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1
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López-Collazo E, Hurtado-Navarro L. Cell fusion as a driver of metastasis: re-evaluating an old hypothesis in the age of cancer heterogeneity. Front Immunol 2025; 16:1524781. [PMID: 39967663 PMCID: PMC11832717 DOI: 10.3389/fimmu.2025.1524781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 01/17/2025] [Indexed: 02/20/2025] Open
Abstract
Numerous studies have investigated the molecular mechanisms and signalling pathways underlying cancer metastasis, as there is still no effective treatment for this terminal stage of the disease. However, the exact processes that enable primary cancer cells to acquire a metastatic phenotype remain unclear. Increasing attention has been focused on the fusion of cancer cells with myeloid cells, a phenomenon that may result in hybrid cells, so-called Tumour Hybrid Cells (THCs), with enhanced migratory, angiogenic, immune evasion, colonisation, and metastatic properties. This process has been shown to potentially drive tumour progression, drug resistance, and cancer recurrence. In this review, we explore the potential mechanisms that govern cancer cell fusion, the molecular mediators involved, the metastatic characteristics acquired by fusion-derived hybrids, and their clinical significance in human cancer. Additionally, we discuss emerging pharmacological strategies aimed at targeting fusogenic molecules as a means to prevent metastatic dissemination.
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Affiliation(s)
- Eduardo López-Collazo
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
- CIBER of Respiratory Diseases (CIBERES), Madrid, Spain
- UNIE University, Madrid, Spain
| | - Laura Hurtado-Navarro
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
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2
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Liu Z, Wang Y, Peng Z, Li H, Wang H, Wu Y, Jiang X, Fu P. Fusion of tumor cells and mesenchymal stem/stroma cells: a source of tumor heterogeneity, evolution and recurrence. Med Oncol 2025; 42:52. [PMID: 39838167 DOI: 10.1007/s12032-024-02595-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 12/28/2024] [Indexed: 01/23/2025]
Abstract
The heterogeneity and evolution of tumors remain significant obstacles in cancer treatment, contributing to both therapy resistance and relapse. Mesenchymal stem/stromal cells (MSCs) are multipotent stromal cells within the tumor microenvironment that interact with tumor cells through various mechanisms, including cell fusion. While previous research has largely focused on the effects of MSC-tumor cell fusion on tumor proliferation, migration, and tumorigenicity, emerging evidence indicates that its role in tumor maintenance, evolution, and recurrence, particularly under stress conditions, may be even more pivotal. This review examines the connection between MSC-tumor cell fusion and several critical factors like tumor heterogeneity, cancer stem cells, and therapy resistance, highlighting the crucial role of cell fusion in tumor survival, evolution, and recurrence. Additionally, we explore potential therapeutic strategies aimed at targeting this process.
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Affiliation(s)
- Zhen Liu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yihao Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zesheng Peng
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hui Li
- Department of Cataract, Nanyang Eye Hospital, Nanyang, 473000, China
| | - Haofei Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuyi Wu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaobing Jiang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Peng Fu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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3
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Liu SH, Zhang J, Zuo YG. Macrophages in inflammatory skin diseases and skin tumors. Front Immunol 2024; 15:1430825. [PMID: 39703508 PMCID: PMC11656021 DOI: 10.3389/fimmu.2024.1430825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 11/18/2024] [Indexed: 12/21/2024] Open
Abstract
Macrophages, as specialized, long-lasting phagocytic cells of the innate immune system, have garnered increasing attention due to their wide distribution and various functions. The skin, being the largest immune organ in the human body, presents an intriguing landscape for macrophage research, particularly regarding their roles in inflammatory skin diseases and skin tumors. In this review, we compile the latest research on macrophages in conditions such as atopic dermatitis, psoriasis, systemic sclerosis, systemic lupus erythematosus, rosacea, bullous pemphigoid, melanoma and cutaneous T-cell lymphoma. We aim to contribute to illustrating the pathogenesis and potential new therapies for inflammatory skin diseases and skin tumors from the perspective of macrophages.
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Affiliation(s)
| | | | - Ya-Gang Zuo
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, National Clinical Research Center for Dermatologic and Immunologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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4
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Kzhyshkowska J, Shen J, Larionova I. Targeting of TAMs: can we be more clever than cancer cells? Cell Mol Immunol 2024; 21:1376-1409. [PMID: 39516356 PMCID: PMC11607358 DOI: 10.1038/s41423-024-01232-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
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Affiliation(s)
- Julia Kzhyshkowska
- Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 1-3, 68167, Mannheim, Germany.
- German Red Cross Blood Service Baden-Württemberg - Hessen, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany.
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050, Lenina av.36, Tomsk, Russia.
- Bashkir State Medical University of the Ministry of Health of Russia, 450000, Teatralnaya Street, 2a, Ufa, Russia.
| | - Jiaxin Shen
- Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 1-3, 68167, Mannheim, Germany
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050, Lenina av.36, Tomsk, Russia
- Bashkir State Medical University of the Ministry of Health of Russia, 450000, Teatralnaya Street, 2a, Ufa, Russia
- Laboratory of Molecular Therapy of Cancer, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009, Kooperativnyi st, Tomsk, Russia
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5
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Marabitti V, Vulpis E, Nazio F, Campello S. Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions. Pharmacol Res 2024; 208:107382. [PMID: 39218420 DOI: 10.1016/j.phrs.2024.107382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy.
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Affiliation(s)
- Veronica Marabitti
- Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy
| | - Elisabetta Vulpis
- Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy
| | - Francesca Nazio
- Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy
| | - Silvia Campello
- Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy.
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Park R, Yu J, Shahzad M, Lee S, Ji JD. The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages. Immunol Res 2024; 72:526-537. [PMID: 38265550 DOI: 10.1007/s12026-024-09458-9] [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: 11/29/2023] [Accepted: 01/17/2024] [Indexed: 01/25/2024]
Abstract
B7-H3 is a member of the B7 superfamily and a putative inhibitory immune checkpoint molecule. Several early-phase clinical trials have reported promising anti-tumor activity and safety of anti-cancer drugs targeting B7-H3, suggesting that it may be a promising target for a potential next-generation immune checkpoint inhibitor. Despite ongoing clinical studies, most B7-H3-targeted drugs being currently investigated rely on direct cytotoxicity as their mechanisms of action rather than modulating its function as an immune checkpoint, at least in part due to its incompletely understood immune regulatory function. Recent studies have begun to elucidate the role of B7-H3 in regulating the tumor microenvironment (TME). Emerging evidence suggests that B7-H3 may regulate the interferon-STAT1 axis in the TME and promote immune suppression. Similarly, increasing evidence shows B7-H3 may be implicated in promoting M1 to M2 polarization of tumor-associated macrophages (TAMs). There is also accumulating evidence suggesting that B7-H3 may play a role in the heterotypic fusion of cancer stem cells and macrophages, thereby promoting tumor invasion and metastasis. Here, we review the recent advances in the understanding of B7-H3 cancer immunobiology with a focus on highlighting its potential role in the interferon priming of TAMs and the heterotypic fusion of TAMs with cancer stem cells and suggest future direction in elucidating its immune checkpoint function.
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Affiliation(s)
- Robin Park
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - James Yu
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - Moazzam Shahzad
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - Sunggon Lee
- Department of Internal Medicine, Korea University, Seoul, South Korea
| | - Jong Dae Ji
- Department of Rheumatology, College of Medicine, Korea University, Seoul, South Korea.
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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8
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Nowosh V, Braun AC, Ruano APC, Chinén LTD, de Oliveira Massoco C. Pilot study to evaluate isolation by size of circulating tumour cells in canine oral melanoma. Vet Comp Oncol 2024. [PMID: 38837514 DOI: 10.1111/vco.12982] [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: 01/28/2024] [Revised: 04/21/2024] [Accepted: 05/06/2024] [Indexed: 06/07/2024]
Abstract
Liquid biopsy for circulating tumour cell (CTC) detection is generally unexplored in veterinary medicine. Dogs with highly aggressive and heterogeneous tumours, such as oral malignant melanoma (OMM), could benefit from studies involving size-based isolation methods for CTCs, as they do not depend on specific antibodies. This pilot study aimed to detect CTCs from canine OMM using Isolation by Size of Epithelial Tumor Cells (ISET), a microfiltration methodology, followed by immunocytochemistry (ICC) with Melan-A, PNL2, and S100 antibodies. Ten canine patients diagnosed by histopathology and confirmed as OMM by immunohistochemistry were enrolled, their prognostic data was assessed, and blood samples were collected for CTC analysis. Results have shown the detection of intact cells in 9/10 patients. ICC has shown 3/9 Melan-A-positive, 3/9 PNL2-positive, and 8/9 S100-positive patients, confirming the importance of opting for a multimarker assay. A significant number of negative-stained CTCs were found, suggesting their high heterogeneity in circulation. Microemboli stained with either PNL2 or S100 were found in a patient with a high isolated cell count and advanced clinical stage. Preliminary statistical analysis shows a significant difference in CTC count between patients with and without lymph node metastasis (p < .05), which may correlate with tumour metastatic potential. However, we recommend further studies with more extensive sampling to confirm this result. This pilot study is the first report of intact CTC detection in canine OMM and the first application of ISET in veterinary medicine, opening new possibilities for liquid biopsy studies in canine OMM and other tumours.
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Affiliation(s)
- Victor Nowosh
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Alexcia Camila Braun
- Secretaria de Ciência, Tecnologia e Inovação do Complexo Econômico-Industrial da Saúde, Coordenação Geral de Pesquisa Clínica, Ministério da Saúde, Brasilia, Brazil
| | | | | | - Cristina de Oliveira Massoco
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
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9
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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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10
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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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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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Chou CW, Hung CN, Chiu CHL, Tan X, Chen M, Chen CC, Saeed M, Hsu CW, Liss MA, Wang CM, Lai Z, Alvarez N, Osmulski PA, Gaczynska ME, Lin LL, Ortega V, Kirma NB, Xu K, Liu Z, Kumar AP, Taverna JA, Velagaleti GVN, Chen CL, Zhang Z, Huang THM. Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination. Nat Commun 2023; 14:6569. [PMID: 37848444 PMCID: PMC10582093 DOI: 10.1038/s41467-023-42303-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 10/06/2023] [Indexed: 10/19/2023] Open
Abstract
While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel this engulfment. Here we report that the reverse signaling using CD47 as a receptor additionally enhances a pro-survival function of prostate cancer cells under phagocytic attack. Although low CD47-expressing cancer cells still allow phagocytosis, the reverse signaling delays the process, leading to incomplete digestion of the entrapped cells and subsequent tumor hybrid cell (THC) formation. Viable THCs acquire c-Myc from parental cancer cells to upregulate both M1- and M2-like macrophage polarization genes. Consequently, THCs imitating dual macrophage features can confound immunosurveillance, gaining survival advantage in the host. Furthermore, these cells intrinsically express low levels of androgen receptor and its targets, resembling an adenocarcinoma-immune subtype of metastatic castration-resistant prostate cancer. Therefore, phagocytosis-generated THCs may represent a potential target for treating the disease.
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Affiliation(s)
- Chih-Wei Chou
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Chia-Nung Hung
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Cheryl Hsiang-Ling Chiu
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Xi Tan
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Meizhen Chen
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Chien-Chin Chen
- Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Moawiz Saeed
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Che-Wei Hsu
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Michael A Liss
- Department of Urology, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Chiou-Miin Wang
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Zhao Lai
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Nathaniel Alvarez
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Pawel A Osmulski
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Maria E Gaczynska
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Li-Ling Lin
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Veronica Ortega
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Nameer B Kirma
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Kexin Xu
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Zhijie Liu
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Addanki P Kumar
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Department of Urology, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Josephine A Taverna
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Gopalrao V N Velagaleti
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Chun-Liang Chen
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
- Biobehavior Laboratory, School of Nursing, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
| | - Zhao Zhang
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
| | - Tim Hui-Ming Huang
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
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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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Fernández-Santiago C, López-López R, Piñeiro R. Models to study CTCs and CTC culture methods. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 381:57-98. [PMID: 37739484 DOI: 10.1016/bs.ircmb.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/24/2023]
Abstract
The vast majority of cancer-related deaths are due to the presence of disseminated disease. Understanding the metastatic process is key to achieving a reduction in cancer mortality. Particularly, there is a need to understand the molecular mechanisms that drive cancer metastasis, which will allow the identification of curative treatments for metastatic cancers. Liquid biopsies have arisen as a minimally invasive approach to gain insights into the biology of metastasis. Circulating tumour cells (CTCs), shed to the circulation from the primary tumour or metastatic lesions, are a key component of liquid biopsy. As metastatic precursors, CTCs hold the potential to unravel the mechanisms involved in metastasis formation as well as new therapeutic strategies for treating metastatic disease. However, the complex biology of CTCs together with their low frequency in circulation are factors hampering an in-depth mechanistic investigation of the metastatic process. To overcome these problems, CTC-derived models, including CTC-derived xenograft (CDX) and CTC-derived ex vivo cultures, in combination with more traditional in vivo models of metastasis, have emerged as powerful tools to investigate the biological features of CTCs facilitating cancer metastasis and uncover new therapeutic opportunities. In this chapter, we provide an up to date view of the diverse models used in different cancers to study the biology of CTCs, and of the methods developed for CTC culture and expansion, in vivo and ex vivo. We also report some of the main challenges and limitations that these models are facing.
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Affiliation(s)
- Cristóbal Fernández-Santiago
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain
| | - Rafael López-López
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain; University Clinical Hospital of Santiago de Compostela (CHUS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
| | - Roberto Piñeiro
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.
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15
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Jahandideh A, Yarizadeh M, Noei-Khesht Masjedi M, Fatehnejad M, Jahandideh R, Soheili R, Eslami Y, Zokaei M, Ahmadvand A, Ghalamkarpour N, Kumar Pandey R, Nabi Afjadi M, Payandeh Z. Macrophage's role in solid tumors: two edges of a sword. Cancer Cell Int 2023; 23:150. [PMID: 37525217 PMCID: PMC10391843 DOI: 10.1186/s12935-023-02999-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023] Open
Abstract
The tumor microenvironment is overwhelmingly dictated by macrophages, intimately affiliated with tumors, exercising pivotal roles in multiple processes, including angiogenesis, extracellular matrix reconfiguration, cellular proliferation, metastasis, and immunosuppression. They further exhibit resilience to chemotherapy and immunotherapy via meticulous checkpoint blockades. When appropriately stimulated, macrophages can morph into a potent bidirectional component of the immune system, engulfing malignant cells and annihilating them with cytotoxic substances, thus rendering them intriguing candidates for therapeutic targets. As myelomonocytic cells relentlessly amass within tumor tissues, macrophages rise as prime contenders for cell therapy upon the development of chimeric antigen receptor effector cells. Given the significant incidence of macrophage infiltration correlated with an unfavorable prognosis and heightened resistance to chemotherapy in solid tumors, we delve into the intricate role of macrophages in cancer propagation and their promising potential in confronting four formidable cancer variants-namely, melanoma, colon, glioma, and breast cancers.
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Affiliation(s)
- Arian Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- Usern Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahsa Yarizadeh
- Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Maryam Noei-Khesht Masjedi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Fatehnejad
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Romina Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roben Soheili
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Yeganeh Eslami
- Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Zokaei
- Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardavan Ahmadvand
- Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nogol Ghalamkarpour
- Department of Clinical Laboratory Sciences, School of Allied Medicine, Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Rajan Kumar Pandey
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
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16
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Cozzo AJ, Coleman MF, Hursting SD. You complete me: tumor cell-myeloid cell nuclear fusion as a facilitator of organ-specific metastasis. Front Oncol 2023; 13:1191332. [PMID: 37427108 PMCID: PMC10324515 DOI: 10.3389/fonc.2023.1191332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/25/2023] [Indexed: 07/11/2023] Open
Abstract
Every cancer genome is unique, resulting in potentially near infinite cancer cell phenotypes and an inability to predict clinical outcomes in most cases. Despite this profound genomic heterogeneity, many cancer types and subtypes display a non-random distribution of metastasis to distant organs, a phenomenon known as organotropism. Proposed factors in metastatic organotropism include hematogenous versus lymphatic dissemination, the circulation pattern of the tissue of origin, tumor-intrinsic factors, compatibility with established organ-specific niches, long-range induction of premetastatic niche formation, and so-called "prometastatic niches" that facilitate successful colonization of the secondary site following extravasation. To successfully complete the steps required for distant metastasis, cancer cells must evade immunosurveillance and survive in multiple new and hostile environments. Despite substantial advances in our understanding of the biology underlying malignancy, many of the mechanisms used by cancer cells to survive the metastatic journey remain a mystery. This review synthesizes the rapidly growing body of literature demonstrating the relevance of an unusual cell type known as "fusion hybrid" cells to many of the hallmarks of cancer, including tumor heterogeneity, metastatic conversion, survival in circulation, and metastatic organotropism. Whereas the concept of fusion between tumor cells and blood cells was initially proposed over a century ago, only recently have technological advancements allowed for detection of cells containing components of both immune and neoplastic cells within primary and metastatic lesions as well as among circulating malignant cells. Specifically, heterotypic fusion of cancer cells with monocytes and macrophages results in a highly heterogeneous population of hybrid daughter cells with enhanced malignant potential. Proposed mechanisms behind these findings include rapid, massive genome rearrangement during nuclear fusion and/or acquisition of monocyte/macrophage features such as migratory and invasive capability, immune privilege, immune cell trafficking and homing, and others. Rapid acquisition of these cellular traits may increase the likelihood of both escape from the primary tumor site and extravasation of hybrid cells at a secondary location that is amenable to colonization by that particular hybrid phenotype, providing a partial explanation for the patterns observed in some cancers with regard to sites of distant metastases.
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Affiliation(s)
- Alyssa J. Cozzo
- Duke University School of Medicine, Durham, NC, United States
- Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Michael F. Coleman
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Stephen D. Hursting
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
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17
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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] [MESH Headings] [Grants] [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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18
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Bates M, Mohamed BM, Ward MP, Kelly TE, O'Connor R, Malone V, Brooks R, Brooks D, Selemidis S, Martin C, O'Toole S, O'Leary JJ. Circulating tumour cells: The Good, the Bad and the Ugly. Biochim Biophys Acta Rev Cancer 2023; 1878:188863. [PMID: 36796527 DOI: 10.1016/j.bbcan.2023.188863] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/06/2023] [Accepted: 01/21/2023] [Indexed: 02/17/2023]
Abstract
This review is an overview of the current knowledge regarding circulating tumour cells (CTCs), which are potentially the most lethal type of cancer cell, and may be a key component of the metastatic cascade. The clinical utility of CTCs (the "Good"), includes their diagnostic, prognostic, and therapeutic potential. Conversely, their complex biology (the "Bad"), including the existence of CD45+/EpCAM+ CTCs, adds insult to injury regarding their isolation and identification, which in turn hampers their clinical translation. CTCs are capable of forming microemboli composed of both non-discrete phenotypic populations such as mesenchymal CTCs and homotypic and heterotypic clusters which are poised to interact with other cells in the circulation, including immune cells and platelets, which may increase their malignant potential. These microemboli (the "Ugly") represent a prognostically important CTC subset, however, phenotypic EMT/MET gradients bring additional complexities to an already challenging situation.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Mark P Ward
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Tanya E Kelly
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland
| | - Roisin O'Connor
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Victoria Malone
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Robert Brooks
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Doug Brooks
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Stavros Selemidis
- School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology, Bundoora, VIC 3083, Australia
| | - Cara Martin
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin 2, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin 2, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, Dublin 8, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin 8, Ireland
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19
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Jain N, Srinivasarao DA, Famta P, Shah S, Vambhurkar G, Shahrukh S, Singh SB, Srivastava S. The portrayal of macrophages as tools and targets: A paradigm shift in cancer management. Life Sci 2023; 316:121399. [PMID: 36646378 DOI: 10.1016/j.lfs.2023.121399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/02/2023] [Accepted: 01/12/2023] [Indexed: 01/15/2023]
Abstract
Macrophages play a major role in maintaining an organism's physiology, such as development, homeostasis, tissue repair, and immunity. These immune cells are known to be involved in tumor progression and modulation. Monocytes can be polarized to two types of macrophages (M1 macrophages and pro-tumor M2 macrophages). Through this article, we aim to emphasize the potential of targeting macrophages in order to improve current strategies for tumor management. Various strategies that target macrophages as a therapeutic target have been discussed along with ongoing clinical trials. We have discussed the role of macrophages in various stages of tumor progression epithelial-to-mesenchymal transition (EMT), invasion, maintaining the stability of circulating tumor cells (CTCs) in blood, and establishing a premetastatic niche along with the role of various cytokines and chemokines involved in these processes. Intriguingly macrophages can also serve as drug carriers due to their tumor tropism along the chemokine gradient. They surpass currently explored nanotherapeutics in tumor accumulation and circulation half-life. We have emphasized on macrophage-based biomimetic formulations and macrophage-hitchhiking as a strategy to effectively target tumors. We firmly believe that targeting macrophages or utilizing them as an indigenous carrier system could transform cancer management.
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Affiliation(s)
- Naitik Jain
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Dadi A Srinivasarao
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Paras Famta
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Saurabh Shah
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Ganesh Vambhurkar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Syed Shahrukh
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Shashi Bala Singh
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
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20
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Dittmar T, Hass R. Extracellular Events Involved in Cancer Cell-Cell Fusion. Int J Mol Sci 2022; 23:16071. [PMID: 36555709 PMCID: PMC9784959 DOI: 10.3390/ijms232416071] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Fusion among different cell populations represents a rare process that is mediated by both intrinsic and extracellular events. Cellular hybrid formation is relayed by orchestrating tightly regulated signaling pathways that can involve both normal and neoplastic cells. Certain important cell merger processes are often required during distinct organismal and tissue development, including placenta and skeletal muscle. In a neoplastic environment, however, cancer cell fusion can generate new cancer hybrid cells. Following survival during a subsequent post-hybrid selection process (PHSP), the new cancer hybrid cells express different tumorigenic properties. These can include elevated proliferative capacity, increased metastatic potential, resistance to certain therapeutic compounds, and formation of cancer stem-like cells, all of which characterize significantly enhanced tumor plasticity. However, many parts within this multi-step cascade are still poorly understood. Aside from intrinsic factors, cell fusion is particularly affected by extracellular conditions, including an inflammatory microenvironment, viruses, pH and ionic stress, hypoxia, and exosome signaling. Accordingly, the present review article will primarily highlight the influence of extracellular events that contribute to cell fusion in normal and tumorigenic tissues.
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Affiliation(s)
- Thomas Dittmar
- Institute of Immunology, Center 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 Gynecology, Hannover Medical School, 30625 Hannover, Germany
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21
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Nitschke C, Markmann B, Konczalla L, Kropidlowski J, Pereira-Veiga T, Scognamiglio P, Schönrock M, Sinn M, Tölle M, Izbicki J, Pantel K, Uzunoglu FG, Wikman H. Circulating Cancer Associated Macrophage-like Cells as a Potential New Prognostic Marker in Pancreatic Ductal Adenocarcinoma. Biomedicines 2022; 10:biomedicines10112955. [PMID: 36428523 PMCID: PMC9687633 DOI: 10.3390/biomedicines10112955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/07/2022] [Accepted: 11/12/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Circulating Cancer Associated Macrophage-like cells (CAMLs) have been described as novel liquid biopsy analytes and unfavorable prognostic markers in some tumor entities, with scarce data for Pancreatic Ductal Adenocarcinomas (PDAC). METHODS Baseline and follow-up blood was drawn from resected curative (n = 36) and palliative (n = 19) PDAC patients. A microfluidic size-based cell enrichment approach (ParsortixTM) was used for CAML detection, followed by immunofluorescence staining using pan-keratin, CD14, and CD45 antibodies to differentiate between CAMLs, circulating tumor cells (CTCs), and leukocytes. RESULTS CAMLs were detectable at baseline in 36.1% of resected patients and 47.4% of palliative PDAC patients. CAML detection was tumor stage independent. Follow-up data indicated that detection of CAMLs (in 45.5% of curative patients) was an independent prognostic factor for shorter recurrence-free survival (RFS) (HR: 4.3, p = 0.023). Furthermore, a combined analysis with CTCs showed the detectability of at least one of these cell populations in 68.2% of resected patients at follow-up. The combined detection of CAMLs and CTCs was also significantly associated with short RFS (HR: 8.7, p = 0.003). CONCLUSIONS This pilot study shows that detection of CAMLs in PDAC patients can provide prognostic information, either alone or even more pronounced in combination with CTCs, which indicates the power of liquid biopsy marker analyses.
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Affiliation(s)
- Christine Nitschke
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
- Mildred Scheel Cancer Career Center, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Benedikt Markmann
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Leonie Konczalla
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
- Mildred Scheel Cancer Career Center, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jolanthe Kropidlowski
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Thais Pereira-Veiga
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Pasquale Scognamiglio
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Martin Schönrock
- II Medical Clinic and Polyclinic (Oncology), University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marianne Sinn
- II Medical Clinic and Polyclinic (Oncology), University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marie Tölle
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jakob Izbicki
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Faik G. Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Harriet Wikman
- Department of Tumor Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
- Correspondence: ; Tel.: +49-40-7510-51913
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22
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Sulaiman R, De P, Aske JC, Lin X, Dale A, Vaselaar E, Ageton C, Gaster K, Espaillat LR, Starks D, Dey N. Identification and Morphological Characterization of Features of Circulating Cancer-Associated Macrophage-like Cells (CAMLs) in Endometrial Cancers. Cancers (Basel) 2022; 14:cancers14194577. [PMID: 36230499 PMCID: PMC9558552 DOI: 10.3390/cancers14194577] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/09/2022] [Accepted: 09/18/2022] [Indexed: 11/16/2022] Open
Abstract
The blood of patients with solid tumors contains circulating tumor-associated cells, including epithelial cells originating from the tumor mass, such as circulating tumor cells (CTCs), or phagocytic myeloid cells (differentiated monocytes), such as circulating cancer-associated macrophage-like cells (CAMLs). We report for the first time the identification and in-depth morphologic characterization of CAMLs in patients with endometrial cancers. We isolated CAMLs by size-based filtration on lithographically fabricated membranes followed by immunofluorescence, using a CD45+/CK 8,18,19+/EpCAM+/CD31+/macrophage-like nuclear morphology, from > 70 patients. Irrespective of the histological and pathological parameters, 98% of patients were positive for CAMLs. Two size-based subtypes of CAMLs, <20 µm (tiny) and >20 µm (giant) CAMLs, of distinctive polymorphic morphologies with mononuclear or fused polynuclear structures in several morphological states were observed, including apoptotic CAMLs, CAML−WBC doublets, conjoined CAMLs, CAML−WBC clusters, and CTC−CAML−WBC clusters. In contrast, CAMLs were absent in patients with non-neoplastic/benign tumors, healthy donors, and leucopaks. Enumerating CTCs simultaneously from the same patient, we observed that CTC-positive patients are positive for CAMLs, while 55% out of all CAML-positive patients were found positive for CTCs. Our study demonstrated for the first time the distinctive morphological characteristics of endometrial CAMLs in the context of the presence of CTCs in patients.
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Affiliation(s)
- Raed Sulaiman
- Department of Pathology, Avera Cancer Institute, Sioux Falls, SD 57105, USA
| | - Pradip De
- Translational Oncology Laboratory, Avera Research Institute, Sioux Falls, SD 57105, USA
- Department of Internal Medicine, University of South Dakota SSOM, Sioux Falls, SD 57069, USA
| | - Jennifer C. Aske
- Translational Oncology Laboratory, Avera Research Institute, Sioux Falls, SD 57105, USA
| | - Xiaoqian Lin
- Translational Oncology Laboratory, Avera Research Institute, Sioux Falls, SD 57105, USA
| | - Adam Dale
- Translational Oncology Laboratory, Avera Research Institute, Sioux Falls, SD 57105, USA
| | - Ethan Vaselaar
- Translational Oncology Laboratory, Avera Research Institute, Sioux Falls, SD 57105, USA
| | - Cheryl Ageton
- Department of Research Oncology, Avera Cancer Institute, Sioux Falls, SD 57105, USA
| | - Kris Gaster
- Outpatient Cancer Clinics, Avera Cancer Institute, Sioux Falls, SD 57105, USA
| | - Luis Rojas Espaillat
- Department of Gynecologic Oncology, Avera Cancer Institute, Sioux Falls, SD 57105, USA
| | - David Starks
- Department of Gynecologic Oncology, Avera Cancer Institute, Sioux Falls, SD 57105, USA
| | - Nandini Dey
- Translational Oncology Laboratory, Avera Research Institute, Sioux Falls, SD 57105, USA
- Department of Internal Medicine, University of South Dakota SSOM, Sioux Falls, SD 57069, USA
- Correspondence:
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Pereira-Veiga T, Schneegans S, Pantel K, Wikman H. Circulating tumor cell-blood cell crosstalk: Biology and clinical relevance. Cell Rep 2022; 40:111298. [PMID: 36044866 DOI: 10.1016/j.celrep.2022.111298] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/28/2022] [Accepted: 08/09/2022] [Indexed: 01/17/2023] Open
Abstract
Circulating tumor cells (CTCs) are the seeds of distant metastasis, and the number of CTCs detected in the blood of cancer patients is associated with a worse prognosis. CTCs face critical challenges for their survival in circulation, such as anoikis, shearing forces, and immune surveillance. Thus, understanding the mechanisms and interactions of CTCs within the blood microenvironment is crucial for better understanding of metastatic progression and the development of novel treatment strategies. CTCs interact with different hematopoietic cells, such as platelets, red blood cells, neutrophils, macrophages, natural killer (NK) cells, lymphocytes, endothelial cells, and cancer-associated fibroblasts, which can affect CTC survival in blood. This interaction may take place either via direct cell-cell contact or through secreted molecules. Here, we review interactions of CTCs with blood cells and discuss the potential clinical relevance of these interactions as biomarkers or as targets for anti-metastatic therapies.
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Affiliation(s)
- Thais Pereira-Veiga
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Svenja Schneegans
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Harriet Wikman
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
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Jinesh GG, Brohl AS. Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis. Signal Transduct Target Ther 2022; 7:296. [PMID: 35999218 PMCID: PMC9399134 DOI: 10.1038/s41392-022-01132-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 07/14/2022] [Accepted: 07/24/2022] [Indexed: 12/13/2022] Open
Abstract
Metastasis is a pivotal event that accelerates the prognosis of cancer patients towards mortality. Therapies that aim to induce cell death in metastatic cells require a more detailed understanding of the metastasis for better mitigation. Towards this goal, we discuss the details of two distinct but overlapping pathways of metastasis: a classical reversible epithelial-to-mesenchymal transition (hybrid-EMT)-driven transport pathway and an alternative cell death process-driven blebbishield metastatic-witch (BMW) transport pathway involving reversible cell death process. The knowledge about the EMT and BMW pathways is important for the therapy of metastatic cancers as these pathways confer drug resistance coupled to immune evasion/suppression. We initially discuss the EMT pathway and compare it with the BMW pathway in the contexts of coordinated oncogenic, metabolic, immunologic, and cell biological events that drive metastasis. In particular, we discuss how the cell death environment involving apoptosis, ferroptosis, necroptosis, and NETosis in BMW or EMT pathways recruits immune cells, fuses with it, migrates, permeabilizes vasculature, and settles at distant sites to establish metastasis. Finally, we discuss the therapeutic targets that are common to both EMT and BMW pathways.
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Affiliation(s)
- Goodwin G Jinesh
- Department of Molecular Oncology, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA. .,Sarcoma Department, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA.
| | - Andrew S Brohl
- Department of Molecular Oncology, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA. .,Sarcoma Department, 12902 USF Magnolia Drive, H. Lee Moffitt Cancer Center & Research Institute, Tampa, 33612, FL, USA.
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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: 30] [Impact Index Per Article: 10.0] [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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Montalbán-Hernández K, Cantero-Cid R, Casalvilla-Dueñas JC, Avendaño-Ortiz J, Marín E, Lozano-Rodríguez R, Terrón-Arcos V, Vicario-Bravo M, Marcano C, Saavedra-Ambrosy J, Prado-Montero J, Valentín J, Pérez de Diego R, Córdoba L, Pulido E, del Fresno C, Dueñas M, López-Collazo E. Colorectal Cancer Stem Cells Fuse with Monocytes to Form Tumour Hybrid Cells with the Ability to Migrate and Evade the Immune System. Cancers (Basel) 2022; 14:3445. [PMID: 35884505 PMCID: PMC9324286 DOI: 10.3390/cancers14143445] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The cancer cell fusion theory could be one of the best explanations for the metastasis from primary tumours. METHODS Herein, we co-cultured colorectal cancer (CRC) stem cells with human monocytes and analysed the properties of the generated tumour hybrid cells (THCs). The presence of THCs in the bloodstream together with samples from primary and metastatic lesions and their clinical correlations were evaluated in CRC patients and were detected by both FACS and immunofluorescence methods. Additionally, the role of SIGLEC5 as an immune evasion molecule in colorectal cancer was evaluated. RESULTS Our data demonstrated the generation of THCs after the in vitro co-culture of CRC stem cells and monocytes. These cells, defined as CD45+CD14+EpCAM+, showed enhanced migratory and proliferative abilities. The THC-specific cell surface signature allows identification in matched primary tumour tissues and metastases as well as in the bloodstream from patients with CRC, thus functioning as a biomarker. Moreover, SIG-LEC5 expression on in vitro generated THCs has shown to be involved in the mechanism for immune evasion. Additionally, sSIGLEC5 levels correlated with THC numbers in the prospective cohort of patients. CONCLUSIONS Our results indicate the generation of a hybrid entity after the in vitro co-culture between CRC stem cells and human monocytes. Moreover, THC numbers present in patients are related to both prognosis and the later spread of metastases in CRC patients.
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Affiliation(s)
- Karla Montalbán-Hernández
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Ramón Cantero-Cid
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
- Digestive Surgery Service, La Paz Univeristy Hospital, 28046 Madrid, Spain; (M.V.-B.); (C.M.); (J.S.-A.)
- Translational Research and Innovation in Surgery Group, La Paz Univeristy Hospital, 28046 Madrid, Spain
| | - José Carlos Casalvilla-Dueñas
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - José Avendaño-Ortiz
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
- Biobank Platform, IdiPAZ, La Paz Universitary Hospital, 28046 Madrid, Spain
| | - Elvira Marín
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Roberto Lozano-Rodríguez
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Verónica Terrón-Arcos
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Marina Vicario-Bravo
- Digestive Surgery Service, La Paz Univeristy Hospital, 28046 Madrid, Spain; (M.V.-B.); (C.M.); (J.S.-A.)
| | - Cristóbal Marcano
- Digestive Surgery Service, La Paz Univeristy Hospital, 28046 Madrid, Spain; (M.V.-B.); (C.M.); (J.S.-A.)
| | - Jorge Saavedra-Ambrosy
- Digestive Surgery Service, La Paz Univeristy Hospital, 28046 Madrid, Spain; (M.V.-B.); (C.M.); (J.S.-A.)
| | - Julia Prado-Montero
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Jaime Valentín
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Rebeca Pérez de Diego
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Laura Córdoba
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
- Biobank Platform, IdiPAZ, La Paz Universitary Hospital, 28046 Madrid, Spain
| | - Elisa Pulido
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Carlos del Fresno
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Marta Dueñas
- Molecular Oncology Unit, Biomedical Innovation Department, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain;
- Centre for Biomedical Research Network of Oncological Diseases (CIBERONC), 29029 Madrid, Spain
| | - Eduardo López-Collazo
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain; (K.M.-H.); (R.C.-C.); (J.C.C.-D.); (J.A.-O.); (E.M.); (R.L.-R.); (V.T.-A.); (J.P.-M.); (J.V.); (R.P.d.D.); (L.C.); (E.P.); (C.d.F.)
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
- Centre for Biomedical Research Network of Respiratory Diseases (CIBERES), 28029 Madrid, Spain
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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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Tretyakova MS, Subbalakshmi AR, Menyailo ME, Jolly MK, Denisov EV. Tumor Hybrid Cells: Nature and Biological Significance. Front Cell Dev Biol 2022; 10:814714. [PMID: 35242760 PMCID: PMC8886020 DOI: 10.3389/fcell.2022.814714] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/25/2022] [Indexed: 11/13/2022] Open
Abstract
Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate, and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention, and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.
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Affiliation(s)
- Maria S Tretyakova
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Ayalur R Subbalakshmi
- Cancer Systems Biology Laboratory, Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Maxim E Menyailo
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Mohit Kumar Jolly
- Cancer Systems Biology Laboratory, Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Evgeny V Denisov
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
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Abstract
Microenvironment of cancer stem cells (CSCs) consists of a variety of cells and inter-cellular matrix and communications of the components. The microenvironment of CSCs maintains the stemness feature of the CSCs. Several cell types which communicate each other via signaling molecules surrounding CSCs are main factors of the CSC microenvironment. A key question is "What kind of information the cells exchange in the CSC microenvironment?" to reveal the microenvironment and CSC features. Components and molecular markers of CSC microenvironment, signaling cross-talks in CSC microenvironment, and targeting CSC microenvironment are focused in this review.
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Lin D, Shen L, Luo M, Zhang K, Li J, Yang Q, Zhu F, Zhou D, Zheng S, Chen Y, Zhou J. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther 2021; 6:404. [PMID: 34803167 PMCID: PMC8606574 DOI: 10.1038/s41392-021-00817-8] [Citation(s) in RCA: 466] [Impact Index Per Article: 116.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/06/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.
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Affiliation(s)
- Danfeng Lin
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Breast Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lesang Shen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Luo
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Zhang
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinfan Li
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Yang
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangfang Zhu
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dan Zhou
- Department of Surgery, Traditional Chinese Medical Hospital of Zhuji, Shaoxing, China
| | - Shu Zheng
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiding Chen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jiaojiao Zhou
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Dittmar T, Weiler J, Luo T, Hass R. Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression. Cancers (Basel) 2021; 13:5363. [PMID: 34771528 PMCID: PMC8582398 DOI: 10.3390/cancers13215363] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/22/2021] [Accepted: 10/24/2021] [Indexed: 12/13/2022] Open
Abstract
Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. Among cell fusion-inducing and -regulating factors, so-called fusogens have been identified as a specific type of proteins that are indispensable for overcoming fusion-associated energetic barriers and final merging of plasma membranes. About 8% of the human genome is of retroviral origin and some well-known fusogens, such as syncytin-1, are expressed by human (cancer) cells. Likewise, enveloped viruses can enable and facilitate cell fusion due to evolutionarily optimized fusogens, and are also capable to induce bi- and multinucleation underlining their fusion capacity. Moreover, multinucleated giant cancer cells have been found in tumors derived from oncogenic viruses. Accordingly, a potential correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion will be summarized in this review.
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Affiliation(s)
- Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany;
| | - Julian Weiler
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany;
| | - Tianjiao Luo
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
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Hass R, von der Ohe J, Dittmar T. Hybrid Formation and Fusion of Cancer Cells In Vitro and In Vivo. Cancers (Basel) 2021; 13:4496. [PMID: 34503305 PMCID: PMC8431460 DOI: 10.3390/cancers13174496] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/13/2022] Open
Abstract
The generation of cancer hybrid cells by intra-tumoral cell fusion opens new avenues for tumor plasticity to develop cancer stem cells with altered properties, to escape from immune surveillance, to change metastatic behavior, and to broaden drug responsiveness/resistance. Genomic instability and chromosomal rearrangements in bi- or multinucleated aneuploid cancer hybrid cells contribute to these new functions. However, the significance of cell fusion in tumorigenesis is controversial with respect to the low frequency of cancer cell fusion events and a clonal advantage of surviving cancer hybrid cells following a post-hybrid selection process. This review highlights alternative processes of cancer hybrid cell development such as entosis, emperipolesis, cannibalism, therapy-induced polyploidization/endoreduplication, horizontal or lateral gene transfer, and focusses on the predominant mechanisms of cell fusion. Based upon new properties of cancer hybrid cells the arising clinical consequences of the subsequent tumor heterogeneity after cancer cell fusion represent a major therapeutic challenge.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Thomas Dittmar
- Institute of Immunology, Center of Biomedical Education and Research (ZABF), Witten/Herdecke University, 58448 Witten, Germany
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33
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Sieler M, Weiler J, Dittmar T. Cell-Cell Fusion and the Roads to Novel Properties of Tumor Hybrid Cells. Cells 2021; 10:cells10061465. [PMID: 34207991 PMCID: PMC8230653 DOI: 10.3390/cells10061465] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 12/15/2022] Open
Abstract
The phenomenon of cancer cell–cell fusion is commonly associated with the origin of more malignant tumor cells exhibiting novel properties, such as increased drug resistance or an enhanced metastatic capacity. However, the whole process of cell–cell fusion is still not well understood and seems to be rather inefficient since only a certain number of (cancer) cells are capable of fusing and only a rather small population of fused tumor hybrids will survive at all. The low survivability of tumor hybrids is attributed to post-fusion processes, which are characterized by the random segregation of mixed parental chromosomes, the induction of aneuploidy and further random chromosomal aberrations and genetic/epigenetic alterations in daughter cells. As post-fusion processes also run in a unique manner in surviving tumor hybrids, the occurrence of novel properties could thus also be a random event, whereby it might be speculated that the tumor microenvironment and its spatial habitats could direct evolving tumor hybrids towards a specific phenotype.
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Soltantoyeh T, Akbari B, Karimi A, Mahmoodi Chalbatani G, Ghahri-Saremi N, Hadjati J, Hamblin MR, Mirzaei HR. Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead. Cells 2021; 10:cells10061450. [PMID: 34207884 PMCID: PMC8230324 DOI: 10.3390/cells10061450] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/31/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022] Open
Abstract
Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. These include targeted molecular therapy and novel immune-based approaches such as immune checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T-lymphocytes such as chimeric antigen receptor (CAR) T cells. Among these, CAR T cell therapy has recently made promising strides towards the treatment of advanced hematological and solid cancers. Although CAR T cell therapy might offer new hope for melanoma patients, it is not without its shortcomings, which include off-target toxicity, and the emergence of resistance to therapy (e.g., due to antigen loss), leading to eventual relapse. The present review will not only describe the basic steps of melanoma metastasis, but also discuss how CAR T cells could treat metastatic melanoma. We will outline specific strategies including combination approaches that could be used to overcome some limitations of CAR T cell therapy for metastatic melanoma.
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Affiliation(s)
- Tahereh Soltantoyeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Behnia Akbari
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Amirali Karimi
- School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran;
| | - Ghanbar Mahmoodi Chalbatani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Navid Ghahri-Saremi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Jamshid Hadjati
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa;
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; (T.S.); (B.A.); (G.M.C.); (N.G.-S.); (J.H.)
- Correspondence: ; Tel.: +98-21-64053268; Fax: +98-21-66419536
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Guimarães GR, Almeida PP, de Oliveira Santos L, Rodrigues LP, de Carvalho JL, Boroni M. Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging. Cells 2021; 10:cells10061323. [PMID: 34073434 PMCID: PMC8228751 DOI: 10.3390/cells10061323] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/22/2021] [Accepted: 05/22/2021] [Indexed: 12/12/2022] Open
Abstract
The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer.
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Affiliation(s)
- Gabriela Rapozo Guimarães
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231-050, Brazil; (G.R.G.); (P.P.A.); (L.d.O.S.)
| | - Palloma Porto Almeida
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231-050, Brazil; (G.R.G.); (P.P.A.); (L.d.O.S.)
| | - Leandro de Oliveira Santos
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231-050, Brazil; (G.R.G.); (P.P.A.); (L.d.O.S.)
| | - Leane Perim Rodrigues
- Genomic Sciences and Biotechnology Program, Catholic University of Brasilia, Brasilia 70790-160, Brazil; (L.P.R.); (J.L.d.C.)
| | - Juliana Lott de Carvalho
- Genomic Sciences and Biotechnology Program, Catholic University of Brasilia, Brasilia 70790-160, Brazil; (L.P.R.); (J.L.d.C.)
- Faculty of Medicine, University of Brasilia, Brasilia 70910-900, Brazil
| | - Mariana Boroni
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231-050, Brazil; (G.R.G.); (P.P.A.); (L.d.O.S.)
- Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas 13083-970, Brazil
- Correspondence:
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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: 20] [Impact Index Per Article: 5.0] [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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Baudoin NC, Bloomfield M. Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment. Genes (Basel) 2021; 12:558. [PMID: 33921421 PMCID: PMC8068843 DOI: 10.3390/genes12040558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/27/2021] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally very different compared to the healthy cells from which they evolved. Genomic alterations include aneuploidy (numerical and structural changes in chromosome content) and polyploidy (e.g., whole genome doubling), which can have considerable effects on cell physiology and phenotype. Likewise, conditions in the tumor microenvironment are spatially heterogeneous and vastly different than in healthy tissues, resulting in a number of environmental niches that play important roles in driving the evolution of tumor cells. While a number of studies have documented abnormal conditions of the tumor microenvironment and the cellular consequences of aneuploidy and polyploidy, a thorough overview of the interplay between karyotypically abnormal cells and the tissue and tumor microenvironments is not available. Here, we examine the evidence for how this interaction may unfold during tumor evolution. We describe a bidirectional interplay in which aneuploid and polyploid cells alter and shape the microenvironment in which they and their progeny reside; in turn, this microenvironment modulates the rate of genesis for new karyotype aberrations and selects for cells that are most fit under a given condition. We conclude by discussing the importance of this interaction for tumor evolution and the possibility of leveraging our understanding of this interplay for cancer therapy.
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Affiliation(s)
- Nicolaas C. Baudoin
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Biological Sciences and Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA 24061, USA
| | - Mathew Bloomfield
- Department of Biological Sciences and Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA 24061, USA
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38
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Di Martile M, Farini V, Consonni FM, Trisciuoglio D, Desideri M, Valentini E, D'Aguanno S, Tupone MG, Buglioni S, Ercolani C, Gallo E, Amadio B, Terrenato I, Foddai ML, Sica A, Del Bufalo D. Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages. J Immunother Cancer 2021; 8:jitc-2019-000489. [PMID: 32269145 PMCID: PMC7254128 DOI: 10.1136/jitc-2019-000489] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2020] [Indexed: 12/11/2022] Open
Abstract
Background A bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression. Methods THP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice. Results Higher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+ and CD8+IFNγ+ effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+ macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment. Conclusions Taken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies.
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Affiliation(s)
- Marta Di Martile
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Valentina Farini
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | | | - Daniela Trisciuoglio
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.,Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
| | - Marianna Desideri
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Elisabetta Valentini
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Simona D'Aguanno
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Maria Grazia Tupone
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.,Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Simonetta Buglioni
- Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Cristiana Ercolani
- Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Enzo Gallo
- Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Bruno Amadio
- SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Irene Terrenato
- Biostatistics and Bioinformatic Unit-Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Maria Laura Foddai
- Immunohematology and Transfusional Medicine Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Antonio Sica
- Molecular Immunology Lab, Humanitas Clinical and Research Center, Milan, Italy .,Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy
| | - Donatella Del Bufalo
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
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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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Cell Fusion of Mesenchymal Stem/Stromal Cells and Breast Cancer Cells Leads to the Formation of Hybrid Cells Exhibiting Diverse and Individual (Stem Cell) Characteristics. Int J Mol Sci 2020; 21:ijms21249636. [PMID: 33348862 PMCID: PMC7765946 DOI: 10.3390/ijms21249636] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the most common diseases worldwide, and treatment bears many challenges such as drug and radioresistance and formation of metastases. These difficulties are due to tumor heterogeneity, which has many origins. One may be cell fusion, a process that is relevant in both physiological (e.g., wound healing) and pathophysiological (cancer and viral infection) processes. In this study, we examined if cell fusion between mesenchymal stem/stromal cells (MSCs) and breast cancer (BC) cells occurs and if newly generated hybrid cells may exhibit cancer stem/initiating cell (CS/IC) characteristics. Therefore, several methods such as mammosphere assay, AldeRed assay, flow cytometry (CD24, CD44, CD104) and Western blot analysis (of epithelial to mesenchymal transition markers such as SNAIL, SLUG and Twist) were applied. In short, four different hybrid clones, verified by short tandem repeat (STR) analysis, were analyzed; each expressed an individual phenotype that seemed not to be explicitly related to either a more stem cell or cancer cell phenotype. These results show that cancer cells and MSCs are able to fuse spontaneously in vitro, thereby giving rise to hybrid cells with new properties, which likely indicate that cell fusion may be a trigger for tumor heterogeneity.
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Abstract
ATP is required for mammalian cells to remain viable and to perform genetically programmed functions. Maintenance of the ΔG′ATP hydrolysis of −56 kJ/mole is the endpoint of both genetic and metabolic processes required for life. Various anomalies in mitochondrial structure and function prevent maximal ATP synthesis through OxPhos in cancer cells. Little ATP synthesis would occur through glycolysis in cancer cells that express the dimeric form of pyruvate kinase M2. Mitochondrial substrate level phosphorylation (mSLP) in the glutamine-driven glutaminolysis pathway, substantiated by the succinate-CoA ligase reaction in the TCA cycle, can partially compensate for reduced ATP synthesis through both OxPhos and glycolysis. A protracted insufficiency of OxPhos coupled with elevated glycolysis and an auxiliary, fully operational mSLP, would cause a cell to enter its default state of unbridled proliferation with consequent dedifferentiation and apoptotic resistance, i.e., cancer. The simultaneous restriction of glucose and glutamine offers a therapeutic strategy for managing cancer.
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Affiliation(s)
- Thomas N Seyfried
- Biology Department, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA
| | - Gabriel Arismendi-Morillo
- Electron Microscopy Laboratory, Biological Researches Institute, Faculty of Medicine, University of Zulia, Maracaibo, Venezuela
| | - Purna Mukherjee
- Biology Department, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA
| | - Christos Chinopoulos
- Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary
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Peng Y, Li X, Liu H, Deng X, She C, Liu C, Wang X, Liu A. microRNA-18a from M2 Macrophages Inhibits TGFBR3 to Promote Nasopharyngeal Carcinoma Progression and Tumor Growth via TGF-β Signaling Pathway. NANOSCALE RESEARCH LETTERS 2020; 15:196. [PMID: 33006671 PMCID: PMC7532261 DOI: 10.1186/s11671-020-03416-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 09/14/2020] [Indexed: 05/04/2023]
Abstract
OBJECTIVES Nasopharyngeal carcinoma (NPC) is a type of nasopharyngeal disease with high metastasis and invasion properties. Tumor-associated alternative activated (M2) macrophages are evidenced to connect with NPC. Based on this, this study purposes to explore the mechanism and participation of microRNA-18a (miR-18a) from M2 macrophages in NPC. METHODS Peripheral blood mononuclear cells were differentiated to macrophages and macrophages were polarized to M2 type by interleukin-4. SUNE-1 and CNE2 cells were transfected with restored or depleted miR-18a or transforming growth factor-beta III receptor (TGFBR3) to explore their roles in NPC progression with the involvement of the TGF-β signaling pathway. Next, SUNE-1 and CNE2 cells were co-cultured with M2 macrophages that had been treated with restored or depleted miR-18a or TGFBR3 to comprehend their combined roles in NPC with the involvement of the TGF-β signaling pathway. RESULTS MiR-18a was highly expressed and TGFBR3 was lowly expressed in NPC cells. MiR-18a restoration, TGFBR3 knockdown or co-culture with miR-18a mimics, or si-TGFBR3-transfected M2 macrophages promoted SUNE-1 cell progression, tumor growth in mice, decreased p-Smad1/t-Smad1, and elevated p-Smad3/t-Smad3. miR-18a downregulation, TGFBR3 overexpression, or co-culture with miR-18a inhibitors or OE-TGFBR3-transfected M2 macrophages depressed CNE2 cell progression, tumor growth in mice, increased p-Smad1/t-Smad1, and decreased p-Smad3/t-Smad3. CONCLUSION Our study elucidates that miR-18a from M2 macrophages results in promoted NPC cell progression and tumor growth in nude mice via TGFBR3 repression, along with the Smad1 inactivation and Smad3 activation.
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Affiliation(s)
- Ya Peng
- Department of Otolaryngology Head and Neck Surgery, Affiliated Changsha Hospital of Hunan Normal University, The Fourth Hospital of Changsha, Changsha, Hunan, 410006, People's Republic of China
| | - Xiangsheng Li
- Department of Otolaryngology Head and Neck Surgery, Affiliated Changsha Hospital of Hunan Normal University, The Fourth Hospital of Changsha, Changsha, Hunan, 410006, People's Republic of China
| | - Huowang Liu
- Department of Otolaryngology Head and Neck Surgery, Third Xiangya Hospital, Central South University, 138th Tongzipo Road, Yuelu District, Changsha, Hunan, 410013, People's Republic of China
| | - Xiaowen Deng
- Department of Otolaryngology Head and Neck Surgery, Affiliated Changsha Hospital of Hunan Normal University, The Fourth Hospital of Changsha, Changsha, Hunan, 410006, People's Republic of China
| | - Chang She
- 5th Department of Cardiology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, 410005, People's Republic of China
| | - Chenxi Liu
- Third Xiangya Hospital, Central South University, 138th Tongzipo Road, Yuelu District, Changsha, Hunan, 410013, People's Republic of China
| | - Xinxing Wang
- Third Xiangya Hospital, Central South University, 138th Tongzipo Road, Yuelu District, Changsha, Hunan, 410013, People's Republic of China
| | - An Liu
- Department of Otolaryngology Head and Neck Surgery, Third Xiangya Hospital, Central South University, 138th Tongzipo Road, Yuelu District, Changsha, Hunan, 410013, People's Republic of China.
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Circulating Giant Tumor-Macrophage Fusion Cells Are Independent Prognosticators in Patients With NSCLC. J Thorac Oncol 2020; 15:1460-1471. [DOI: 10.1016/j.jtho.2020.04.034] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/09/2020] [Accepted: 04/28/2020] [Indexed: 12/24/2022]
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Skytthe MK, Graversen JH, Moestrup SK. Targeting of CD163 + Macrophages in Inflammatory and Malignant Diseases. Int J Mol Sci 2020; 21:E5497. [PMID: 32752088 PMCID: PMC7432735 DOI: 10.3390/ijms21155497] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/28/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163+ macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163+ macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates.
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Affiliation(s)
- Maria K. Skytthe
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (M.K.S.); (S.K.M.)
| | - Jonas Heilskov Graversen
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (M.K.S.); (S.K.M.)
| | - Søren K. Moestrup
- Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (M.K.S.); (S.K.M.)
- Department of Biomedicine, Aarhus University, 8200 Aarhus, Denmark
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Aguirre LA, Montalbán-Hernández K, Avendaño-Ortiz J, Marín E, Lozano R, Toledano V, Sánchez-Maroto L, Terrón V, Valentín J, Pulido E, Casalvilla JC, Rubio C, Diekhorst L, Laso-García F, del Fresno C, Collazo-Lorduy A, Jiménez-Munarriz B, Gómez-Campelo P, Llanos-González E, Fernández-Velasco M, Rodríguez-Antolín C, Pérez de Diego R, Cantero-Cid R, Hernádez-Jimenez E, Álvarez E, Rosas R, dies López-Ayllón B, de Castro J, Wculek SK, Cubillos-Zapata C, Ibáñez de Cáceres I, Díaz-Agero P, Gutiérrez Fernández M, Paz de Miguel M, Sancho D, Schulte L, Perona R, Belda-Iniesta C, Boscá L, López-Collazo E. Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells. Oncoimmunology 2020; 9:1773204. [PMID: 32923132 PMCID: PMC7458638 DOI: 10.1080/2162402x.2020.1773204] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/14/2020] [Accepted: 05/10/2020] [Indexed: 02/07/2023] Open
Abstract
The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36+CD14+PANK+ allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.
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Affiliation(s)
- Luis Augusto Aguirre
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Karla Montalbán-Hernández
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - José Avendaño-Ortiz
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centre for Biomedical Research Network of Respiratory Diseases (CIBERES), Madrid, Spain
| | - Elvira Marín
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Roberto Lozano
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Víctor Toledano
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centre for Biomedical Research Network of Respiratory Diseases (CIBERES), Madrid, Spain
| | - Laura Sánchez-Maroto
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Verónica Terrón
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Jaime Valentín
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Elisa Pulido
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - José Carlos Casalvilla
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Carolina Rubio
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Luke Diekhorst
- Department of Neurology and Stroke Centre, Neuroscience and Cerebrovascular Research Laboratory, IdiPAZ, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain
| | - Fernando Laso-García
- Department of Neurology and Stroke Centre, Neuroscience and Cerebrovascular Research Laboratory, IdiPAZ, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain
| | - Carlos del Fresno
- Immunobiology Laboratory, National Centre for Cardiovascular Research (CNIC), Madrid, Spain
| | | | | | - Paloma Gómez-Campelo
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Emilio Llanos-González
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - María Fernández-Velasco
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centre for Biomedical Research Network, CIBER-CV, Madrid, Spain
| | - Carlos Rodríguez-Antolín
- Biomarkers and Experimental Therapeutics in Cancer Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Rebeca Pérez de Diego
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ, Madrid, Spain
| | - Ramón Cantero-Cid
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Enrique Hernádez-Jimenez
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Enrique Álvarez
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Rocío Rosas
- Biomarkers and Experimental Therapeutics in Cancer Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Blanca dies López-Ayllón
- Biomarkers and Experimental Therapeutics in Cancer Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Laboratory of Experimental Models of Human Diseases, Biomedical Research Institute CSIC/UAM, Madrid, Spain
- Centre for Biomedical Research Network, CIBERER, Madrid, Spain
| | - Javier de Castro
- Biomarkers and Experimental Therapeutics in Cancer Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Stefanie K. Wculek
- Immunobiology Laboratory, National Centre for Cardiovascular Research (CNIC), Madrid, Spain
| | - Carolina Cubillos-Zapata
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centre for Biomedical Research Network of Respiratory Diseases (CIBERES), Madrid, Spain
| | | | | | - María Gutiérrez Fernández
- Department of Neurology and Stroke Centre, Neuroscience and Cerebrovascular Research Laboratory, IdiPAZ, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain
| | - María Paz de Miguel
- Cell Engineering Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - David Sancho
- Immunobiology Laboratory, National Centre for Cardiovascular Research (CNIC), Madrid, Spain
| | - Leon Schulte
- Institute for Lung Research/iLung, Research Group “Rna-biology of Inflammation & Infection,” Philipps University, Marburg, Germany
| | - Rosario Perona
- Biomarkers and Experimental Therapeutics in Cancer Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Laboratory of Experimental Models of Human Diseases, Biomedical Research Institute CSIC/UAM, Madrid, Spain
- Centre for Biomedical Research Network, CIBERER, Madrid, Spain
| | | | - Lisardo Boscá
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centre for Biomedical Research Network, CIBER-CV, Madrid, Spain
- Laboratory of Experimental Models of Human Diseases, Biomedical Research Institute CSIC/UAM, Madrid, Spain
| | - Eduardo López-Collazo
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Tumour Immunology Lab, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centre for Biomedical Research Network of Respiratory Diseases (CIBERES), Madrid, Spain
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Nasrollahzadeh E, Razi S, Keshavarz-Fathi M, Mazzone M, Rezaei N. Pro-tumorigenic functions of macrophages at the primary, invasive and metastatic tumor site. Cancer Immunol Immunother 2020; 69:1673-1697. [PMID: 32500231 DOI: 10.1007/s00262-020-02616-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 05/16/2020] [Indexed: 12/19/2022]
Abstract
The tumor microenvironment (TME) not only facilitates cancer progression from the early formation to distant metastasis, but also it differs itself from time to time alongside the tumor evolution. Tumor-associated macrophages (TAMs), whether as pre-existing tissue-resident macrophages or recruited monocytes, are an inseparable part of this microenvironment. As their parents are broadly classified into a dichotomic, simplistic M1 and M2 subtypes, TAMs also exert paradoxical and diverse phenotypes as they are settled in different regions of TME and receive different microenvironmental signals. Briefly, M1 macrophages induce an inflammatory precancerous niche and flame the early oncogenic mutations, whereas their M2 counterparts are reprogrammed to release various growth factors and providing an immunosuppressive state in TME as long as abetting hypoxic cancer cells to set up a new vasculature. Further, they mediate stromal micro-invasion and co-migrate with invasive cancer cells to invade the vascular wall and neural sheath, while another subtype of TAMs prepares suitable niches much earlier than metastatic cells arrive at the target tissues. Accordingly, at the neoplastic transformation, during the benign-to-malignant transition and through the metastatic cascade, macrophages are involved in shaping the primary, micro-invasive and pre-metastatic TMEs. Whether their behavioral plasticity is derived from distinct genotypes or is fueled by microenvironmental cues, it could define these cells as remarkably interesting therapeutic targets.
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Affiliation(s)
- Elaheh Nasrollahzadeh
- School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Keshavarz-Fathi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, VIB, KU Leuven, Louvain, B3000, Belgium
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, 14194, Tehran, Iran. .,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. .,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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Fahlbusch SS, Keil S, Epplen JT, Zänker KS, Dittmar T. Comparison of hybrid clones derived from human breast epithelial cells and three different cancer cell lines regarding in vitro cancer stem/ initiating cell properties. BMC Cancer 2020; 20:446. [PMID: 32430004 PMCID: PMC7236176 DOI: 10.1186/s12885-020-06952-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 05/12/2020] [Indexed: 12/19/2022] Open
Abstract
Background Several physiological (fertilization, placentation, wound healing) and pathophysiological processes (infection with enveloped viruses, cancer) depend on cell fusion. In cancer it was postulated that the fusion of cancer cells with normal cells such as macrophages or stem cells may not only give rise to hybrid cells exhibiting novel properties, such as an increased metastatic capacity and drug resistance, but possibly also cancer stem/ initiating cell properties. Hence, hybrid clone cells (M13HS, M13MDA435 and M13MDA231) that were derived from spontaneous fusion events of human M13SV1-EGFP-Neo breast epithelial cells and HS578T-Hyg, MDA-MB-435-Hyg and MDA-MB-231-Hyg cancer cells were investigated regarding potential in vitro cancer stem/ initiating cell properties. Methods CD44/CD24 expression pattern and ALDH1 activity of parental cells and hybrid clones was determined by flow cytometry. A colony formation and mammosphere formation assay was applied to determine the cells’ capability to form colonies and mammospheres. Sox9, Slug and Snail expression levels were determined by Western blot analysis. Results Flow cytometry revealed that all hybrid clone cells were CD44+/CD24−/low, but differed markedly among each other regarding ALDH1 activity. Likewise, each hybrid clone possessed a unique colony formation and mammosphere capacity as well as unique Snail, Slug and Sox9 expression patterns. Nonetheless, comparison of hybrid clones revealed that M13HS hybrids exhibited more in vitro cancer stem/ initiating cell properties than M13MDA231 and M13MDA435 hybrids, such as more ALDH1 positive cells or an increased capacity to form colonies and mammospheres. Conclusion The fate whether cancer stem/ initiating cells may originate from cell fusion events likely depends on the specific characteristics of the parental cells.
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Affiliation(s)
- Sera Selina Fahlbusch
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany
| | - Silvia Keil
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany
| | - Jörg T Epplen
- Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany
| | - Kurt S Zänker
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany
| | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany.
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Merle C, Thébault N, LeGuellec S, Baud J, Pérot G, Lesluyes T, Delespaul L, Lartigue L, Chibon F. Tetraploidization of Immortalized Myoblasts Induced by Cell Fusion Drives Myogenic Sarcoma Development with DMD Deletion. Cancers (Basel) 2020; 12:cancers12051281. [PMID: 32438562 PMCID: PMC7281535 DOI: 10.3390/cancers12051281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/13/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
Whole-genome doubling is the second most frequent genomic event, after TP53 alterations, in advanced solid tumors and is associated with poor prognosis. Tetraploidization step will lead to aneuploidy and chromosomic rearrangements. The mechanism leading to tetraploid cells is important since endoreplication, abortive cytokinesis and cell fusion could have distinct consequences. Unlike processes based on duplication, cell fusion involves the merging of two different genomes, epigenomes and cellular states. Since it is involved in muscle differentiation, we hypothesized that it could play a role in the oncogenesis of myogenic cancers. Spontaneous hybrids, but not their non-fused immortalized myoblast counterparts they are generated from, induced tumors in mice. Unstable upon fusion, the hybrid genome evolved from initial mitosis to tumors with a highly rearranged genome. This genome remodeling finally produced targeted DMD deletions associated with replicative stress, isoform relocalization and metastatic spreading, exactly as observed in human myogenic sarcomas. In conclusion, these results draw a model of myogenic oncogenesis in which cell fusion and oncogene activation combine to produce pleomorphic aggressive sarcomas.
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Affiliation(s)
- Candice Merle
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1037, Cancer Research Center in Toulouse (CRCT), 31037 Toulouse, France; (C.M.); (N.T.); (S.L.); (G.P.); (T.L.); (L.D.)
- Department of Biology, University of Toulouse 3, Paul Sabatier, 118 route de Narbonne, 31062 Toulouse CEDEX 9, France
- Institut Claudius Régaud, IUCT-Oncopole, 31037 Toulouse, France
| | - Noémie Thébault
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1037, Cancer Research Center in Toulouse (CRCT), 31037 Toulouse, France; (C.M.); (N.T.); (S.L.); (G.P.); (T.L.); (L.D.)
| | - Sophie LeGuellec
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1037, Cancer Research Center in Toulouse (CRCT), 31037 Toulouse, France; (C.M.); (N.T.); (S.L.); (G.P.); (T.L.); (L.D.)
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31037 Toulouse, France
| | - Jessica Baud
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1218, 229 cours de l’Argonne, F-33076 Bordeaux, France; (J.B.); (L.L.)
- Department of Life and Health Sciences, University of Bordeaux, 146 rue Léo Saignat, F-33000 Bordeaux, France
| | - Gaëlle Pérot
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1037, Cancer Research Center in Toulouse (CRCT), 31037 Toulouse, France; (C.M.); (N.T.); (S.L.); (G.P.); (T.L.); (L.D.)
- Centre Hospitalier Universitaire (CHU) de Toulouse, IUCT-Oncopole, 31037 Toulouse, France
| | - Tom Lesluyes
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1037, Cancer Research Center in Toulouse (CRCT), 31037 Toulouse, France; (C.M.); (N.T.); (S.L.); (G.P.); (T.L.); (L.D.)
| | - Lucile Delespaul
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1037, Cancer Research Center in Toulouse (CRCT), 31037 Toulouse, France; (C.M.); (N.T.); (S.L.); (G.P.); (T.L.); (L.D.)
| | - Lydia Lartigue
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1218, 229 cours de l’Argonne, F-33076 Bordeaux, France; (J.B.); (L.L.)
- Department of Life and Health Sciences, University of Bordeaux, 146 rue Léo Saignat, F-33000 Bordeaux, France
| | - Frédéric Chibon
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1037, Cancer Research Center in Toulouse (CRCT), 31037 Toulouse, France; (C.M.); (N.T.); (S.L.); (G.P.); (T.L.); (L.D.)
- Institut Claudius Régaud, IUCT-Oncopole, 31037 Toulouse, France
- Centre de Recherche en Cancérologie de Toulouse—Institut Universitaire de Cancérologie de Toulouse—Oncopôle (CRCT-IUCT-O), 2 Avenue Hubert Curien, 31037 Toulouse CEDEX 1, France
- Correspondence:
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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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Manjunath Y, Porciani D, Mitchem JB, Suvilesh KN, Avella DM, Kimchi ET, Staveley-O’Carroll KF, Burke DH, Li G, Kaifi JT. Tumor-Cell-Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer. Int J Mol Sci 2020; 21:E1872. [PMID: 32182935 PMCID: PMC7084898 DOI: 10.3390/ijms21051872] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/06/2020] [Accepted: 03/07/2020] [Indexed: 02/06/2023] Open
Abstract
Although molecular mechanisms driving tumor progression have been extensively studied, the biological nature of the various populations of circulating tumor cells (CTCs) within the blood is still not well understood. Tumor cell fusion with immune cells is a longstanding hypothesis that has caught more attention in recent times. Specifically, fusion of tumor cells with macrophages might lead to the development of metastasis by acquiring features such as genetic and epigenetic heterogeneity, chemotherapeutic resistance, and immune tolerance. In addition to the traditional FDA-approved definition of a CTC (CD45-, EpCAM+, cytokeratins 8+, 18+ or 19+, with a DAPI+ nucleus), an additional circulating cell population has been identified as being potential fusions cells, characterized by distinct, large, polymorphonuclear cancer-associated cells with a dual epithelial and macrophage/myeloid phenotype. Artificial fusion of tumor cells with macrophages leads to migratory, invasive, and metastatic phenotypes. Further studies might investigate whether these have a potential impact on the immune response towards the cancer. In this review, the background, evidence, and potential relevance of tumor cell fusions with macrophages is discussed, along with the potential role of intercellular connections in their formation. Such fusion cells could be a key component in cancer metastasis, and therefore, evolve as a diagnostic and therapeutic target in cancer precision medicine.
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Affiliation(s)
- Yariswamy Manjunath
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - David Porciani
- Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65212, USA; (D.P.); (D.H.B.)
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, USA
| | - Jonathan B. Mitchem
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Kanve N. Suvilesh
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
| | - Diego M. Avella
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Eric T. Kimchi
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
| | - Donald H. Burke
- Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65212, USA; (D.P.); (D.H.B.)
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, USA
- Department of Biochemistry, University of Missouri, Columbia, MO 65212, USA
| | - Guangfu Li
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65212, USA; (D.P.); (D.H.B.)
| | - Jussuf T. Kaifi
- Department of Surgery, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA; (Y.M.); (J.B.M.); (K.N.S.); (D.M.A.); (E.T.K.); (K.F.S.-O.); (G.L.)
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
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