paramount to the development of effective therapeutic approaches for clinical management of malignant disease. Mounting reports over the past two decades have provided evidence for the existence of a minor population of highly malignant cells within liquid and solid tumors, which are capable of self-renewing and of regenerating secondary growths with the heterogeneity of the primary tumors from which they derive. These cells, called tumor-initiating cells or cancer stem cells (CSCs) exhibit increased resistance to standard radio- and chemotherapies and appear to have mechanisms that enable them to evade immune surveillance. CSCs are therefore considered to be responsible for systemic residual disease after cancer therapy, as well as for disease relapse. How CSCs develop, the nature of the interactions they establish with their microenvironment, their phenotypic and functional characteristics, as well as their molecular dependencies have all taken center stage in cancer therapy. Indeed, improved understanding of CSC biology is critical to the development of important CSC-based anti-neoplastic approaches that have the potential to radically improve cancer management. Here, we summarize some of the most pertinent elements regarding CSC development and properties, and highlight some of the clinical modalities in current development as anti-CSC therapeutics.
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Affiliation(s)
| | - Antoine E Karnoub
- Department of Pathology, Beth Israel Deaconess Cancer Center and Harvard Medical School, Boston, Massachusetts, US; Harvard Stem Cell Institute, Cambridge, Massachusetts, US; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, US
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Yan B, Wang J, Liu L. Chemotherapy promotes tumour cell hybridization in vivo. Tumour Biol 2016; 37:5025-30. [PMID: 26537586 PMCID: PMC4844647 DOI: 10.1007/s13277-015-4337-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 10/28/2015] [Indexed: 01/06/2023] Open
Abstract
Spontaneous cell-cell fusion has been recognized to be an important mechanism for tissue and organ development and repair. In cancer, cell fusion is critically involved in tumourigenesis, metastasis and drug resistance, as illustrated by in vitro experiments. However, there has been no direct detection of tumour cell fusion or hybridization in an in vivo tumour environment, and the features of hybridized cells under selective pressures, such as chemotherapy, are unknown. Here, we expressed two fluorescent marker proteins in the human breast cancer cell line SKBR3 to detect tumour cell hybridization in vivo and performed a xenograft chemotherapy experiment in mice to evaluate the chemotherapeutic response of the hybrids. The mice treated by epirubicin showed that chemotherapy promoted tumour cell hybridization in vivo, which elicited the production of more hybrids in the outer section of the tumour. These results provide the first in vivo evidence of tumour cell fusion and indicate that chemotherapy may contribute to a poor prognosis by enriching for fused cells, which are more malignant. It is therefore necessary to reassess chemotherapy strategies.
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Affiliation(s)
- Bingyu Yan
- State Key Laboratory of Biocontrol, College of Ecology and Evolution, Sun Yat-sen University, #135 Xinggang West, Guangzhou, 510275, China
| | - Jianguo Wang
- State Key Laboratory of Biocontrol, College of Ecology and Evolution, Sun Yat-sen University, #135 Xinggang West, Guangzhou, 510275, China
| | - Li Liu
- State Key Laboratory of Biocontrol, College of Ecology and Evolution, Sun Yat-sen University, #135 Xinggang West, Guangzhou, 510275, China.
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Tumorigenic hybrids between mesenchymal stem cells and gastric cancer cells enhanced cancer proliferation, migration and stemness. BMC Cancer 2015; 15:793. [PMID: 26498753 PMCID: PMC4620013 DOI: 10.1186/s12885-015-1780-1] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 10/12/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Emerging evidence indicates that inappropriate cell-cell fusion might contribute to cancer progression. Similarly, mesenchymal stem cells (MSCs) can also fuse with other cells spontaneously and capable of adopting the phenotype of other cells. The aim of our study was to investigate the role of MSCs participated cell fusion in the tumorigenesis of gastric cancer. METHODS We fused human umbilical cord mesenchymal stem cells (hucMSCs) with gastric cancer cells in vitro by polyethylene glycol (PEG), the hybrid cells were sorted by flow cytometer. The growth and migration of hybrids were assessed by cell counting, cell colony formation and transwell assays. The proteins and genes related to epithelial- mesenchymal transition and stemness were tested by western blot, immunocytochemistry and real-time RT-PCR. The expression of CD44 and CD133 was examined by immunocytochemistry and flow cytometry. The xenograft assay was used to evaluation the tumorigenesis of the hybrids. RESULTS The obtained hybrids exhibited epithelial- mesenchymal transition (EMT) change with down-regulation of E-cadherin and up-regulation of Vimentin, N-cadherin, α-smooth muscle actin (α-SMA), and fibroblast activation protein (FAP). The hybrids also increased expression of stemness factors Oct4, Nanog, Sox2 and Lin28. The expression of CD44 and CD133 on hybrid cells was stronger than parental gastric cancer cells. Moreover, the migration and proliferation of heterotypic hybrids were enhanced. In addition, the heterotypic hybrids promoted the growth abilities of gastric xenograft tumor in vivo. CONCLUSIONS Taken together, our results suggest that cell fusion between hucMSCs and gastric cancer cells could contribute to tumorigenic hybrids with EMT and stem cell-like properties, which may provide a flexible tool for investigating the roles of MSCs in gastric cancer.
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Shen Y, Zhang Q, Zhang J, Lu Z, Wang A, Fei X, Dai X, Wu J, Wang Z, Zhao Y, Tian YE, Dong J, Lan Q, Huang Q. Advantages of a dual-color fluorescence-tracing glioma orthotopic implantation model: Detecting tumor location, angiogenesis, cellular fusion and the tumor microenvironment. Exp Ther Med 2015; 10:2047-2054. [PMID: 26668594 PMCID: PMC4665803 DOI: 10.3892/etm.2015.2821] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Accepted: 09/01/2015] [Indexed: 12/18/2022] Open
Abstract
Various organs of the body have distinct microenvironments with diverse biological characteristics that can influence the growth of tumors within them. However, the mechanisms underlying the interactions between tumor and host cells are currently not well understood. In the present study, a dual-color fluorescence-tracing glioma orthotopic implantation model was developed, in which C6 rat glioma cells labeled with the red fluorescent dye CM-Dil, and SU3 human glioma cells stably expressing red fluorescence protein, were inoculated into the right caudate nucleus of transgenic female C57BL/6 nude mice expressing enhanced green fluorescent protein. The dual-color tracing with whole-body in vivo fluorescence imaging of xenografts was performed using a live imaging system. Frozen sections of the transplanted tumor were prepared for histological analyses, in order to detect the presence of invading tumor cells, blood vessels and cellular fusion. Dual-color images were able to distinguish between red tumor cells and green host cells. The results of the present study suggested that a dual-color fluorescence-tracing glioma orthotopic implantation model may be convenient for detecting tumor location, angiogenesis, cellular fusion, and the tumor microenvironment.
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Affiliation(s)
- Yuntian Shen
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Quanbin Zhang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Shanghai 200072, P.R. China
| | - Jinshi Zhang
- Department of Neurosurgery, Ganzhou People's Hospital, Ganzhou, Jiangxi 341000, P.R. China
| | - Zhaohui Lu
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Aidong Wang
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Xifeng Fei
- Department of Neurosurgery, Suzhou Kowloon Hospital, Suzhou, Jiangsu 215002, P.R. China
| | - Xingliang Dai
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Jinding Wu
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Zhimin Wang
- Department of Neurosurgery, Suzhou Kowloon Hospital, Suzhou, Jiangsu 215002, P.R. China
| | - Yaodong Zhao
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Shanghai 200072, P.R. China
| | - Y E Tian
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Jun Dong
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Qing Lan
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Qiang Huang
- Department of Neurosurgery, Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
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Sun C, Zhao D, Dai X, Chen J, Rong X, Wang H, Wang A, Li M, Dong J, Huang Q, Lan Q. Fusion of cancer stem cells and mesenchymal stem cells contributes to glioma neovascularization. Oncol Rep 2015; 34:2022-30. [PMID: 26238144 DOI: 10.3892/or.2015.4135] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/22/2015] [Indexed: 11/06/2022] Open
Abstract
The ability of tumor cells to autonomously generate tumor vessels has received considerable attention in recent years. However, the degree of autonomy is relative. Meanwhile, the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on tumor neovascularization has not been fully elucidated. The present study aimed to illuminate whether cell fusion between glioma stem cells and BMSC is involved in glioma neovascularization. BMSCs were isolated from transgenic nude mice, of which all nucleated cells express green fluorescent protein (GFP). The immunophenotype and multilineage differentiation potential of BMSC were confirmed. SU3 glioma stem/progenitor cells were transfected with red fluorescent protein (SU3-RFP cells). In a co-culture system of BMSC-GFP and SU3-RFP, RFP+/GFP+ cells were detected and isolated by dual colors using FACS. The angiogenic effect of RFP+/GFP+ cells was determined in vivo and in vitro. Flow cytometry analysis showed that BMSC expressed high levels of CD105, C44, and very low levels of CD45 and CD11b. When co-cultured with SU3-RFP, 73.8% of cells co-expressing RFP and GFP were identified as fused cells in the 5th generation. The fused cells exhibited tube formation ability in vitro and could give rise to a solid tumor and form tumor blood vessels in vivo. In the dual-color orthotopic model of transplantable xenograft glioma, yellow vessel-like structures that expressed CD105, RFP and GFP were identified as de novo-formed vessels derived from the fused cells. The yellow vessels observed in the tumor-bearing mice directly arose from the fusion of BMSCs and SU3-RFP cells. Thus, cell fusion is one of the driving factors for tumor neovascularization.
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Affiliation(s)
- Chao Sun
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Dongliang Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Xingliang Dai
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Jinsheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Xiaoci Rong
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Haiyang Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Aidong Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Ming Li
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Jun Dong
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Qiang Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Qing Lan
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
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Safety and Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Therapy for Retinal Degeneration. PLoS One 2015; 10:e0128973. [PMID: 26107378 PMCID: PMC4479609 DOI: 10.1371/journal.pone.0128973] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 05/04/2015] [Indexed: 01/01/2023] Open
Abstract
Purpose To investigate the safety and efficacy of subretinal injection of human Wharton’s Jelly-derived mesenchymal stem cells (hWJ-MSCs) on retinal structure and function in Royal College of Surgeons (RCS) rats. Methods RCS rats were divided into 2 groups: hWJ-MSCs treated group (n = 8) and placebo control group (n = 8). In the treatment group, hWJ-MSCs from healthy donors were injected into the subretinal space in one eye of each rat at day 21. Control group received saline injection of the same volume. Additional 3 animals were injected with nanogold-labelled stem cells for in vivo tracking of cells localisation using a micro-computed tomography (microCT). Retinal function was assessed by electroretinography (ERG) 3 days before the injection and repeated at days 15, 30 and 70 after the injection. Eyes were collected at day 70 for histology, cellular and molecular studies. Results No retinal tumor formation was detected by histology during the study period. MicroCT scans showed that hWJ-MSCs stayed localised in the eye with no systemic migration. Transmission electron microscopy showed that nanogold-labelled cells were located within the subretinal space. Histology showed preservation of the outer nuclear layer (ONL) in the treated group but not in the control group. However, there were no significant differences in the ERG responses between the groups. Confocal microscopy showed evidence of hWJ-MSCs expressing markers for photoreceptor, Müller cells and bipolar cells. Conclusions Subretinal injection of hWJ-MSCs delay the loss of the ONL in RCS rats. hWJ-MSCs appears to be safe and has potential to differentiate into retinal-like cells. The potential of this cell-based therapy for the treatment of retinal dystrophies warrants further studies.
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Parris GE. Cell-Cell Fusion, Chemotaxis and Metastasis. INTERCELLULAR COMMUNICATION IN CANCER 2015:227-254. [DOI: 10.1007/978-94-017-7380-5_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Siemionow MZ. A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries. Plast Reconstr Surg 2014. [PMID: 24263394 PMCID: PMC7121457 DOI: 10.1007/978-1-4471-6335-0_72] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dupuytren disease is a fibroproliferative disease of palmar fascia of the hand. Its prevalence has been the subject of several reviews; however, an accurate description of the prevalence range in the general population--and of the relation between age and disease--is lacking. METHODS Embase and PubMed were searched using database-specific Medical Subject Headings; titles and abstracts were searched for the words "Dupuytren," "incidence," and "prevalence." Two reviewers independently assessed the articles using inclusion and exclusion criteria, and rated the included studies with a quality assessment instrument. In a meta-analysis, the median prevalence, as a function of age by sex, was estimated, accompanied by 95 percent prediction intervals. The observed heterogeneity in prevalence was investigated with respect to study quality and geographic location. RESULTS Twenty-three of 199 unique identified articles were included. The number of participants ranged from 37 to 97,537, and age ranged from 18 to 100 years. Prevalence varied from 0.6 to 31.6 percent. The quality of studies differed but could not explain the heterogeneity among studies. Mean prevalence was estimated as 12, 21, and 29 percent at ages 55, 65, and 75 years, respectively, based on the relation between age and prevalence determined from 10 studies. CONCLUSIONS The authors describe a prevalence range of Dupuytren disease in the general population of Western countries. The relation between age and prevalence of Dupuytren disease is given according to sex, including 95 percent prediction intervals. It is possible to determine disease prevalence at a certain age for the total population, and for men and women separately.
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Affiliation(s)
- Maria Z. Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, Illinois USA
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Abstract
Cancer stem cells (CSCs) have been identified in a growing list of malignancies and are believed to be responsible for cancer initiation, metastasis and relapse following certain therapies, even though they may only represent a small fraction of the cells in a given cancer. Like somatic stem cells and embryonic stem cells, CSCs are capable of self-renewal and differentiation into more mature, less tumorigenic cells that make up the bulk populations of cancer cells. Elimination of CSCs promises intriguing therapeutic potential and this concept has been adopted in preclinical drug discovery programs. Herein we will discuss the progress of these efforts, general considerations in practice, major challenges and possible solutions.
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Li H, Feng Z, Tsang TC, Tang T, Jia X, He X, Pennington ME, Badowski MS, Liu AKM, Chen D, Harris DT, Martinez J, Meade-Tollin LC. Fusion of HepG2 cells with mesenchymal stem cells increases cancer‑associated and malignant properties: an in vivo metastasis model. Oncol Rep 2014; 32:539-547. [PMID: 24926698 DOI: 10.3892/or.2014.3264] [Citation(s) in RCA: 170] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 02/21/2014] [Indexed: 11/05/2022] Open
Abstract
In the present study, we have tested the hypothesis that fusion between an altered cell and a mesenchymal stem cell produces a hybrid cell with enhanced characteristics associated with metastatic cancer cells, and we have developed a flexible model for investigating the mechanisms of metastasis. Human HepG2 cells with low metastatic potential were induced to fuse with rat bone marrow mesenchymal stem cells, and the progeny were compared with the parental cells for possession of enhanced in vitro and in vivo characteristics of malignant cells. Compared to the parental cells, the fused cells exhibited enhanced expression of E-cadherin, vimentin, Twist, Snail, matrix metalloproteinase 2 and 9 activities, aneuploidy and enhanced in vitro invasion and migration. In an in vivo xenograft assay, the fused cells generated increased numbers of metastatic liver and lung lesions. This model system is a flexible tool for investigation of the mechanisms of stem cell fusion in carcinogenesis and metastasis and for the discovery of new therapeutic targets to inhibit metastasis.
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Affiliation(s)
- Hong Li
- Department of Pathology, Binzhou Medical University Hospital, Binzhou 256603, P.R. China
| | - Zhenqing Feng
- Key Laboratory of Antibody Technique of the Ministry of Health, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Tom C Tsang
- Key Laboratory of Antibody Technique of the Ministry of Health, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Tian Tang
- Key Laboratory of Antibody Technique of the Ministry of Health, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Xiaoqin Jia
- Key Laboratory of Antibody Technique of the Ministry of Health, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Xianghui He
- Department of General Surgery, Tianjin General Surgery Institute, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | | | - Michael S Badowski
- Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA
| | - Anna K M Liu
- Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA
| | - Deyu Chen
- Department of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - David T Harris
- Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA
| | - Jesse Martinez
- Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA
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Yu H, Liu T, Zhao Z, Chen Y, Zeng J, Liu S, Zhu F. Mutations in 3'-long terminal repeat of HERV-W family in chromosome 7 upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb. Oncogene 2014; 33:3947-3958. [PMID: 24013223 DOI: 10.1038/onc.2013.366] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 07/19/2013] [Accepted: 07/22/2013] [Indexed: 12/15/2022]
Abstract
Human endogenous retrovirus (HERV) accounts for ∼8% of the human genome. Recent studies have reported that multiple HERV genes and long terminal repeats (LTRs) are involved in human tumorigenesis. Here we demonstrated that HERV-W env (syncytin-1) was overexpressed in 75.6% (62/82) of urothelial cell carcinoma (UCC) tissues of the bladder compared with only 6.1% (5/82) of matched tumor-adjacent tissues (P<0.001). Syncytin-1 overexpression increased proliferation and viability of immortalized human uroepithelial cells. Colony-formation experiments and in-vivo tumor xenografts suggested that syncytin-1 overexpression had oncogenic potential. Syncytin-1 3'-LTR mutations (142T>C and 277A>G) were present in 87.8% (72/82) of UCC tissues. Normal 3'-LTR was found in 12.2% (10/82) of UCC tissues compared with 95.1% (78/82) of matched tumor-adjacent tissues (P<0.001). Interestingly, 3'-LTR mutations were significantly associated with syncytin-1 overexpression. Luciferase assay and expression analysis revealed that 3'-LTR mutations, especially the 142T>C mutation, enhanced the syncytin-1 promoter activity and expression. In-silico analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation assays demonstrated the binding of c-Myb to 3'-LTRs when the mutations occurred. This alternative interaction was found to be dependent on 142T>C mutation. C-Myb activated syncytin-1 promoter activity and expression by binding to mutant 3'-LTRs. Taken together, these data indicate that syncytin-1 overexpression may be an indicator of UCC risk. The 3'-LTR mutations may upregulate syncytin-1 expression, enabling it to participate in UCC tumorigenesis and development by interacting with c-Myb.
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MESH Headings
- Animals
- Base Sequence
- Carcinoma, Transitional Cell/genetics
- Carcinoma, Transitional Cell/metabolism
- Carcinoma, Transitional Cell/virology
- Cell Proliferation
- Chromosomes, Human, Pair 7/genetics
- DNA Mutational Analysis
- Endogenous Retroviruses/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Gene Products, env/genetics
- Gene Products, env/metabolism
- Humans
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Molecular Sequence Data
- Neoplasm Transplantation
- Point Mutation
- Pregnancy Proteins/genetics
- Pregnancy Proteins/metabolism
- Promoter Regions, Genetic
- Proto-Oncogene Proteins c-myb/metabolism
- Rats
- Terminal Repeat Sequences
- Up-Regulation
- Urinary Bladder Neoplasms/genetics
- Urinary Bladder Neoplasms/metabolism
- Urinary Bladder Neoplasms/virology
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Affiliation(s)
- H Yu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China
| | - T Liu
- State Key Laboratory of Proteomics, Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Z Zhao
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Y Chen
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China
| | - J Zeng
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China
| | - S Liu
- State Key Laboratory of Proteomics, Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - F Zhu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China
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A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries. Plast Reconstr Surg 2014; 133:593-603. [PMID: 24263394 DOI: 10.1097/01.prs.0000438455.37604.0f] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Dupuytren disease is a fibroproliferative disease of palmar fascia of the hand. Its prevalence has been the subject of several reviews; however, an accurate description of the prevalence range in the general population--and of the relation between age and disease--is lacking. METHODS Embase and PubMed were searched using database-specific Medical Subject Headings; titles and abstracts were searched for the words "Dupuytren," "incidence," and "prevalence." Two reviewers independently assessed the articles using inclusion and exclusion criteria, and rated the included studies with a quality assessment instrument. In a meta-analysis, the median prevalence, as a function of age by sex, was estimated, accompanied by 95 percent prediction intervals. The observed heterogeneity in prevalence was investigated with respect to study quality and geographic location. RESULTS Twenty-three of 199 unique identified articles were included. The number of participants ranged from 37 to 97,537, and age ranged from 18 to 100 years. Prevalence varied from 0.6 to 31.6 percent. The quality of studies differed but could not explain the heterogeneity among studies. Mean prevalence was estimated as 12, 21, and 29 percent at ages 55, 65, and 75 years, respectively, based on the relation between age and prevalence determined from 10 studies. CONCLUSIONS The authors describe a prevalence range of Dupuytren disease in the general population of Western countries. The relation between age and prevalence of Dupuytren disease is given according to sex, including 95 percent prediction intervals. It is possible to determine disease prevalence at a certain age for the total population, and for men and women separately.
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Liu WH, You N, Zhang N, Yan HT, Wang T, Huang Z, Liu HB, Tang LJ. Interpretation of interlocking key issues of cancer stem cells in malignant solid tumors. Cell Oncol (Dordr) 2012; 35:397-409. [PMID: 23179790 DOI: 10.1007/s13402-012-0110-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2012] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE In this review, several interlinking issues related to cancer stem cells (CSCs) in malignant solid tumors are sequentially discussed. METHODS A literature search was performed using PubMed, Web of Science and the Cochrane library, combining the words CSCs, solid tumor, isolation, identification, origination, therapy, target and epithelial-mesenchymal transition. RESULTS Because a primary problem is the isolation of CSCs, we first analyzed the advantages and disadvantages of recently used methods, which were mostly based on the physical or immunochemical characteristics of CSCs. Once CSCs are isolated, they should be identified by their stem cell properties. Here, we suggest how to establish a standard identification strategy. We also focused on the origination hypotheses of CSCs. The supporting molecular mechanisms for each theory were thoroughly analyzed and integrated. Especially, epithelial- mesenchymal transition is an increasingly recognized mechanism to generate CSCs that are endowed with a more invasive and metastatic phenotype. Finally, we discuss putative strategies of eliminating CSCs as effective cancer therapies. CONCLUSION After several interlocking issues of CSCs are thoroughly clarified, these CSCs in solid malignant tumors may specifically be targeted, which raises a new hope for eliminating these tumors.
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Affiliation(s)
- Wei-Hui Liu
- PLA Center of General Surgery, General Hospital of Chengdu Army Region, Chengdu, Sichuan Province, China
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Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability. Blood 2012; 120:603-12. [DOI: 10.1182/blood-2011-10-388629] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Abstract
Human cancers display substantial intratumoral genetic heterogeneity, which facilitates tumor survival under changing microenvironmental conditions. Tumor substructure and its effect on disease progression and relapse are incompletely understood. In the present study, a high-throughput method that uses neutral somatic mutations accumulated in individual cells to reconstruct cell lineage trees was applied to hundreds of cells of human acute leukemia harvested from multiple patients at diagnosis and at relapse. The reconstructed cell lineage trees of patients with acute myeloid leukemia showed that leukemia cells at relapse were shallow (divide rarely) compared with cells at diagnosis and were closely related to their stem cell subpopulation, implying that in these instances relapse might have originated from rarely dividing stem cells. In contrast, among patients with acute lymphoid leukemia, no differences in cell depth were observed between diagnosis and relapse. In one case of chronic myeloid leukemia, at blast crisis, most of the cells at relapse were mismatch-repair deficient. In almost all leukemia cases, > 1 lineage was observed at relapse, indicating that diverse mechanisms can promote relapse in the same patient. In conclusion, diverse relapse mechanisms can be observed by systematic reconstruction of cell lineage trees of patients with leukemia.
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Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:2504-15. [PMID: 22542847 DOI: 10.1016/j.ajpath.2012.02.020] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 01/13/2012] [Accepted: 02/13/2012] [Indexed: 12/12/2022]
Abstract
Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in immunodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer-mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm.
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Abstract
INTRODUCTION The crosstalk between tumor and stromal cells has become an increasing important subject of the biology of oncogenesis, also involving new therapy paradigms for treating tumor-reactive host cells and vasculature. AREAS COVERED This article describes the long-term propagation in hamsters of a human glioblastoma which was derived from the in-vivo fusion of the human tumor cells with hamster stromal cells. The hybrid tumor cells retained at least seven human genes, of which three were able to translate their protein products during serial passages in vitro and in vivo, as well as features of the original tumor's histological appearance. This heterospecific fusion of cancer and normal host stromal cells is discussed as a mechanism for the horizontal transmission of malignancy, which may be a more common phenomenon in human cancer than appreciated previously. EXPERT OPINION Cell-cell fusion in vivo is one of several mechanisms by which genetic information can be transmitted from tumor to host cells, resulting in new and different (more aggressive) tumor cell populations.
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Affiliation(s)
- David M Goldenberg
- Garden State Cancer Center, Center for Molecular Medicine and Immunology, 300 The American Road, Morris Plains, NJ 07950, USA.
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35
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Brunner TB, Kunz-Schughart LA, Grosse-Gehling P, Baumann M. Cancer Stem Cells as a Predictive Factor in Radiotherapy. Semin Radiat Oncol 2012; 22:151-74. [DOI: 10.1016/j.semradonc.2011.12.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Krajcovic M, Overholtzer M. Mechanisms of ploidy increase in human cancers: a new role for cell cannibalism. Cancer Res 2012; 72:1596-601. [PMID: 22447569 DOI: 10.1158/0008-5472.can-11-3127] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Aneuploidy is a hallmark of human cancers originating from abnormal mitoses. Many aneuploid cancer cells also have greater-than-diploid DNA content, suggesting that polyploidy is a common precursor to aneuploidy during tumor progression. Polyploid cells can originate from cell fusion, endoreplication, and cytokinesis failure. Recently we found that cell cannibalism by entosis, a form of cell engulfment involving live cells, also leads to polyploidy, as internalized cells disrupt cytokinesis of their engulfing cell hosts. By this mechanism, cannibalistic cell behavior could promote tumor progression by leading to aneuploidy. Here, we discuss cell cannibalism in cancer and other mechanisms that result in the formation of polyploid cancer cells.
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Affiliation(s)
- Matej Krajcovic
- Cell Biology Program, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York 10065, USA
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Han JP, Liu B, Yang YL, Su QJ, Shi M, Qian Z, Dong L, Zhang CL, Ha YD. Relationship between characteristics of CD44 +/ki-67 - colorectal cancer stem cells and clinicopathological characteristics in patients with colorectal cancer. Shijie Huaren Xiaohua Zazhi 2011; 19:3483-3488. [DOI: 10.11569/wcjd.v19.i34.3483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the number, location, distribution and staining features of CD44+/ki-67- colorectal cancer stem cells and to analyze their relation with clinicopathological characteristics in patients with colorectal carcinoma.
METHODS: Streptavidin-HRP immunohistochemical staining, double immunohistochemical staining and hematoxylin-eosin staining were performed to detect the expression of CD44 and ki-67 in 10 cases of normal mucosal tissue, 15 cases of adenoma with atypical hyperplasia, 59 cases of colorectal carcinoma, and human colon cancer cell line SW620. The number, location, distribution and staining features of CD44+/ki-67- colorectal cancer stem cells were observed, and their relation with clinicopathological characteristics was analyzed.
RESULTS: The number of CD44+/ki-67- tumor cells accounted for 0.1%-25.0% (average 5.82%) of all tumor cells, and the cells were mainly distributed in the sides of the basal membrane or common wall of glands. These cells had round or oval nuclei that were consistent in size, and contained deep stained chromatin and less cytoplasm. These features are consistent with those of stem cells in the intestinal crypts. The number of CD44+/ki-67- tumor cells was significantly correlated with depth of cancer infiltration (χ2 = 1.851, P < 0.05) and lymph node metastasis (χ2 = -4.113, P < 0.01).
CONCLUSION: CD44+/ki-67- are suitable specific markers for tumor stem cells and can be used for tumor stem cell isolation, targeted therapy, individualized treatment, prediction of tumor metastasis, and estimation of prognosis in patients with colorectal cancer.
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Zhu YZ, Fu D, Liu LL, Ma YS, Shen XZ, Chen XM. A high-throughput two-dimensional screening technique for cellular recognition and localization in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2011; 19:2455-2460. [DOI: 10.11569/wcjd.v19.i23.2455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a novel high-throughput two-dimensional screening technique for cellular recognition and localization in hepatocellular carcinoma (HCC).
METHODS: HCC specimen was collected from a patient who underwent radical resection. The paraffin-embedded specimen was serially sectioned at a thickness of 1 μm. Five serial sections were used for staining: one for H&E staining and the other four for immunofluorescence staining for detecting eight reported liver cancer stem cell (LCSC) markers. Fluorescein isothiocyanate (FITC) and tetramethyl rhodamine isothiocyanate (rhodamine) were used for fluorescent imaging for double staining. The sections were counterstained with Hoechst33342 to demonstrate the nuclei for cellular localization. Fluorescence microscopy was used to detect the fluorescence intensity and localization.
RESULTS: We identified the valid number of cells in a visual field (1 × 100) of microscopy and delineated the merged cell map. The results showed that 8 LCSCs biomarkers could be detected in 2 772 valid cells. The expression levels of biomarkers were different in these cells and a single valid cell could express 0-8 biomarkers. No biomarkers could be detected in 2 453 cells (88.5%).
CONCLUSION: A high-throughput two-dimensional screening technique for cellular recognition and localization has been successfully developed and can be used to detect the expression of two or more LCSC markers in one liver cancer cell.
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