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Shabo I, Midtbö K, Bränström R, Lindström A. Monocyte-cancer cell fusion is mediated by phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation. PLoS One 2025; 20:e0311027. [PMID: 39752516 PMCID: PMC11698428 DOI: 10.1371/journal.pone.0311027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 09/11/2024] [Indexed: 01/06/2025] Open
Abstract
Emerging evidence suggests that fusion of cancer cells with leucocytes, such as macrophages, plays a significant role in cancer metastasis and results in tumor hybrid cells that acquire resistance to chemo- and radiation therapy. However, the precise mechanisms behind the leukocyte-cancer cell fusion remain unclear. The present in vitro study explores the presence of fusion between the monocyte cell line (THP-1) and the breast cancer cell line (MCF-7) in relation to the expression of CD36 and phosphatidylserine with and without treatment of these cells with ionizing radiation. The study reveals that spontaneous THP-1/MCF-7 cell fusion increases significantly from 2.8% to 6% after irradiation. The interaction between CD36 and phosphatidylserine plays a pivotal role in THP-1/MCF-7 cell fusion, as inhibiting this interaction using anti-CD36 antibodies significantly reduces cell fusion. While irradiation leads to a dose-dependent escalation in phosphatidylserine expression in MCF-7 cells, it does not impact the expression of CD36 in either THP-1 or MCF-7 cells. To the best of our knowledge, this is the first study to demonstrate the involvement of the CD36-phosphatidylserine interaction in the fusion between monocytes and cancer cells, shedding light on a novel explanatory mechanism for the roles of CD36 and phosphatidylserine in tumor progression.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Kristine Midtbö
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Robert Bränström
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Annelie Lindström
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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2
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Patel RK, Parappilly M, Farley HC, Latour EJ, Wang LG, Nair AM, Lu ES, Sims Z, Park B, Nelson K, Mayo SC, Mills GB, Sheppard BC, Chang YH, Gibbs SL, Kardosh A, Lopez CD, Wong MH. Circulating Neoplastic-Immune Hybrid Cells Are Biomarkers of Occult Metastasis and Treatment Response in Pancreatic Cancer. Cancers (Basel) 2024; 16:3650. [PMID: 39518088 PMCID: PMC11545756 DOI: 10.3390/cancers16213650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) presents significant diagnostic and prognostic challenges, as current biomarkers frequently fail to accurately stage disease, predict rapid metastatic recurrence (rPDAC), or assess response to neoadjuvant therapy (NAT). We investigated the potential for circulating neoplastic-immune hybrid cells (CHCs) as a non-invasive, multifunctional biomarker for PDAC. METHODS Peripheral blood specimens were obtained from patients diagnosed with PDAC. CHCs were detected by co-expression of pan-cytokeratin and CD45, normalized to 50,000 peripheral blood mononuclear cells. rPDAC was defined as metastatic recurrence within six months of margin-negative pancreatectomy. Cyclic immunofluorescence (CyCIF) analyses compared hybrid phenotypes in blood and tumors. RESULTS Blood samples were collected from 42 patients with PDAC prior to resection. Those with radiographically occult metastatic disease and rPDAC had higher preoperative CHC numbers compared to patients who did not (65.0 and 74.4, vs. 11.52 CHCs; p < 0.001). Patients with complete or near-complete pathologic responses to NAT had lower preoperative CHC numbers than partial and/or non-responders (1.7 vs. 13.1 CHCs; p = 0.008). When assessed longitudinally, those with partial pathologic response saw CHC levels become undetectable while on treatment but increase in the interval between NAT completion and resection. In contrast, patients with poor responses or development of metastatic disease experienced persistent CHC detection during therapy or rising levels prior to radiographic evidence of metastases. Further, in metastatic PDAC patients, treatment-induced phenotypic changes in hybrid cells mirrored those in paired metastatic tumor samples. CONCLUSIONS CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC.
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Affiliation(s)
- Ranish K. Patel
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University (OHSU), Portland, OR 97239, USA; (R.K.P.)
| | - Michael Parappilly
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Hannah C. Farley
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Emile J. Latour
- Biostatistics Shared Resource, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Lei G. Wang
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
| | - Ashvin M. Nair
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Ethan S. Lu
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Zachary Sims
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
| | - Byung Park
- Biostatistics Shared Resource, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Katherine Nelson
- Gastrointestinal Clinical Trials, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Skye C. Mayo
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University (OHSU), Portland, OR 97239, USA; (R.K.P.)
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Gordon B. Mills
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Division of Oncological Sciences, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Brett C. Sheppard
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Department of Surgery, Division of General Surgery, OHSU, Portland, OR 97239, USA
| | - Young Hwan Chang
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Summer L. Gibbs
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Adel Kardosh
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Department of Medicine, Division of Medical Oncology, OHSU, Portland, OR 97239, USA
| | - Charles D. Lopez
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Department of Medicine, Division of Medical Oncology, OHSU, Portland, OR 97239, USA
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
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Gou S, Wu A, Luo Z. Integrins in cancer stem cells. Front Cell Dev Biol 2024; 12:1434378. [PMID: 39239559 PMCID: PMC11375753 DOI: 10.3389/fcell.2024.1434378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024] Open
Abstract
Integrins are a class of adhesion receptors on cell membranes, consisting of α and β subunits. By binding to the extracellular matrix, integrins activate intracellular signaling pathways, participating in every step of cancer initiation and progression. Tumor stem cells possess self-renewal and self-differentiation abilities, along with strong tumorigenic potential. In this review, we discussed the role of integrins in cancer, with a focus on their impact on tumor stem cells and tumor stemness. This will aid in targeting tumor stem cells as a therapeutic approach, leading to the exploration of novel cancer treatment strategies.
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Affiliation(s)
- Siqi Gou
- The Second Affiliated Hospital, Department of urology, Hengyang Medical School, University of South China, Hengyang, China
| | - Anqi Wu
- The Second Affiliated Hospital, Department of Clinical Research Center, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhigang Luo
- The Second Affiliated Hospital, Department of urology, Hengyang Medical School, University of South China, Hengyang, China
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Sieler M, Dörnen J, Dittmar T. How Much Do You Fuse? A Comparison of Cell Fusion Assays in a Breast Cancer Model. Int J Mol Sci 2024; 25:5668. [PMID: 38891857 PMCID: PMC11172233 DOI: 10.3390/ijms25115668] [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: 04/23/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Cell fusion is a biological process that is crucial for the development and homeostasis of different tissues, but it is also pathophysiologically associated with tumor progression and malignancy. The investigation of cell fusion processes is difficult because there is no standardized marker. Many studies therefore use different systems to observe and quantify cell fusion in vitro and in vivo. The comparability of the results must be critically questioned, because both the experimental procedure and the assays differ between studies. The comparability of the fluorescence-based fluorescence double reporter (FDR) and dual split protein (DSP) assay was investigated as part of this study, in which general conditions were kept largely constant. In order to be able to induce both a high and a low cell fusion rate, M13SV1 breast epithelial cells were modified with regard to the expression level of the fusogenic protein Syncytin-1 and its receptor ASCT2 and were co-cultivated for 72 h with different breast cancer cell lines. A high number of fused cells was found in co-cultures with Syncytin-1-overexpressing M13SV1 cells, but differences between the assays were also observed. This shows that the quantification of cell fusion events in particular is highly dependent on the assay selected, but the influence of fusogenic proteins can be visualized very well.
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Affiliation(s)
- Mareike Sieler
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58453 Witten, Germany; (M.S.); (J.D.)
| | - Jessica Dörnen
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58453 Witten, Germany; (M.S.); (J.D.)
- Faculty of Medicine, Ruhr University Bochum, 44789 Bochum, Germany
| | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58453 Witten, Germany; (M.S.); (J.D.)
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5
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Wei S, Li M, Wang Q, Zhao Y, Du F, Chen Y, Deng S, Shen J, Wu K, Yang J, Sun Y, Gu L, Li X, Li W, Chen M, Ling X, Yu L, Xiao Z, Dong L, Wu X. Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease. J Inflamm Res 2024; 17:3307-3334. [PMID: 38800593 PMCID: PMC11128225 DOI: 10.2147/jir.s458103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
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Affiliation(s)
- Shulin Wei
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Mingxing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Qin Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yueshui Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Fukuan Du
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yu Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Shuai Deng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jing Shen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Ke Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jiayue Yang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yuhong Sun
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Li Gu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiaobing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Wanping Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Meijuan Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiao Ling
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lei Yu
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Zhangang Xiao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lishu Dong
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xu Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
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6
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Budzynska K, Siemionow M, Stawarz K, Chambily L, Siemionow K. Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration. Biomolecules 2024; 14:575. [PMID: 38785982 PMCID: PMC11117592 DOI: 10.3390/biom14050575] [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: 04/02/2024] [Revised: 05/06/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
Chimerism-based strategies represent a pioneering concept which has led to groundbreaking advancements in regenerative medicine and transplantation. This new approach offers therapeutic potential for the treatment of various diseases, including inherited disorders. The ongoing studies on chimeric cells prompted the development of Dystrophin-Expressing Chimeric (DEC) cells which were introduced as a potential therapy for Duchenne Muscular Dystrophy (DMD). DMD is a genetic condition that leads to premature death in adolescent boys and remains incurable with current methods. DEC therapy, created via the fusion of human myoblasts derived from normal and DMD-affected donors, has proven to be safe and efficacious when tested in experimental models of DMD after systemic-intraosseous administration. These studies confirmed increased dystrophin expression, which correlated with functional and morphological improvements in DMD-affected muscles, including cardiac, respiratory, and skeletal muscles. Furthermore, the application of DEC therapy in a clinical study confirmed its long-term safety and efficacy in DMD patients. This review summarizes the development of chimeric cell technology tested in preclinical models and clinical studies, highlighting the potential of DEC therapy in muscle regeneration and repair, and introduces chimeric cell-based therapies as a promising, novel approach for muscle regeneration and the treatment of DMD and other neuromuscular disorders.
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Affiliation(s)
- Katarzyna Budzynska
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
- Chair and Department of Traumatology, Orthopaedics, and Surgery of the Hand, Poznan University of Medical Sciences, 61-545 Poznan, Poland
| | - Katarzyna Stawarz
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Lucile Chambily
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Krzysztof Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
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7
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Ali AM, Raza A. scRNAseq and High-Throughput Spatial Analysis of Tumor and Normal Microenvironment in Solid Tumors Reveal a Possible Origin of Circulating Tumor Hybrid Cells. Cancers (Basel) 2024; 16:1444. [PMID: 38611120 PMCID: PMC11010995 DOI: 10.3390/cancers16071444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/31/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Metastatic cancer is a leading cause of death in cancer patients worldwide. While circulating hybrid cells (CHCs) are implicated in metastatic spread, studies documenting their tissue origin remain sparse, with limited candidate approaches using one-two markers. Utilizing high-throughput single-cell and spatial transcriptomics, we identified tumor hybrid cells (THCs) co-expressing epithelial and macrophage markers and expressing a distinct transcriptome. Rarely, normal tissue showed these cells (NHCs), but their transcriptome was easily distinguishable from THCs. THCs with unique transcriptomes were observed in breast and colon cancers, suggesting this to be a generalizable phenomenon across cancer types. This study establishes a framework for HC identification in large datasets, providing compelling evidence for their tissue residence and offering comprehensive transcriptomic characterization. Furthermore, it sheds light on their differential function and identifies pathways that could explain their newly acquired invasive capabilities. THCs should be considered as potential therapeutic targets.
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Affiliation(s)
- Abdullah Mahmood Ali
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA
- Edward P Evans MDS Center, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA
| | - Azra Raza
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA
- Edward P Evans MDS Center, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA
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Patel RK, Parappilly M, Rahman S, Schwantes IR, Sewell M, Giske NR, Whalen RM, Durmus NG, Wong MH. The Hallmarks of Circulating Hybrid Cells. Results Probl Cell Differ 2024; 71:467-485. [PMID: 37996690 DOI: 10.1007/978-3-031-37936-9_21] [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: 11/25/2023]
Abstract
While tumor metastases represent the primary driver of cancer-related mortality, our understanding of the mechanisms that underlie metastatic initiation and progression remains incomplete. Recent work identified a novel tumor-macrophage hybrid cell population, generated through the fusion between neoplastic and immune cells. These hybrid cells are detected in primary tumor tissue, peripheral blood, and in metastatic sites. In-depth analyses of hybrid cell biology indicate that they can exploit phenotypic properties of both parental tumor and immune cells, in order to intravasate into circulation, evade the immune response, and seed tumors at distant sites. Thus, it has become increasingly evident that the development and dissemination of tumor-immune hybrid cells play an intricate and fundamental role in the metastatic cascade and can provide invaluable information regarding tumor characteristics and patient prognostication. In this chapter, we review the current understanding of this novel hybrid cell population, the specific hallmarks of cancer that these cells exploit to promote cancer progression and metastasis, and discuss exciting new frontiers that remain to be explored.
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Affiliation(s)
- Ranish K Patel
- Department of Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Michael Parappilly
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Shahrose Rahman
- Department of Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Issac R Schwantes
- Department of Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Marisa Sewell
- Department of Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Nicole R Giske
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Riley M Whalen
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Naside Gozde Durmus
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Melissa H Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
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9
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Tajima Y, Shibasaki F, Masai H. Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance. Cancer Gene Ther 2024; 31:158-173. [PMID: 37990063 DOI: 10.1038/s41417-023-00693-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 10/22/2023] [Accepted: 11/07/2023] [Indexed: 11/23/2023]
Abstract
MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that ~5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high tumorigenicity. In eleven fusion cell clones that have been established, Mb-scale deletions carried by the bladder cancer cells are mostly absent in the fusion cells, but copy number gains contributed by the cancer cells have stayed. Fusion cells exhibit increased populations of mitotic cells with 3-polar spindles, indicative of genomic instability. They grow faster in vitro and exhibit higher colony formation in anchorage-independent growth assay in soft agar than the parent UMUC-3 does. Fusion cells develop tumors, after 4 weeks of time lag, as efficiently as the parent UMUC-3 does in xenograft experiments. 264 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that cause tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscore the efficacy of cancer immunotherapy.
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Affiliation(s)
- Youichi Tajima
- Genome Dynamics Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
| | - Futoshi Shibasaki
- Center for Medical Research Cooperation, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan
| | - Hisao Masai
- Genome Dynamics Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
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10
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Noubissi FK, Odubanjo OV, Ogle BM, Tchounwou PB. Mechanisms of Cell Fusion in Cancer. Results Probl Cell Differ 2024; 71:407-432. [PMID: 37996688 PMCID: PMC10893907 DOI: 10.1007/978-3-031-37936-9_19] [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] [Indexed: 11/25/2023]
Abstract
Cell-cell fusion is a normal physiological mechanism that requires a well-orchestrated regulation of intracellular and extracellular factors. Dysregulation of this process could lead to diseases such as osteoporosis, malformation of muscles, difficulties in pregnancy, and cancer. Extensive literature demonstrates that fusion occurs between cancer cells and other cell types to potentially promote cancer progression and metastasis. However, the mechanisms governing this process in cancer initiation, promotion, and progression are less well-studied. Fusogens involved in normal physiological processes such as syncytins and associated factors such as phosphatidylserine and annexins have been observed to be critical in cancer cell fusion as well. Some of the extracellular factors associated with cancer cell fusion include chronic inflammation and inflammatory cytokines, hypoxia, and viral infection. The interaction between these extracellular factors and cell's intrinsic factors potentially modulates actin dynamics to drive the fusion of cancer cells. In this review, we have discussed the different mechanisms that have been identified or postulated to drive cancer cell fusion.
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Affiliation(s)
- Felicite K Noubissi
- Department of Biology, Jackson State University, Jackson, MS, USA.
- Research Centers in Minority Institutions (RCMI), Center for Health Disparity Research (RCMI-CHDR), Jackson State University, Jackson, MS, USA.
| | - Oluwatoyin V Odubanjo
- Department of Biology, Jackson State University, Jackson, MS, USA
- Research Centers in Minority Institutions (RCMI), Center for Health Disparity Research (RCMI-CHDR), Jackson State University, Jackson, MS, USA
| | - Brenda M Ogle
- Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, MN, USA
- Department of Pediatrics, University of Minnesota-Twin Cities, Minneapolis, MN, USA
- Stem Cell Institute, University of Minnesota-Twin Cities, Minneapolis, MN, USA
| | - Paul B Tchounwou
- Department of Biology, Jackson State University, Jackson, MS, USA
- Research Centers in Minority Institutions (RCMI), Center for Health Disparity Research (RCMI-CHDR), Jackson State University, Jackson, MS, USA
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11
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Sieler M, Dittmar T. Cell Fusion and Syncytia Formation in Cancer. Results Probl Cell Differ 2024; 71:433-465. [PMID: 37996689 DOI: 10.1007/978-3-031-37936-9_20] [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: 11/25/2023]
Abstract
The natural phenomenon of cell-cell fusion does not only take place in physiological processes, such as placentation, myogenesis, or osteoclastogenesis, but also in pathophysiological processes, such as cancer. More than a century ago postulated, today the hypothesis that the fusion of cancer cells with normal cells leads to the formation of cancer hybrid cells with altered properties is in scientific consensus. Some studies that have investigated the mechanisms and conditions for the fusion of cancer cells with other cells, as well as studies that have characterized the resulting cancer hybrid cells, are presented in this review. Hypoxia and the cytokine TNFα, for example, have been found to promote cell fusion. In addition, it has been found that both the protein Syncytin-1, which normally plays a role in placentation, and phosphatidylserine signaling on the cell membrane are involved in the fusion of cancer cells with other cells. In human cancer, cancer hybrid cells were detected not only in the primary tumor, but also in the circulation of patients as so-called circulating hybrid cells, where they often correlated with a worse outcome. Although some data are available, the questions of how and especially why cancer cells fuse with other cells are still not fully answered.
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Affiliation(s)
- Mareike Sieler
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke, Witten, Germany.
| | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke, Witten, Germany
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12
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Kurup S, Tan C, Kume T. Cardiac and intestinal tissue conduct developmental and reparative processes in response to lymphangiocrine signaling. Front Cell Dev Biol 2023; 11:1329770. [PMID: 38178871 PMCID: PMC10764504 DOI: 10.3389/fcell.2023.1329770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 12/08/2023] [Indexed: 01/06/2024] Open
Abstract
Lymphatic vessels conduct a diverse range of activities to sustain the integrity of surrounding tissue. Besides facilitating the movement of lymph and its associated factors, lymphatic vessels are capable of producing tissue-specific responses to changes within their microenvironment. Lymphatic endothelial cells (LECs) secrete paracrine signals that bind to neighboring cell-receptors, commencing an intracellular signaling cascade that preludes modifications to the organ tissue's structure and function. While the lymphangiocrine factors and the molecular and cellular mechanisms themselves are specific to the organ tissue, the crosstalk action between LECs and adjacent cells has been highlighted as a commonality in augmenting tissue regeneration within animal models of cardiac and intestinal disease. Lymphangiocrine secretions have been owed for subsequent improvements in organ function by optimizing the clearance of excess tissue fluid and immune cells and stimulating favorable tissue growth, whereas perturbations in lymphatic performance bring about the opposite. Newly published landmark studies have filled gaps in our understanding of cardiac and intestinal maintenance by revealing key players for lymphangiocrine processes. Here, we will expand upon those findings and review the nature of lymphangiocrine factors in the heart and intestine, emphasizing its involvement within an interconnected network that supports daily homeostasis and self-renewal following injury.
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Affiliation(s)
- Shreya Kurup
- Department of Medicine, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Honors College, University of Illinois at Chicago, Chicago, IL, United States
| | - Can Tan
- Department of Medicine, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Tsutomu Kume
- Department of Medicine, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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13
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Dittmar T, Sieler M, Hass R. Why do certain cancer cells alter functionality and fuse? Biol Chem 2023; 404:951-960. [PMID: 37246410 DOI: 10.1515/hsz-2023-0162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/11/2023] [Indexed: 05/30/2023]
Abstract
Cancer cell fusion represents a rare event. However, the surviving cancer hybrid cells after a post-hybrid selection process (PHSP) can overgrow other cancer cells by exhibiting a proliferation advantage and/or expression of cancer stem-like properties. Addition of new tumor properties during hetero-fusion of cancer cells e.g. with mesenchymal stroma-/stem-like cells (MSC) contribute to enhanced tumor plasticity via acquisition of new/altered functionalities. This provides new avenues for tumor development and metastatic behavior. Consequently, the present review article will also address the question as to whether cancer cell fusion represents a general and possibly evolutionary-conserved program or rather a random process?
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Affiliation(s)
- Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, D-58448 Witten, Germany
| | - Mareike Sieler
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, D-58448 Witten, Germany
| | - Ralf Hass
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, D-30625 Hannover, Germany
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14
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Niu N, Ye J, Hu Z, Zhang J, Wang Y. Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis. Int J Mol Sci 2023; 24:ijms24087076. [PMID: 37108242 PMCID: PMC10139088 DOI: 10.3390/ijms24087076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.
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Affiliation(s)
- Nan Niu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
- College of Physics and Optoelectronic Engineering, Canghai Campus of Shenzhen University, Shenzhen 518060, China
| | - Jinfeng Ye
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Zhangli Hu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Junbin Zhang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Yun Wang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
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15
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Dittmar T, Hass R. Intrinsic signalling factors associated with cancer cell-cell fusion. Cell Commun Signal 2023; 21:68. [PMID: 37016404 PMCID: PMC10071245 DOI: 10.1186/s12964-023-01085-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 02/21/2023] [Indexed: 04/06/2023] Open
Abstract
Cellular fusion e.g. between cancer cells and normal cells represents a stepwise process that is tightly regulated. During a pre-hybrid preparation program somatic cells and/or cancer cells are promoted to a pro-fusogenic state as a prerequisite to prepare a fusion process. A pro-fusogenic state requires significant changes including restructure of the cytoskeleton, e.g., by the formation of F-actin. Moreover, distinct plasma membrane lipids such as phosphatidylserine play an important role during cell fusion. In addition, the expression of distinct fusogenic factors such as syncytins and corresponding receptors are of fundamental importance to enable cellular mergers. Subsequent hybrid formation and fusion are followed by a post-hybrid selection process. Fusion among normal cells is important and often required during organismal development. Cancer cells fusion appears more rarely and is associated with the generation of new cancer hybrid cell populations. These cancer hybrid cells contribute to an elevated tumour plasticity by altered metastatic behaviour, changes in therapeutic and apoptotic responses, and even in the formation of cancer stem/ initiating cells. While many parts within this multi-step cascade are still poorly understood, this review article predominantly focusses on the intracellular necessities for fusion among cancer cells or with other cell populations of the tumour microenvironment. Video Abstract.
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Affiliation(s)
- Thomas Dittmar
- Institute of Immunology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany.
| | - Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynaecology, Hannover Medical School, 30625, Hannover, Germany.
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16
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Sutton TL, Patel RK, Anderson AN, Bowden SG, Whalen R, Giske NR, Wong MH. Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer. Cancers (Basel) 2022; 14:cancers14163871. [PMID: 36010865 PMCID: PMC9405966 DOI: 10.3390/cancers14163871] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary In cancer, disseminated neoplastic cells circulating in blood are a source of tumor DNA, RNA, and protein, which can be harnessed to diagnose, monitor, and better understand the biology of the tumor from which they are derived. Historically, circulating tumor cells (CTCs) have dominated this field of study. While CTCs are shed directly into circulation from a primary tumor, they remain relatively rare, particularly in early stages of disease, and thus are difficult to utilize as a reliable cancer biomarker. Neoplastic-immune hybrid cells represent a novel subpopulation of circulating cells that are more reliably attainable as compared to their CTC counterparts. Here, we review two recently identified circulating cell populations in cancer—cancer-associated macrophage-like cells and circulating hybrid cells—and discuss the future impact for the exciting area of disseminated hybrid cells. Abstract Cancer remains a significant cause of mortality in developed countries, due in part to difficulties in early detection, understanding disease biology, and assessing treatment response. If effectively harnessed, circulating biomarkers promise to fulfill these needs through non-invasive “liquid” biopsy. While tumors disseminate genetic material and cellular debris into circulation, identifying clinically relevant information from these analytes has proven difficult. In contrast, cell-based circulating biomarkers have multiple advantages, including a source for tumor DNA and protein, and as a cellular reflection of the evolving tumor. While circulating tumor cells (CTCs) have dominated the circulating cell biomarker field, their clinical utility beyond that of prognostication has remained elusive, due to their rarity. Recently, two novel populations of circulating tumor-immune hybrid cells in cancer have been characterized: cancer-associated macrophage-like cells (CAMLs) and circulating hybrid cells (CHCs). CAMLs are macrophage-like cells containing phagocytosed tumor material, while CHCs can result from cell fusion between cancer and immune cells and play a role in the metastatic cascade. Both are detected in higher numbers than CTCs in peripheral blood and demonstrate utility in prognostication and assessing treatment response. Additionally, both cell populations are heterogeneous in their genetic, transcriptomic, and proteomic signatures, and thus have the potential to inform on heterogeneity within tumors. Herein, we review the advances in this exciting field.
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Affiliation(s)
- Thomas L. Sutton
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Ranish K. Patel
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Ashley N. Anderson
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Stephen G. Bowden
- Department of Neurological Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Riley Whalen
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Nicole R. Giske
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Correspondence: ; Tel.: +1-503-494-8749; Fax: +1-503-494-4253
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17
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Che Z, Ye Z, Zhang X, Lin B, Yang W, Liang Y, Zeng J. Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases. Front Immunol 2022; 13:952071. [PMID: 35990688 PMCID: PMC9386516 DOI: 10.3389/fimmu.2022.952071] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/12/2022] [Indexed: 12/02/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) represent a group of chronic inflammatory disorders of the gastrointestinal (GI) tract including ulcerative colitis (UC), Crohn’s disease (CD), and unclassified IBDs. The pathogenesis of IBDs is related to genetic susceptibility, environmental factors, and dysbiosis that can lead to the dysfunction of immune responses and dysregulated homeostasis of local mucosal tissues characterized by severe inflammatory responses and tissue damage in GI tract. To date, extensive studies have indicated that IBDs cannot be completely cured and easy to relapse, thus prompting researchers to find novel and more effective therapeutics for this disease. Due to their potent multipotent differentiation and immunomodulatory capabilities, mesenchymal stem/stromal cells (MSCs) not only play an important role in regulating immune and tissue homeostasis but also display potent therapeutic effects on various inflammatory diseases, including IBDs, in both preclinical and clinical studies. In this review, we present a comprehensive overview on the pathological mechanisms, the currently available therapeutics, particularly, the potential application of MSCs-based regenerative therapy for IBDs.
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Affiliation(s)
- Zhengping Che
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Ziyu Ye
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xueying Zhang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Bihua Lin
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, School of Basic Medicine, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
| | - Weiqing Yang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yanfang Liang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- *Correspondence: Jincheng Zeng, ; Yanfang Liang,
| | - Jincheng Zeng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, School of Basic Medicine, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
- Dongguan Metabolite Analysis Engineering Technology Center of Cells for Medical Use, Guangdong Xinghai Institute of Cell, Dongguan, China
- *Correspondence: Jincheng Zeng, ; Yanfang Liang,
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18
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Cao Q, Mertens RT, Sivanathan KN, Cai X, Xiao P. Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine. J Leukoc Biol 2022; 112:313-331. [PMID: 35593111 PMCID: PMC9543232 DOI: 10.1002/jlb.3ru0322-176r] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/06/2022] Open
Abstract
The intestinal tract is a complex ecosystem where numerous cell types of epithelial, immune, neuronal, and endothelial origin coexist in an intertwined, highly organized manner. The functional equilibrium of the intestine relies heavily on the proper crosstalk and cooperation among each cell population. Furthermore, macrophages are versatile, innate immune cells that participate widely in the modulation of inflammation and tissue remodeling. Emerging evidence suggest that macrophages are central in orchestrating tissue homeostasis. Herein, we describe how macrophages interact with epithelial cells, neurons, and other types of mesenchymal cells under the context of intestinal inflammation, followed by the therapeutic implications of cellular crosstalk pertaining to the treatment of inflammatory bowel disease.
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Affiliation(s)
- Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Randall Tyler Mertens
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kisha Nandini Sivanathan
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Xuechun Cai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.,The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
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19
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Belansky J, Yelin D. Optimization study of plasmonic cell fusion. Sci Rep 2022; 12:7159. [PMID: 35504928 PMCID: PMC9065096 DOI: 10.1038/s41598-022-11168-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 04/07/2022] [Indexed: 11/28/2022] Open
Abstract
Artificial cell fusion often serves as a valuable tool for studying different applications in biology and medicine, including natural development, immune response, cancer metastasis and production of therapeutic molecules. Plasmonic cell fusion, a technique that uses specific cell labeling by gold nanoparticles and resonant femtosecond pulse irradiation for fusing neighboring cells, has been demonstrated useful for such applications, allowing high cell specificity and an overall low toxicity. Despite these advantages, the numerous experimental factors contributing to plasmonic fusion have often led to subpar fusion efficiencies, requiring repeated experiments and extensive calibration protocols for achieving optimal results. In this work we present a study that aims to improve the overall performance of plasmonic cell fusion in terms of fusion efficiency and cell viability. By varying the pulse fluence, nanoparticle concentration, incubation times, and culture handling protocols, we demonstrate up to 100% fusion of malignant epithelial cells across the entire irradiated area of the culture. We also show that some of the smaller cells may stay viable for up to several days. The results would allow plasmonic fusion to play a key role in numerous studies and applications that require specific, high-efficiency cell-cell fusion.
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Affiliation(s)
- Julia Belansky
- Russel Berrie Nanotechnology Institute, Technion, 32000, Haifa, Israel
| | - Dvir Yelin
- Faculty of Biomedical Engineering, Technion, 32000, Haifa, Israel.
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20
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Generation of Cancer Stem/Initiating Cells by Cell-Cell Fusion. Int J Mol Sci 2022; 23:ijms23094514. [PMID: 35562905 PMCID: PMC9101717 DOI: 10.3390/ijms23094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.
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21
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Lee J, Ung A, Kim H, Lee K, Cho HJ, Bandaru P, Ahadian S, Dokmeci MR, Khademhosseini A. Engineering liver microtissues to study the fusion of HepG2 with mesenchymal stem cells and invasive potential of fused cells. Biofabrication 2021; 14. [PMID: 34740205 DOI: 10.1088/1758-5090/ac36de] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/05/2021] [Indexed: 12/26/2022]
Abstract
Increasing evidence from cancer cell fusion with different cell types in the tumor microenvironment has suggested a probable mechanism for how metastasis-initiating cells could be generated in tumors. Although human mesenchymal stem cells (hMSCs) have been known as promising candidates to create hybrid cells with cancer cells, the role of hMSCs in fusion with cancer cells is still controversial. Here, we fabricated a liver-on-a-chip platform to monitor the fusion of liver hepatocellular cells (HepG2) with hMSCs and study their invasive potential. We demonstrated that hMSCs might play dual roles in HepG2 spheroids. The analysis of tumor growth with different fractions of hMSCs in HepG2 spheroids revealed hMSCs' role in preventing HepG2 growth and proliferation, while the hMSCs presented in the HepG2 spheroids led to the generation of HepG2-hMSC hybrid cells with much higher invasiveness compared to HepG2. These invasive HepG2-hMSC hybrid cells expressed high levels of markers associated with stemness, proliferation, epithelial to mesenchymal transition, and matrix deposition, which corresponded to the expression of these markers for hMSCs escaping from hMSC spheroids. In addition, these fused cells were responsible for collective invasion following HepG2 by depositing Collagen I and Fibronectin in their surrounding microenvironment. Furthermore, we showed that hepatic stellate cells (HSCs) could also be fused with HepG2, and the HepG2-HSC hybrid cells possessed similar features to those from HepG2-hMSC fusion. This fusion of HepG2 with liver-resident HSCs may propose a new potential mechanism of hepatic cancer metastasis.
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Affiliation(s)
- Junmin Lee
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.,Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America
| | - Aly Ung
- Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America
| | - Hanjun Kim
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America
| | - KangJu Lee
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America.,School of Healthcare and Biomedical Engineering, Chonnam National University, Yeosu, 59626, Republic of Korea
| | - Hyun-Jong Cho
- Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America.,College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Praveen Bandaru
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America
| | - Samad Ahadian
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America
| | - Mehmet R Dokmeci
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America.,Department of Radiological Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America
| | - Ali Khademhosseini
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America.,Department of Radiological Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America.,Department of Chemical and Biomolecular Engineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA 90095, United States of America.,Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA 90095, United States of America
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22
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Dietz MS, Sutton TL, Walker BS, Gast CE, Zarour L, Sengupta SK, Swain JR, Eng J, Parappilly M, Limbach K, Sattler A, Burlingame E, Chin Y, Gower A, Mira JLM, Sapre A, Chiu YJ, Clayburgh DR, Pommier SJ, Cetnar JP, Fischer JM, Jaboin JJ, Pommier RF, Sheppard BC, Tsikitis VL, Skalet AH, Mayo SC, Lopez CD, Gray JW, Mills GB, Mitri Z, Chang YH, Chin K, Wong MH. Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors. Sci Rep 2021; 11:13630. [PMID: 34211050 PMCID: PMC8249418 DOI: 10.1038/s41598-021-93053-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/09/2021] [Indexed: 02/06/2023] Open
Abstract
Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the potential to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.
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Affiliation(s)
- Matthew S Dietz
- Department of Pediatrics, Oregon Health & Science University (OHSU), Portland, OR, 97239, USA.,Department of Pediatrics, University of Utah, Salt Lake City, UT, 84113, USA
| | | | | | - Charles E Gast
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Luai Zarour
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,Department of General Surgery, Legacy Medical Group, Gresham, OR, 97030, USA
| | - Sidharth K Sengupta
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - John R Swain
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Jennifer Eng
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA
| | - Michael Parappilly
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | | | - Ariana Sattler
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Erik Burlingame
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,Computational Biology Program, OHSU, Portland, OR, 97239, USA
| | - Yuki Chin
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Austin Gower
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Jose L Montoya Mira
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Ajay Sapre
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Yu-Jui Chiu
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Daniel R Clayburgh
- Department of Otolaryngology, OHSU, Portland, OR, 97239, USA.,Operative Care Division, Portland Veterans Affairs Medical Center, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | | | - Jeremy P Cetnar
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Medicine, OHSU, Portland, OR, 97239, USA
| | - Jared M Fischer
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Molecule and Medical Genetics, OHSU, Portland, OR, 97239, USA
| | - Jerry J Jaboin
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Radiation Medicine, OHSU, Portland, OR, 97239, USA
| | - Rodney F Pommier
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Brett C Sheppard
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | | | - Alison H Skalet
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Casey Eye Institute, OHSU, Portland, OR, 97239, USA
| | - Skye C Mayo
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Charles D Lopez
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Medicine, OHSU, Portland, OR, 97239, USA
| | - Joe W Gray
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Gordon B Mills
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Zahi Mitri
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Medicine, OHSU, Portland, OR, 97239, USA
| | - Young Hwan Chang
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,Computational Biology Program, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Koei Chin
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Melissa H Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA. .,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.
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23
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Wang HF, Xiang W, Xue BZ, Wang YH, Yi DY, Jiang XB, Zhao HY, Fu P. Cell fusion in cancer hallmarks: Current research status and future indications. Oncol Lett 2021; 22:530. [PMID: 34055095 PMCID: PMC8138896 DOI: 10.3892/ol.2021.12791] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 04/09/2021] [Indexed: 12/13/2022] Open
Abstract
Cell fusion is involved in several physiological processes, such as reproduction, development and immunity. Although cell fusion in tumors was reported 130 years ago, it has recently attracted great interest, with recent progress in tumorigenesis research. However, the role of cell fusion in tumor progression remains unclear. The pattern of cell fusion and its role under physiological conditions are the basis for our understanding of the pathological role of cell fusion. However, the role of cell fusion in tumors and its functions are complicated. Cell fusion can directly increase tumor heterogeneity by forming polyploids or aneuploidies. Several studies have reported that cell fusion is associated with tumorigenesis, metastasis, recurrence, drug resistance and the formation of cancer stem cells. Given the diverse roles cell fusion plays in different tumor phenotypes, methods based on targeted cell fusion have been designed to treat tumors. Research on cell fusion in tumors may provide novel ideas for further treatment.
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Affiliation(s)
- Hao-Fei Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Wei Xiang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Bing-Zhou Xue
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yi-Hao Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Dong-Ye Yi
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xiao-Bing Jiang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Hong-Yang Zhao
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Peng Fu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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24
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Cwykiel J, Jundzill A, Klimczak A, Madajka-Niemeyer M, Siemionow M. Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts. Arch Immunol Ther Exp (Warsz) 2021; 69:13. [PMID: 33970329 PMCID: PMC8110509 DOI: 10.1007/s00005-021-00614-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/08/2021] [Indexed: 11/30/2022]
Abstract
This study evaluated the efficacy of donor recipient chimeric cell (DRCC) therapy created by fusion of donor and recipient derived bone marrow cells (BMC) in chimerism and tolerance induction in a rat vascularized composite allograft (VCA) model. Twenty-four VCA (groin flaps) from MHC-mismatched ACI (RT1a) donors were transplanted to Lewis (RT1l) recipients. Rats were randomly divided into (n = 6/group): Group 1—untreated controls, Groups 2—7-day immunosuppression controls, Group 3—DRCC, and Group 4—DRCC with 7-day anti-αβTCR monoclonal antibody and cyclosporine A protocol. DRCC created by polyethylene glycol-mediated fusion of ACI and Lewis BMC were cultured and transplanted (2–4 × 106) to VCA recipients via intraosseous delivery route. Flow cytometry assessed peripheral blood chimerism while fluorescent microscopy and PCR tested the presence of DRCC in the recipient’s blood, bone marrow (BM), and lymphoid organs at the study endpoint (VCA rejection). No complications were observed after DRCC intraosseous delivery. Group 4 presented the longest average VCA survival (79.3 ± 30.9 days) followed by Group 2 (53.3 ± 13.6 days), Group 3 (18 ± 7.5 days), and Group 1 (8.5 ± 1 days). The highest chimerism level was detected in Group 4 (57.9 ± 6.2%) at day 7 post-transplant. The chimerism declined at day 21 post-transplant and remained at 10% level during the entire follow-up period. Single dose of DRCC therapy induced long-term multilineage chimerism and extended VCA survival. DRCC introduces a novel concept of customized donor-recipient cell-based therapy supporting solid organ and VCA transplants.
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Affiliation(s)
- Joanna Cwykiel
- Department of Orthopaedics, University of Illinois At Chicago, Molecular Biology Research Building, 900 S. Ashland Ave. Room# 3356, Chicago, IL, 60607, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Arkadiusz Jundzill
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,Chair of Urology, Department of Regenerative Medicine, Nicolaus Copernicus University in Torun, Ludwik Rydygier Medical College in Bydgoszcz, Bydgoszcz, Poland.,Department of Plastic, Reconstructive and Aesthetic Surgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Aleksandra Klimczak
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | | | - Maria Siemionow
- Department of Orthopaedics, University of Illinois At Chicago, Molecular Biology Research Building, 900 S. Ashland Ave. Room# 3356, Chicago, IL, 60607, USA. .,Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA. .,Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland.
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25
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Cwykiel J, Madajka-Niemeyer M, Siemionow M. Development of Donor Recipient Chimeric Cells of bone marrow origin as a novel approach for tolerance induction in transplantation. Stem Cell Investig 2021; 8:8. [PMID: 33969113 DOI: 10.21037/sci-2020-044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Background Cell therapies and chimerism-based strategies are currently the most successful approach for tolerance induction in transplantation. This study aimed to establish and characterize novel Donor Recipient Chimeric Ccell (DRCC) therapy of bone marrow (BM) origin presenting donor-recipient phenotype to support tolerance induction. Methods Ex vivo fusions of fully MHC-mismatched BM cells from ACI (RT1a) and Lewis (RT1l) rats were performed using polyethylene-glycol (PEG). The creation of rat DRCC was tested by flow cytometry (FC), confocal microscopy and PCR. FC characterized DRCC's phenotype (CD3, CD4, CD8, CD45, CD90, CD11b/c, CD45RA, OX-82, or CD4/CD25) and apoptosis, while mixed lymphocyte reaction assessed DRCC's immunogenicity and colony forming unit assay tested DRCC's differentiation and proliferation. DRCC's polyploidy was evaluated using Hoechst33342 staining and COMET assay tested genotoxicity of fusion procedure. ELISA analyzed the secretion of IL-2, IL-4, IL-10, TGFß1, IFNγ and TNFα by DRCC at day 1, 5 and 14 post-fusion. The DRCC's phenotype after long-term culturing was assessed by reverse-transcription PCR. Results The chimeric state of DRCC was confirmed. Fusion did not change the expression of hematopoietic markers compared to BM controls. Although an increased number of early and late apoptotic (Annexin V+/Sytox blue- and Annexin V+/Sytox blue+, respectively) DRCC was detected at 24h post-fusion, the number significantly decreased at day 5 (38.4%±3.1% and 22.6%±2.5%, vs. 28.3%±2.5% and 13.9%±2.6%, respectively, P<0.05). DRCC presented decreased immunogenicity, increased expression of IL-10 and TGFβ1 and proliferative potential comparable to BM controls. The average percentage of tetraploid DRCC was 3.1%±0.2% compared to 0.96%±0.1% in BM controls. The lack of damage to the DRCC's DNA content supported the DRCC's safety. In culture, DRCC maintained proliferation for up to 28 days while preserving hematopoietic profile. Conclusions This study confirmed feasibility of DRCC creation via ex vivo PEG mediated fusion. The created DRCC revealed pro-tolerogenic properties indicating potential immunomodulatory effect of DRCC therapy when applied in vivo to support tolerance induction in solid organ and vascularized composite allograft transplantation.
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Affiliation(s)
- Joanna Cwykiel
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland
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26
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Cell-cell fusions and cell-in-cell phenomena in healthy cells and cancer: Lessons from protists and invertebrates. Semin Cancer Biol 2021; 81:96-105. [PMID: 33713795 DOI: 10.1016/j.semcancer.2021.03.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/28/2021] [Accepted: 03/04/2021] [Indexed: 02/08/2023]
Abstract
Herein we analyze two special routes of the multinucleated cells' formation - the fusion of mononuclear cells and the formation of cell-in-cell structures - in the healthy tissues and in tumorigenesis. There are many theories of tumorigenesis based on the phenomenon of emergence of the hybrid cancer cells. We consider the phenomena, which are rarely mentioned in those theories: namely, cellularization of syncytium or coenocytes, and the reversible or irreversible somatogamy. The latter includes the short-term and the long-term vegetative (somatic) cells' fusions in the life cycles of unicellular organisms. The somatogamy and multinuclearity have repeatedly and independently emerged in various groups of unicellular eukaryotes. These phenomena are among dominant survival and biodiversity sustaining strategies in protists and we admit that they can likely play an analogous role in cancer cells.
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27
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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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28
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Liang W, Chen X, Zhang S, Fang J, Chen M, Xu Y, Chen X. Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines. Cell Mol Biol Lett 2021; 26:3. [PMID: 33472580 PMCID: PMC7818947 DOI: 10.1186/s11658-020-00246-5] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/27/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial-mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.
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Affiliation(s)
- Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan, 316000, Zhejiang, People's Republic of China.
| | - Xiaozhen Chen
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Songou Zhang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Jian Fang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Meikai Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Yifan Xu
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Xuerong Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
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29
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Wilkinson PD, Duncan AW. Differential Roles for Diploid and Polyploid Hepatocytes in Acute and Chronic Liver Injury. Semin Liver Dis 2021; 41:42-49. [PMID: 33764484 PMCID: PMC8056861 DOI: 10.1055/s-0040-1719175] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocytes are the primary functional cells of the liver that perform essential roles in homeostasis, regeneration, and injury. Most mammalian somatic cells are diploid and contain pairs of each chromosome, but there are also polyploid cells containing additional sets of chromosomes. Hepatocytes are among the best described polyploid cells, with polyploids comprising more than 25 and 90% of the hepatocyte population in humans and mice, respectively. Cellular and molecular mechanisms that regulate hepatic polyploidy have been uncovered, and in recent years, diploid and polyploid hepatocytes have been shown to perform specialized functions. Diploid hepatocytes accelerate liver regeneration induced by resection and may accelerate compensatory regeneration after acute injury. Polyploid hepatocytes protect the liver from tumor initiation in hepatocellular carcinoma and promote adaptation to tyrosinemia-induced chronic injury. This review describes how ploidy variations influence cellular activity and presents a model for context-specific functions for diploid and polyploid hepatocytes.
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Affiliation(s)
- Patrick D Wilkinson
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Andrew W Duncan
- Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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30
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Liu C, Billet S, Choudhury D, Cheng R, Haldar S, Fernandez A, Biondi S, Liu Z, Zhou H, Bhowmick NA. Bone marrow mesenchymal stem cells interact with head and neck squamous cell carcinoma cells to promote cancer progression and drug resistance. Neoplasia 2021; 23:118-128. [PMID: 33310208 PMCID: PMC7732973 DOI: 10.1016/j.neo.2020.11.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/19/2020] [Accepted: 11/25/2020] [Indexed: 02/05/2023]
Abstract
Head and neck cancers are often diagnosed at later stages with poor outcomes. Mesenchymal stem cells (MSC) are recruited to primary tumor sites where they can have pro- and antitumorigenic influence. In trying to better understand the dynamics between MSC and cancer cells, we found that head and neck cancer-MSC exposure resulted in mesenchymal features, elevated proliferation rate, and were more motile, like the same cells that fused with MSC. We orthotopically grafted the parental head and neck cancer cells, those fused with MSC, or those exposed to MSC into the tongues of mice. The cancer cells originally incubated with MSC developed larger more aggressive tumors compared to the parental cell line. RNA sequencing analysis revealed the expression of genes associated with drug resistance in the cancer cells exposed to MSC compared to parental cancer cells. Strikingly, MSC exposed cancer cell lines developed paclitaxel resistance that could be maintained up to 30 d after the initial co-incubation period. The secretory profile of the MSC suggested IL-6 to be a potential mediator of epigenetic imprinting on the head and neck cancer cells. When the MSC-imprinted cancer cells were exposed to the demethylation agent, 5-aza-2'deoxycytidine, it restored the expression of the drug resistance genes to that of parental cells. This study demonstrated that the recognized recruitment of MSC to tumors could impart multiple protumorigenic properties including chemotherapy resistance like that observed in the relatively rare event of cancer/MSC cell fusion.
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Affiliation(s)
- Chuanxia Liu
- State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; The Affiliated Stomatology Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Sandrine Billet
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Diptiman Choudhury
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ran Cheng
- State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Subhash Haldar
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ana Fernandez
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Shea Biondi
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Zhenqiu Liu
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
| | - Neil A Bhowmick
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
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31
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Ramadan R, Vermeulen L. Confusion on Cell Fusion. Cell Mol Gastroenterol Hepatol 2020; 11:304-306. [PMID: 33191154 PMCID: PMC7768611 DOI: 10.1016/j.jcmgh.2020.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/28/2020] [Accepted: 07/20/2020] [Indexed: 12/10/2022]
Affiliation(s)
| | - Louis Vermeulen
- Correspondence Address correspondence to: Louis Vermeulen, PhD, Amsterdam University Medical Centers, Laboratory for Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
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32
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Digesting the Importance of Cell Fusion in the Intestine. Cell Mol Gastroenterol Hepatol 2020; 11:299-302. [PMID: 33068773 PMCID: PMC7768557 DOI: 10.1016/j.jcmgh.2020.07.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/15/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022]
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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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Abstract
Polyploidy (or whole-genome duplication) is the condition of having more than two basic sets of chromosomes. Polyploidization is well tolerated in many species and can lead to specific biological functions. In mammals, programmed polyploidization takes place during development in certain tissues, such as the heart and placenta, and is considered a feature of differentiation. However, unscheduled polyploidization can cause genomic instability and has been observed in pathological conditions, such as cancer. Polyploidy of the liver parenchyma was first described more than 100 years ago. The liver is one of the few mammalian organs that display changes in polyploidy during homeostasis, regeneration and in response to damage. In the human liver, approximately 30% of hepatocytes are polyploid. The polyploidy of hepatocytes results from both nuclear polyploidy (an increase in the amount of DNA per nucleus) and cellular polyploidy (an increase in the number of nuclei per cell). In this Review, we discuss the regulation of polyploidy in liver development and pathophysiology. We also provide an overview of current knowledge about the mechanisms of hepatocyte polyploidization, its biological importance and the fate of polyploid hepatocytes during liver tumorigenesis.
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35
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Genome remodeling upon mesenchymal tumor cell fusion contributes to tumor progression and metastatic spread. Oncogene 2020; 39:4198-4211. [PMID: 32242148 DOI: 10.1038/s41388-020-1276-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/12/2020] [Accepted: 03/13/2020] [Indexed: 12/17/2022]
Abstract
Cell fusion in tumor progression mostly refers to the merging of a cancer cell with a cell that has migration and immune escape capabilities such as macrophages. Here we show that spontaneous hybrids made from the fusion of transformed mesenchymal cells with partners from the same lineage undergo nonrecurrent large-scale genomic rearrangements, leading to the creation of highly aneuploid cells with novel phenotypic traits, including metastatic spreading capabilities. Moreover, in contrast to their parents, hybrids were the only cells able to recapitulate in vivo all features of human pleomorphic sarcomas, a rare and genetically complex mesenchymal tumor. Hybrid tumors not only displayed specific mesenchymal markers, but also combined a complex genetic profile with a highly metastatic behavior, like their human counterparts. Finally, we provide evidence that patient-derived pleomorphic sarcoma cells are inclined to spontaneous cell fusion. The resulting hybrids also gain in aggressiveness, exhibiting superior growth capacity in mouse models. Altogether, these results indicate that cell fusion has the potential to promote cancer progression by increasing growth and/or metastatic capacities, regardless of the nature of the companion cell. Moreover, such events likely occur upon sarcoma development, paving the way for better understanding of the biology, and aggressiveness of these tumors.
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36
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Eom YW, Kang SH, Kim MY, Lee JI, Baik SK. Mesenchymal stem cells to treat liver diseases. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:563. [PMID: 32775364 PMCID: PMC7347787 DOI: 10.21037/atm.2020.02.163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are being developed for stem cell therapy and can be efficiently used in regenerative medicine. To date, more than 1,000 clinical trials have used MSCs; of these, more than 80 clinical trials have targeted liver disease. MSCs migrate to damaged liver tissues, differentiate into hepatocytes, reduce liver inflammatory responses, reduce liver fibrosis, and act as antioxidants. According to the reported literature, MSCs are safe, have no side effects, and improve liver function; however, their regenerative therapeutic effects are unsatisfactory. Here, we explain, in detail, the basic therapeutic effects and recent clinical advances of MSCs. Furthermore, we discuss future research directions for improving the regenerative therapeutic effects of MSCs.
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Affiliation(s)
- Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seong Hee Kang
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jong In Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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37
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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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38
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Shabo I, Svanvik J, Lindström A, Lechertier T, Trabulo S, Hulit J, Sparey T, Pawelek J. Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis. World J Clin Oncol 2020; 11:121-135. [PMID: 32257843 PMCID: PMC7103524 DOI: 10.5306/wjco.v11.i3.121] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/02/2020] [Accepted: 03/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE 171 77, Sweden
- Patient Area of Breast Cancer, Sarcoma and Endocrine Tumours, Theme Cancer, Karolinska University Hospital, Stockholm SE 171 76, Sweden
| | - Joar Svanvik
- The Transplant Institute, Sahlgrenska University Hospital, Gothenburg SE 413 45, Sweden
- Division of Surgery, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 83, Sweden
| | - Annelie Lindström
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 85, Sweden
| | - Tanguy Lechertier
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Sara Trabulo
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - James Hulit
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Tim Sparey
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - John Pawelek
- Department of Dermatology and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
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39
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Dörnen J, Sieler M, Weiler J, Keil S, Dittmar T. Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy. Int J Mol Sci 2020; 21:E1811. [PMID: 32155721 PMCID: PMC7084716 DOI: 10.3390/ijms21051811] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 12/20/2022] Open
Abstract
The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed that bone marrow-derived stem cells (BMSCs) could adopt the specific properties of a different organ by cell fusion, thereby restoring organ function. Cell fusion first results in the production of bi- or multinucleated hybrid cells, which either remain as heterokaryons or undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST), thereby giving rise to mononucleated daughter cells. This process is characterized by a merging of the chromosomes from the previously discrete nuclei and their subsequent random segregation into daughter cells. Due to extra centrosomes concomitant with multipolar spindles, the ploidy reduction/HST could also be associated with chromosome missegregation and, hence, induction of aneuploidy, genomic instability, and even putative chromothripsis. However, while the majority of such hybrids die or become senescent, aneuploidy and genomic instability appear to be tolerated in hepatocytes, possibly for stress-related adaption processes. Likewise, cell fusion-induced aneuploidy and genomic instability could also lead to a malignant conversion of hybrid cells. This can occur during tissue regeneration mediated by BMSC fusion in chronically inflamed tissue, which is a cell fusion-friendly environment, but is also enriched for mutagenic reactive oxygen and nitrogen species.
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Affiliation(s)
| | | | | | | | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany; (J.D.); (M.S.); (J.W.); (S.K.)
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40
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Oliveira MN, Breznik B, Pillat MM, Pereira RL, Ulrich H, Lah TT. Kinins in Glioblastoma Microenvironment. CANCER MICROENVIRONMENT 2019; 12:77-94. [PMID: 31420805 DOI: 10.1007/s12307-019-00229-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/29/2019] [Indexed: 12/16/2022]
Abstract
Tumour progression involves interactions among various cancer cell clones, including the cancer stem cell subpopulation and exogenous cellular components, termed cancer stromal cells. The latter include a plethora of tumour infiltrating immunocompetent cells, among which are also immuno-modulatory mesenchymal stem cells, which by vigorous migration to growing tumours and susequent transdifferentiation into various types of tumour-residing stromal cells, may either inhibit or support tumour progression. In the light of the scarce therapeutic options existing for the most malignant brain tumour glioblastoma, mesenchymal stem cells may represent a promising novel tool for cell therapy, e.g. drug delivery vectors. Here, we review the increasing number of reports on mutual interactions between mesenchymal stem cells and glioblastoma cells in their microenvironment. We particularly point out two novel aspects: the different responses of cancer cells to their microenvironmental cues, and to the signalling by kinin receptors that complement the immuno-modulating cytokine-signalling networks. Inflammatory glioblastoma microenvironment is characterised by increasing expression of kinin receptors during progressive glioma malignancy, thus making kinin signalling and kinins themselves rather important in this context. In general, their role in tumour microenvironment has not been explored so far. In addition, kinins also regulate blood brain barrier-related drug transfer as well as brain tumour angiogenesis. These studies support the on-going research on kinin antagonists as candidates in the development of anti-invasive agents for adjuvant glioblastoma therapy.
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Affiliation(s)
- Mona N Oliveira
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineus Prestes 748, São Paulo, SP, 05508-000, Brazil.,Jožef Stefan International Postgraduate School, Jamova, 39 1000, Ljubljana, Slovenia
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia.
| | - Micheli M Pillat
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineus Prestes 748, São Paulo, SP, 05508-000, Brazil
| | - Ricardo L Pereira
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineus Prestes 748, São Paulo, SP, 05508-000, Brazil
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineus Prestes 748, São Paulo, SP, 05508-000, Brazil
| | - Tamara T Lah
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia.,Department of Biochemistry, Faculty of Chemistry and Chemical Engineering, University of Ljubljana, Večna pot 113, 1000, Ljubljana, Slovenia
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41
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Circulating Hybrid Cells Join the Fray of Circulating Cellular Biomarkers. Cell Mol Gastroenterol Hepatol 2019; 8:595-607. [PMID: 31319228 PMCID: PMC6889578 DOI: 10.1016/j.jcmgh.2019.07.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 07/03/2019] [Accepted: 07/05/2019] [Indexed: 12/11/2022]
Abstract
Gastrointestinal cancers account for more cancer-related deaths than any other organ system, owing in part to difficulties in early detection, treatment response assessment, and post-treatment surveillance. Circulating biomarkers hold the promise for noninvasive liquid biopsy platforms to overcome these obstacles. Although tumors shed detectable levels of degraded genetic material and cellular debris into peripheral blood, identifying reproducible and clinically relevant information from these analytes (eg, cell-free nucleotides, exosomes, proteins) has proven difficult. Cell-based circulating biomarkers also present challenges, but have multiple advantages including allowing for a more comprehensive tumor analysis, and communicating the risk of metastatic spread. Circulating tumor cells have dominated the cancer cell biomarker field with robust evidence in extraintestinal cancers; however, establishing their clinical utility beyond that of prognostication in colorectal and pancreatic cancers has remained elusive. Recently identified novel populations of tumor-derived cells bring renewed potential to this area of investigation. Cancer-associated macrophage-like cells, immune cells with phagocytosed tumor material, also show utility in prognostication and assessing treatment responsiveness. In addition, circulating hybrid cells are the result of tumor-macrophage fusion, with mounting evidence for a role in the metastatic cascade. Because of their relative abundance in circulation, circulating hybrid cells have great potential as a liquid biomarker for early detection, prognostication, and surveillance. In all, the power of the cell reaches beyond enumeration by providing a cellular source of tumor DNA, RNA, and protein, which can be harnessed to impact overall survival.
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42
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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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Fusion-mediated chromosomal instability promotes aneuploidy patterns that resemble human tumors. Oncogene 2019; 38:6083-6094. [PMID: 31270395 DOI: 10.1038/s41388-019-0859-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 04/04/2019] [Accepted: 04/12/2019] [Indexed: 12/11/2022]
Abstract
Oncogenesis is considered to result from chromosomal instability, in addition to oncogene and tumor-suppressor alterations. Intermediate to aneuploidy and chromosomal instability, genome doubling is a frequent event in tumor development but the mechanisms driving tetraploidization and its impact remain unexplored. Cell fusion, one of the pathways to tetraploidy, is a physiological process involved in mesenchymal cell differentiation. Besides simple genome doubling, cell fusion results in the merging of two different genomes that can be destabilized upon proliferation. By testing whether cell fusion is involved in mesenchymal oncogenesis, we provide evidence that it induces genomic instability and mediates tumor initiation. After a latency period, the tumor emerges with the cells most suited for its development. Furthermore, hybrid tumor genomes were stabilized after this selection process and were very close to those of human pleomorphic mesenchymal tumors. Thus genome restructuring triggered by cell fusion may account for the chromosomal instability involved in oncogenesis.
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44
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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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45
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Sung J, Sodhi CP, Voltaggio L, Hou X, Jia H, Zhou Q, Čiháková D, Hackam DJ. The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model. Mucosal Immunol 2019; 12:503-517. [PMID: 30617302 PMCID: PMC6445662 DOI: 10.1038/s41385-018-0123-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 11/05/2018] [Accepted: 11/20/2018] [Indexed: 02/04/2023]
Abstract
Mucosal healing occurs through migration and proliferation of cells within injured epithelium, yet these processes may be inadequate for mucosal healing after significant injury where the mucosa is denuded. We hypothesize that extra-intestinal cells can contribute to mucosal healing after injury to the small and large intestine. We generated parabiotic pairs between wild-type and tdTomato mice, which were then subjected to radiation-induced enteritis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. We now show that as compared with singleton mice, mice with a parabiotic partner were protected against intestinal damage as revealed by significantly reduced weight loss, reduced expression of pro-inflammatory cytokines, reduced enterocyte apoptosis, and improved crypt proliferation. Donor cells expressed CD45-, Sca-1+, c-kit+, and CXCR4+ and accumulated around the injured crypts but did not transdifferentiate into epithelia, suggesting that extra-intestinal cells play a paracrine role in the healing response, while parabiotic pairings with Rag1-/- mice showed improved healing, indicating that adaptive immune cells were dispensable for mucosal healing. Strikingly, ablation of the bone marrow of the donor parabionts removed the protective effects. These findings reveal that the recruitment of extra-intestinal, bone marrow-derived cells into the injured intestinal mucosa can promote mucosal healing, suggesting novel therapeutic approaches for severe intestinal disease.
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Affiliation(s)
- J Sung
- Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - C P Sodhi
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA
| | - L Voltaggio
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - X Hou
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - H Jia
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA
| | - Q Zhou
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA
| | - D Čiháková
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - D J Hackam
- Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA.
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Weiler J, Dittmar T. Cell Fusion in Human Cancer: The Dark Matter Hypothesis. Cells 2019; 8:E132. [PMID: 30736482 PMCID: PMC6407028 DOI: 10.3390/cells8020132] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/01/2019] [Accepted: 02/04/2019] [Indexed: 12/12/2022] Open
Abstract
Current strategies to determine tumor × normal (TN)-hybrid cells among human cancer cells include the detection of hematopoietic markers and other mesodermal markers on tumor cells or the presence of donor DNA in cancer samples from patients who had previously received an allogenic bone marrow transplant. By doing so, several studies have demonstrated that TN-hybrid cells could be found in human cancers. However, a prerequisite of this cell fusion search strategy is that such markers are stably expressed by TN-hybrid cells over time. However, cell fusion is a potent inducer of genomic instability, and TN-hybrid cells may lose these cell fusion markers, thereby becoming indistinguishable from nonfused tumor cells. In addition, hybrid cells can evolve from homotypic fusion events between tumor cells or from heterotypic fusion events between tumor cells and normal cells possessing similar markers, which would also be indistinguishable from nonfused tumor cells. Such indistinguishable or invisible hybrid cells will be referred to as dark matter hybrids, which cannot as yet be detected and quantified, but which contribute to tumor growth and progression.
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Affiliation(s)
- Julian Weiler
- Chair of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448 Witten, Germany.
| | - Thomas Dittmar
- Chair of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448 Witten, Germany.
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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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Nimmakayala RK, Batra SK, Ponnusamy MP. Unraveling the journey of cancer stem cells from origin to metastasis. Biochim Biophys Acta Rev Cancer 2018; 1871:50-63. [PMID: 30419314 DOI: 10.1016/j.bbcan.2018.10.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 09/27/2018] [Accepted: 10/09/2018] [Indexed: 02/08/2023]
Abstract
Cancer biology research over recent decades has given ample evidence for the existence of self-renewing and drug-resistant populations within heterogeneous tumors, widely recognized as cancer stem cells (CSCs). However, a lack of clear understanding about the origin, existence, maintenance, and metastatic roles of CSCs limit efforts towards the development of CSC-targeted therapy. In this review, we describe novel avenues of current CSC biology. In addition to cell fusion and horizontal gene transfer, CSCs are originated by mutations in somatic or differentiated cancer cells, resulting in de-differentiation and reprogramming. Recent studies also provided evidence for the existence of distinct or heterogeneous CSC populations within a single heterogeneous tumor. Our analysis of the literature also opens the doors for a novel hypothesis that CSC populations with specific phenotypes, metabolic profiles, and clonogenic potential metastasize to specific organs.
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Affiliation(s)
- Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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Gast CE, Silk AD, Zarour L, Riegler L, Burkhart JG, Gustafson KT, Parappilly MS, Roh-Johnson M, Goodman JR, Olson B, Schmidt M, Swain JR, Davies PS, Shasthri V, Iizuka S, Flynn P, Watson S, Korkola J, Courtneidge SA, Fischer JM, Jaboin J, Billingsley KG, Lopez CD, Burchard J, Gray J, Coussens LM, Sheppard BC, Wong MH. Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival. SCIENCE ADVANCES 2018; 4:eaat7828. [PMID: 30214939 PMCID: PMC6135550 DOI: 10.1126/sciadv.aat7828] [Citation(s) in RCA: 207] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 08/01/2018] [Indexed: 05/06/2023]
Abstract
High lethality rates associated with metastatic cancer highlight an urgent medical need for improved understanding of biologic mechanisms driving metastatic spread and identification of biomarkers predicting late-stage progression. Numerous neoplastic cell intrinsic and extrinsic mechanisms fuel tumor progression; however, mechanisms driving heterogeneity of neoplastic cells in solid tumors remain obscure. Increased mutational rates of neoplastic cells in stressed environments are implicated but cannot explain all aspects of tumor heterogeneity. We present evidence that fusion of neoplastic cells with leukocytes (for example, macrophages) contributes to tumor heterogeneity, resulting in cells exhibiting increased metastatic behavior. Fusion hybrids (cells harboring hematopoietic and epithelial properties) are readily detectible in cell culture and tumor-bearing mice. Further, hybrids enumerated in peripheral blood of human cancer patients correlate with disease stage and predict overall survival. This unique population of neoplastic cells provides a novel biomarker for tumor staging, as well as a potential therapeutic target for intervention.
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Affiliation(s)
- Charles E. Gast
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Alain D. Silk
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Luai Zarour
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Lara Riegler
- Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
| | - Joshua G. Burkhart
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Kyle T. Gustafson
- Center for Early Detection Advanced Research, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA
| | - Michael S. Parappilly
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Minna Roh-Johnson
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA
| | - James R. Goodman
- Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Brennan Olson
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Mark Schmidt
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - John R. Swain
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Paige S. Davies
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Vidya Shasthri
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Shinji Iizuka
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Patrick Flynn
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Spencer Watson
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - James Korkola
- Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Sara A. Courtneidge
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Jared M. Fischer
- Center for Early Detection Advanced Research, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
| | - Jerry Jaboin
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR 97239, USA
| | - Kevin G. Billingsley
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Charles D. Lopez
- Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Julja Burchard
- Department of Computational Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Joe Gray
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Lisa M. Coussens
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Brett C. Sheppard
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Corresponding author.
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50
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Wang Z, Yuan Y, Zhang L, Min Z, Zhou D, Yu S, Wang P, Ju S, Jun L, Fu J. Impact of cell fusion in myeloma marrow microenvironment on tumor progression. Oncotarget 2018; 9:30997-31006. [PMID: 30123422 PMCID: PMC6089556 DOI: 10.18632/oncotarget.25742] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 06/05/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) represent a subset of non-hematopoietic adult stem cells, which can also fuse with other cells spontaneously in bone marrow and capable of adopting the phenotype of other cells. The fusion of somatic cells with stem cells can reprogram somatic cells to a pluripotent state. Our research on the fusion of bone marrow mesenchymal stem cells(BM-MSCs) and MM cells demonstrate that the fused cells can exhibit stemness and cancer cell-like characteristics. RESULTS We successfully produced a hybrid cells that acquired larger size and multinucleation, in which partial chromatin condensation, a visible nucleolus, and one or more round or oval nucleus. Experiments results showed that the stemness markers highly expressed in these fused cells and there were much more chromosomes in fused cells than those in parental cells as well as exhibited increased resistance to drug treatment. CONCLUSIONS Our results suggest that cell fusion between BM-MSCs and MM cells could contribute it genomic heterogeneity and play a role on disease progression. METHODS We fused human BM-MSCs with MM cells lines RPMI 8226 or XG1 in vitro by polyethylene glycol (PEG), and the hybrid cells were sorted by sedimentation assays. The growth, migration, cell cycle, chromosome and drug sensitive of hybrids were assessed by cell counting, cell colony formation, transwell assays, cytogenetic assay and flow cytometry (FCM). The proteins and genes related to stemness and cytokines were tested by western blot and/or real-time quantitative RT-PCR.
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Affiliation(s)
- Ziyan Wang
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Yuqing Yuan
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Liying Zhang
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Zhou Min
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Dongming Zhou
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Sun Yu
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Panjun Wang
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Songguang Ju
- Institute of Biotechnology, Soochow University, Suzhou 215007, PR China
| | - Li Jun
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
| | - Jinxiang Fu
- Hematology Department, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China
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