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Shabo I, Midtbö K, Bränström R, Lindström A. Monocyte-cancer cell fusion is mediated by phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation. PLoS One 2025; 20:e0311027. [PMID: 39752516 PMCID: PMC11698428 DOI: 10.1371/journal.pone.0311027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 09/11/2024] [Indexed: 01/06/2025] Open
Abstract
Emerging evidence suggests that fusion of cancer cells with leucocytes, such as macrophages, plays a significant role in cancer metastasis and results in tumor hybrid cells that acquire resistance to chemo- and radiation therapy. However, the precise mechanisms behind the leukocyte-cancer cell fusion remain unclear. The present in vitro study explores the presence of fusion between the monocyte cell line (THP-1) and the breast cancer cell line (MCF-7) in relation to the expression of CD36 and phosphatidylserine with and without treatment of these cells with ionizing radiation. The study reveals that spontaneous THP-1/MCF-7 cell fusion increases significantly from 2.8% to 6% after irradiation. The interaction between CD36 and phosphatidylserine plays a pivotal role in THP-1/MCF-7 cell fusion, as inhibiting this interaction using anti-CD36 antibodies significantly reduces cell fusion. While irradiation leads to a dose-dependent escalation in phosphatidylserine expression in MCF-7 cells, it does not impact the expression of CD36 in either THP-1 or MCF-7 cells. To the best of our knowledge, this is the first study to demonstrate the involvement of the CD36-phosphatidylserine interaction in the fusion between monocytes and cancer cells, shedding light on a novel explanatory mechanism for the roles of CD36 and phosphatidylserine in tumor progression.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Kristine Midtbö
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Robert Bränström
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Annelie Lindström
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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2
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Hoque S, Dhar R, Kar R, Mukherjee S, Mukherjee D, Mukerjee N, Nag S, Tomar N, Mallik S. Cancer stem cells (CSCs): key player of radiotherapy resistance and its clinical significance. Biomarkers 2023; 28:139-151. [PMID: 36503350 DOI: 10.1080/1354750x.2022.2157875] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are self-renewing and slow-multiplying micro subpopulations in tumour microenvironments. CSCs contribute to cancer's resistance to radiation (including radiation) and other treatments. CSCs control the heterogeneity of the tumour. It alters the tumour's microenvironment cellular singling and promotes epithelial-to-mesenchymal transition (EMT). Current research decodes the role of extracellular vesicles (EVs) and CSCs interlink in radiation resistance. Exosome is a subpopulation of EVs and originated from plasma membrane. It is secreted by several active cells. It involed in cellular communication and messenger of healthly and multiple pathological complications. Exosomal biological active cargos (DNA, RNA, protein, lipid and glycan), are capable to transform recipient cells' nature. The molecular signatures of CSCs and CSC-derived exosomes are potential source of cancer theranostics development. This review discusse cancer stem cells, radiation-mediated CSCs development, EMT associated with CSCs, the role of exosomes in radioresistance development, the current state of radiation therapy and the use of CSCs and CSCs-derived exosomes biomolecules as a clinical screening biomarker for cancer. This review gives new researchers a reason to keep an eye on the next phase of scientific research into cancer theranostics that will help mankind.
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Affiliation(s)
- Saminur Hoque
- Department of Radiology, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Rajib Dhar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
| | - Rishav Kar
- Department of Medical Biotechnology, Ramakrishna Mission Vivekananda Educational and Research Institute
| | - Sayantanee Mukherjee
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | | | - Nobendu Mukerjee
- Department of Microbiology, West Bengal State University, Kolkata, West Bengal, India.,Department of Health Sciences, Novel Global Community Educational Foundation, Australia
| | - Sagnik Nag
- Department of Biotechnology, School of Biosciences & Technology, Vellore Institute of Technology (VIT), Tamil Nadu, India
| | - Namrata Tomar
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Saurav Mallik
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Department of Environmental Health, Harvard T H Chan School of Public Health, Boston, MA, USA
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3
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Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion. Commun Biol 2021; 4:575. [PMID: 33990693 PMCID: PMC8121918 DOI: 10.1038/s42003-021-02082-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy. Katagi et al. show that abnormal bone marrow-derived cells originated from hematopoietic stem cells (CD106-positive short-term HSCs) aberrantly fuse with neurons to develop diabetic neuropathy. This study suggests that the pathological abnormality is memorized in the bone marrow and that it cannot be erased by conventional therapy.
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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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5
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Lizier M, Anselmo A, Mantero S, Ficara F, Paulis M, Vezzoni P, Lucchini F, Pacchiana G. Fusion between cancer cells and macrophages occurs in a murine model of spontaneous neu+ breast cancer without increasing its metastatic potential. Oncotarget 2018; 7:60793-60806. [PMID: 27563823 PMCID: PMC5308617 DOI: 10.18632/oncotarget.11508] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 08/11/2016] [Indexed: 12/31/2022] Open
Abstract
Cell fusion between neoplastic and normal cells has been suggested to play a role in the acquisition of a malignant phenotype. Several studies have pointed to the macrophage as the normal partner in this fusion, suggesting that the fused cells could acquire new invasive properties and become able to disseminate to distant organs. However, this conclusion is mainly based on studies with transplantable cell lines. We tested the occurrence of cell fusion in the MMTV-neu model of mouse mammary carcinoma. In the first approach, we generated aggregation chimeras between GFP/neu and RFP/neu embryos. Tumor cells would display both fluorescent proteins only if cell fusion with normal cells occurred. In addition, if cell fusion conferred a growth/dissemination advantage, cells with both markers should be detectable in lung metastases at increased frequency. We confirmed that fused cells are present at low but consistent levels in primary neoplasms and that the macrophage is the normal partner in the fusion events. Similar results were obtained using a second approach in which bone marrow from mice carrying the Cre transgene was transplanted into MMTV-neu/LoxP-tdTomato transgenic animals, in which the Tomato gene is activated only in the presence of CRE recombinase. However, no fused cells were detected in lung metastases in either model. We conclude that fusion between macrophages and tumor cells does not confer a selective advantage in our spontaneous model of breast cancer, although these data do not rule out a possible role in models in which an inflammation environment is prominent.
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Affiliation(s)
- Michela Lizier
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan,Italy.,Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,Centro Ricerche Biotecnologiche, Università Cattolica del Sacro Cuore, Cremona, Milan, Italy
| | - Achille Anselmo
- Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Stefano Mantero
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan,Italy.,Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Francesca Ficara
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan,Italy.,Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Marianna Paulis
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan,Italy.,Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Paolo Vezzoni
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan,Italy.,Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Franco Lucchini
- Centro Ricerche Biotecnologiche, Università Cattolica del Sacro Cuore, Cremona, Milan, Italy
| | - Giovanni Pacchiana
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan,Italy.,Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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6
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Aggressive serous epithelial ovarian cancer is potentially propagated by EpCAM +CD45 + phenotype. Oncogene 2018; 37:2089-2103. [PMID: 29379166 DOI: 10.1038/s41388-017-0106-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 10/24/2017] [Accepted: 11/30/2017] [Indexed: 12/26/2022]
Abstract
Epithelial ovarian carcinoma (EOC) patients often acquire resistance against common chemotherapeutic drugs like paclitaxel and cisplatin. The mechanism responsible for the same is ambiguous. We have identified a putative drug-resistant tumour cell phenotype (EpCAM+CD45+) in the ascitic fluid of EOC patients, which appears to originate from the primary tumour. These cells represent the major tumour burden and are more drug resistant compared to EpCAM+ tumour cells due to the over-expression of SIRT1, ABCA1 and BCL2 genes. We have found that the entire EpCAM+CD45+ population is highly invasive with signature mesenchymal gene expression and also consists of subpopulations of ovarian cancer stem cells (CD133+ and CD117+CD44+). Additionally, we demonstrate that the EpCAM+CD45+ tumour cells over-express major histocompatibility complex class I antigen, which enable them to evade the natural killer cell-mediated immune surveillance. Preliminary evidence obtained in OVCAR-5 cells suggests that exosomes, secreted by non-tumour cells of the ascitic fluid, play an important role in rendering drug resistance and invasive properties to the cancer cells. Identification of such aggressive tumour cells and deciphering their origin is important for designing better drug targets for EOC.
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7
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Parcesepe P, Giordano G, Laudanna C, Febbraro A, Pancione M. Cancer-Associated Immune Resistance and Evasion of Immune Surveillance in Colorectal Cancer. Gastroenterol Res Pract 2016; 2016:6261721. [PMID: 27006653 PMCID: PMC4781955 DOI: 10.1155/2016/6261721] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 01/11/2016] [Accepted: 01/20/2016] [Indexed: 02/08/2023] Open
Abstract
Data from molecular profiles of tumors and tumor associated cells provide a model in which cancer cells can acquire the capability of avoiding immune surveillance by expressing an immune-like phenotype. Recent works reveal that expression of immune antigens (PDL1, CD47, CD73, CD14, CD68, MAC387, CD163, DAP12, and CD15) by tumor cells "immune resistance," combined with prometastatic function of nonmalignant infiltrating cells, may represent a strategy to overcome the rate-limiting steps of metastatic cascade through (a) enhanced interactions with protumorigenic myeloid cells and escape from T-dependent immune response mediated by CD8+ and natural killer (NK) cells; (b) production of immune mediators that establish a local and systemic tumor-supportive environment (premetastatic niche); (c) ability to survive either in the peripheral blood as circulating tumor cells (CTCs) or at the metastatic site forming a cooperative prometastatic loop with foreign "myeloid" cells, macrophages, and neutrophils, respectively. The development of cancer-specific "immune resistance" can be orchestrated either by cooperation with tumor microenvironment or by successive rounds of genetic/epigenetic changes. Recognition of the applicability of this model may provide effective therapeutic avenues for complete elimination of immune-resistant metastatic cells and for enhanced antitumor immunity as part of a combinatorial strategy.
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Affiliation(s)
- Pietro Parcesepe
- Department of Pathology and Diagnostics, University of Verona, 31134 Verona, Italy
| | - Guido Giordano
- Medical Oncology Unit, Fatebenefratelli Hospital, 82100 Benevento, Italy
| | - Carmelo Laudanna
- Department of Experimental and Clinical Medicine “Gaetano Salvatore”, University “Magna Grecia”, 88100 Catanzaro, Italy
| | - Antonio Febbraro
- Medical Oncology Unit, Fatebenefratelli Hospital, 82100 Benevento, Italy
| | - Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy
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8
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Graversen JH, Moestrup SK. Drug Trafficking into Macrophages via the Endocytotic Receptor CD163. MEMBRANES 2015; 5:228-52. [PMID: 26111002 PMCID: PMC4496642 DOI: 10.3390/membranes5020228] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/11/2015] [Indexed: 12/12/2022]
Abstract
In inflammatory diseases, macrophages are a main producer of a range of cytokines regulating the inflammatory state. This also includes inflammation induced by tumor growth, which recruits so-called tumor-associated macrophages supporting tumor growth. Macrophages are therefore relevant targets for cytotoxic or phenotype-modulating drugs in the treatment of inflammatory and cancerous diseases. Such targeting of macrophages has been tried using the natural propensity of macrophages to non-specifically phagocytose circulating foreign particulate material. In addition, the specific targeting of macrophage-expressed receptors has been used in order to obtain a selective uptake in macrophages and reduce adverse effects of off-target delivery of drugs. CD163 is a highly expressed macrophage-specific endocytic receptor that has been studied for intracellular delivery of small molecule drugs to macrophages using targeted liposomes or antibody drug conjugates. This review will focus on the biology of CD163 and its potential role as a target for selective macrophage targeting compared with other macrophage targeting approaches.
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Affiliation(s)
- Jonas Heilskov Graversen
- Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsløws Vej 25, 5000-Odense C, Denmark.
| | - Søren Kragh Moestrup
- Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsløws Vej 25, 5000-Odense C, Denmark.
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000-Odense C, Denmark.
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9
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Parris GE. Cell-Cell Fusion, Chemotaxis and Metastasis. INTERCELLULAR COMMUNICATION IN CANCER 2015:227-254. [DOI: 10.1007/978-94-017-7380-5_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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10
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Shabo I, Olsson H, Elkarim R, Sun XF, Svanvik J. Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer. CANCER MICROENVIRONMENT 2014; 7:61-9. [PMID: 24771466 DOI: 10.1007/s12307-014-0145-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 04/07/2014] [Indexed: 12/11/2022]
Abstract
The scavenger receptor, CD163, is a macrophage-specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffin-embedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P = 0.008) and unfavorable prognosis (p = 0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p = 0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer.
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Affiliation(s)
- Ivan Shabo
- Department of surgery, County Council of Östergötland, Linköping, Sweden,
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Ramakrishnan M, Mathur SR, Mukhopadhyay A. Fusion-derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma. Cancer Res 2013; 73:5360-70. [PMID: 23856249 DOI: 10.1158/0008-5472.can-13-0896] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
For a long time, the external milieu of cancer cells was considered to be of secondary importance when compared with its intrinsic properties. That has changed now as the microenvironment is considered to be a major contributing factor toward the progression of tumor. In this study, we show that in human and mouse epithelial ovarian carcinoma and mouse lung carcinoma, the interaction between tumor-infiltrating hematopoietic cells and epithelial cancer cells results in their fusion. Intriguingly, even after the fusion event, cancer cells retain the expression of the pan-hematopoietic marker (CD45) and various markers of hematopoietic lineage, including those of hematopoietic stem cells, indicating that the hematopoietic genome is not completely reprogrammed. This observation may have implications on the bone marrow contribution to the cancer stem cell population. Interestingly, it was seen that in both cancer models, the expression of chemokine receptor CXCR4 was largely contributed to by the fused compartment of cancer cells. We hypothesize that the superior migratory potential gained by the cancer cells due to the fusion helps in its dissemination to various secondary organs upon activation of the CXCR4/CXCL12 axis. We are the first to report the presence of a hemato-epithelial cancer compartment, which contributes to stem cell markers and CXCR4 in epithelial carcinoma. This finding has repercussions on CXCR4-based therapeutics and opens new avenues in discovering novel molecular targets against fusion and metastasis.
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Affiliation(s)
- Mallika Ramakrishnan
- Stem Cell Biology Laboratory, National Institute of Immunology, All India Institute of Medical Sciences, New Delhi, India
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12
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Breast cancer expression of DAP12 is associated with skeletal and liver metastases and poor survival. Clin Breast Cancer 2013; 13:371-7. [PMID: 23810293 DOI: 10.1016/j.clbc.2013.05.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/30/2013] [Accepted: 05/03/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND The transmembrane adapter protein, DAP12, transduces activation signals for several arrays of receptors, including human signal-regulatory protein, DAP12-associating lectin-1, triggering receptor expressed on myeloid cells-1, -2, and -3, in natural killer cells, granulocytes, monocytes/macrophages, and dendritic cells. The macrophage-specific antigen, Cluster of Differentiation 163 (CD163), is expressed in breast and colorectal cancers and is associated with early cancer recurrence and poor prognosis. It was recently shown that fusion between intestinal tumor cells and macrophages results in nuclear reprogramming with hybrid transcripts from both cells of origin. The role of DAP12 in the fusion process is not known. This study investigates the expression of DAP12 in BRC cells, and its relation to other macrophage traits and to the clinical progression of disease. MATERIALS AND METHODS Immunostaining of DAP12 and CD163 was performed and evaluated in paraffin-embedded specimens from 132 patients with BRC. The outcomes were analyzed in relation to clinicopathological data. RESULTS DAP12 expression in cancer cells was positive in 66 percent of the cancers and was associated with high tumor grade (P = .015), and with liver (P = .047) and skeletal (P = .067), but not with lung metastases (P = 1.00). Patients with BRC expressing DAP12 had poor prognosis, with higher recurrence rates of skeletal (P = .018) and liver metastases (P = .047), and shorter survival time (P = .0060). CONCLUSION We suggest that macrophage traits in BRC cells facilitate the metastatic process and that DAP12 expression might promote metastatic homing to bone and liver tissues.
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Abstract
Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing "seed and soil" hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management.
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Affiliation(s)
- Thomas N Seyfried
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA.
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14
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Shabo I, Svanvik J. Expression of macrophage antigens by tumor cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 714:141-50. [PMID: 21506012 DOI: 10.1007/978-94-007-0782-5_7] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Macrophages are a heterogeneous cell population of the myeloid linage derived from monocytes. These cells show two different polarization states, M1 and M2 macrophages in response to different micro environmental signals. Tumor associated macrophages (TAM) represent the M2 type and promote tumor progression. These cells express antigens that more or less are specific for macrophages like: CD14, CD68, MAC387, CD163, and DAP12. In a series of recent studies it is shown that cancer cells may express these antigens and CD163, MAC387 and DAP12 may be expressed by e.g. breast cancer cells. Thus, 48% of the breast cancers expressed CD163 that is a scavenger receptor normally expressed by macrophages alone. The corresponding figure for rectal cancer is 31%. The expression of CD163 is correlated to early distant recurrence in breast cancer and local recurrence in rectal cancer and reduced survival time in both conditions. Expression of macrophage antigens in breast- and colorectal-cancers may have a prognostic relevance in clinical praxis. One explanation to these findings is that resemblance with macrophages may indicate a more invasive phenotype due to genetic exchange between the primary tumor cells and associated macrophages. This is further supported by the finding that expression of DAP12, a macrophage fusion receptor, in breast cancer is associated with an advanced tumor grade and higher rates of skeletal and liver metastases and overall shorter distant recurrence free survival. Another explanation to the changed phenotype is a genetic exchange between the cells by exosome-mediated transfer.
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Affiliation(s)
- Ivan Shabo
- Department of Surgery, Linköping University, Linköping, Sweden.
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15
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Abstract
Emerging evidence suggests that many metastatic cancers arise from cells of the myeloid/macrophage lineage regardless of the primary tissue of origin. A myeloid origin of metastatic cancer stands apart from origins involving clonal evolution or epithelial-mesenchymal transitions. Evidence is reviewed demonstrating that numerous human cancers express multiple properties of macrophages including phagocytosis, fusogenicity, and gene/protein expression. It is unlikely that the macrophage properties expressed in metastatic cancers arise from sporadic random mutations in epithelial cells, but rather from damage to an already existing mesenchymal cell, e.g., a myeloid/macrophage-type cell. Such cells would naturally embody the capacity to express the multiple behaviors of metastatic cells. The view of metastasis as a myeloid/macrophage disease will impact future cancer research and anti-metastatic therapies.
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Affiliation(s)
- Leanne C. Huysentruyt
- Department of Medicine, Hematology and Oncology, University of California, San Francisco, San Francisco, CA USA
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16
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Lluis F, Cosma MP. Cell-fusion-mediated somatic-cell reprogramming: a mechanism for tissue regeneration. J Cell Physiol 2010; 223:6-13. [PMID: 20049847 DOI: 10.1002/jcp.22003] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Spontaneous cell fusion between two cells of different lineages will originate new hybrid cells that have different features from the original parent cells. It has been shown that injury to a tissue can enhance spontaneous cell-cell fusion events. If one of the parent cells of a cell-cell fusion is highly plastic, such as a stem cell, and the other is a somatic cell, their fusion can be followed by reprogramming events that can generate new hybrid pluripotent cells. These, in turn, have the potential to differentiate and regenerate the damaged tissue. However, if this process is deregulated, this would provide a mechanism for cancer development.
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Affiliation(s)
- Frederic Lluis
- Telethon Institute of Genetics and Medicine and Institute of Genetics and Biophysics, CNR, Naples, Italy
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17
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Shabo I, Olsson H, Sun XF, Svanvik J. Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time. Int J Cancer 2009; 125:1826-31. [PMID: 19582880 DOI: 10.1002/ijc.24506] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Expression of the macrophage antigen CD163 in breast cancer cells is recently shown to be related to early distant recurrence and shortened survival. In this study, 163 patients with rectal cancer, included in the Swedish rectal cancer trial and followed up for a median of 71 months, were examined for the expression of CD163 in the primary tumors. The cancer cells expressed CD163 in the primary tumors in 23% (n = 32) of the patients. In pretreatment biopsies from 101 patients, 10 had CD163-positive cancers and these patients had earlier local recurrence (p < 0.044) and reduced survival time (p < 0.045) compared with those with CD163-negative tumors. When studying surgical specimens from 61 patients randomized to preoperative irradiation (5 x 5 Gy delivered in 1 week), it was found that 31% were CD163 positive whereas the corresponding figure was only 17% for 78 patients who were nonirradiated (p < 0.044), which tentatively may be consistent with X-rays inducing fusion. In CD163-positive tumors there was a reduced apoptotic activity as measured with the Termina deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) technique (p = 0.018). There tended also to be an increased proliferation activity measured as an expression of Ki-67 non significant (NS). It is concluded that primary rectal cancers may express CD-163, and this phenotypic macrophage trait is related to early local recurrence, shorter survival time and reduced apoptosis. Furthermore, the expression of CD163 is more common after irradiation.
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Affiliation(s)
- Ivan Shabo
- Division of Surgery, Institution of Clinical and Experimental Medicine, University of Linköping, Sweden
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18
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Shabo I, Stål O, Olsson H, Doré S, Svanvik J. Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int J Cancer 2008; 123:780-6. [PMID: 18506688 DOI: 10.1002/ijc.23527] [Citation(s) in RCA: 183] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cells of the monocyte/macrophage lineage are important for tumour cell migration, invasion and metastasis. Fusion between macrophages and cancer cells in animal models in vitro and in vivo causes hybrids with increased metastatic potential. Primary breast cancer cells were characterized for macrophage antigens to test if phenotypic resemblance to macrophages is related to early distant recurrence. Immunostaining for CD163, MAC387 and CD68 was performed in a breast cancer tissue micro array from 127 patients consequently followed up for a median of 13 years. Tumour-associated macrophages expressed all 3 antigens. The breast cancers expressed CD163 to 48%, MAC387 to 14% while CD68 was not expressed. TGF-beta staining intensity was positively related to both CD163 and MAC387 expression. Expression of CD163 in the cancer cells was compared to their DNA ploidy, Nottingham Histological Grade, TNM-stage, node state, presence of estrogen receptors and occurrence of distant metastases and survival. Cancers of a more advanced histological grade expressed CD163 to a higher extent. Cells expressing MAC387 were more common in cancers with a high proportion of CD163 positive cells. Multivariate analysis showed that expression of the macrophage antigen CD163 in breast cancer cells has a prognostic impact on the occurrence of distant metastases and reduced patient survival time.
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Affiliation(s)
- Ivan Shabo
- Division of Surgery, Department of Biomedicine and Surgery, University of Linköping, Linköping, Sweden
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19
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Abstract
Cell fusions are important to fertilization, placentation, development of skeletal muscle and bone, calcium homeostasis and the immune defense system. Additionally, cell fusions participate in tissue repair and may be important to cancer development and progression. A large number of factors appear to regulate cell fusions, including receptors and ligands, membrane domain organizing proteins, proteases, signaling molecules and fusogenic proteins forming alpha-helical bundles that bring membranes close together. The syncytin family of proteins represent true fusogens and the founding member, syncytin-1, has been documented to be involved in fusions between placental trophoblasts, between cancer cells and between cancer cells and host cells. We review the literature with emphasis on the syncytin family and propose that syncytins may represent universal fusogens in primates and rodents, which work together with a number of other proteins to regulate the cell fusion machinery.
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20
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Edovitsky E, Elkin M, Zcharia E, Peretz T, Vlodavsky I. Heparanase gene silencing, tumor invasiveness, angiogenesis, and metastasis. J Natl Cancer Inst 2004; 96:1219-30. [PMID: 15316057 DOI: 10.1093/jnci/djh230] [Citation(s) in RCA: 192] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Heparanase is an endoglycosidase that degrades heparan sulfate, the main polysaccharide constituent of the extracellular matrix and basement membrane. Expression of the heparanase gene is associated with the invasive, angiogenic, and metastatic potential of diverse malignant tumors and cell lines. We used gene-silencing strategies to evaluate the role of heparanase in malignancy and to explore the therapeutic potential of its specific targeting. METHODS We designed plasmid vectors to express hammerhead ribozymes or small interfering RNAs (siRNAs) directed against the human or mouse heparanase mRNAs. Human breast carcinoma (MDA-MB-435) and mouse lymphoma (Eb) and melanoma (B16-BL6) tumor cell lines, which have naturally high levels of endogenous heparanase or have been genetically engineered to overexpress heparanase, were transfected with anti-heparanase ribozyme or siRNA. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and measurements of enzymatic activity were used to confirm the efficient silencing of heparanase gene expression. Cells transfected with the anti-heparanase ribozyme and siRNA vectors were tested for invasiveness in vitro and metastatic dissemination in animal models of experimental and spontaneous metastasis. RESULTS Compared with cells transfected with control constructs, cells transfected with the anti-heparanase ribozyme or siRNA vectors had profoundly reduced invasion and adhesion in vitro, regardless of cell type, and expressed less heparanase. In vivo, tumors produced by cells transfected with the anti-heparanase ribozyme and siRNA vectors were less vascularized and less metastatic than tumors produced by cells transfected with the control vectors. Mice injected with cells transfected with the anti-heparanase ribozyme and siRNA vectors lived longer than mice injected with control cells. CONCLUSIONS The association of reduced levels of heparanase and altered tumorigenic properties in cells with anti-heparanase ribozyme- or siRNA-mediated gene-silencing vectors suggests that heparanase is important in cancer progression. Heparanase gene silencing has potential use as a target for anticancer drug development.
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MESH Headings
- Angiogenesis Inducing Agents/metabolism
- Angiogenesis Inhibitors/pharmacology
- Animals
- Basement Membrane/enzymology
- Basement Membrane/pathology
- Disease Progression
- Enzyme Inhibitors/pharmacology
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Genetic Vectors
- Glucuronidase/antagonists & inhibitors
- Glucuronidase/genetics
- Glucuronidase/metabolism
- Growth Substances/metabolism
- Heparitin Sulfate/metabolism
- Humans
- Immunohistochemistry
- Lung Neoplasms/enzymology
- Lung Neoplasms/genetics
- Lung Neoplasms/secondary
- Male
- Melanoma, Experimental/enzymology
- Melanoma, Experimental/genetics
- Mice
- Mice, Inbred C57BL
- Neoplasm Invasiveness/genetics
- Neoplasm Metastasis/drug therapy
- Neoplasm Metastasis/genetics
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/genetics
- Plasmids
- RNA, Catalytic/pharmacology
- RNA, Neoplasm/metabolism
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Transfection
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Affiliation(s)
- Evgeny Edovitsky
- Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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21
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Vassilopoulos G, Russell DW. Cell fusion: an alternative to stem cell plasticity and its therapeutic implications. Curr Opin Genet Dev 2004; 13:480-5. [PMID: 14550412 DOI: 10.1016/s0959-437x(03)00110-2] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cell fusion has long been known to produce viable cells and to have a major role in mammalian development and differentiation. As gene expression profiles can change after cell fusion, this event must be also considered as an alternative explanation for the many cases of 'stem cell plasticity' that have been recently described and are promoted as a promising therapeutic strategy. Cell fusion has been demonstrated to occur in some recent studies, and the available evidence is often not inconsistent with cell fusion in others. Cell fusion itself has therapeutic potential, but low rates of spontaneous fusion and safety concerns may ultimately limit its use.
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Affiliation(s)
- George Vassilopoulos
- Division of Hematology, Department of Medicine, Mailstop 357720, University of Washington, Seattle, Washington 98195-7720, USA.
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22
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Noble M, Dietrich J. The complex identity of brain tumors: emerging concerns regarding origin, diversity and plasticity. Trends Neurosci 2004; 27:148-54. [PMID: 15036880 DOI: 10.1016/j.tins.2003.12.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Elucidation of genetic and epigenetic mechanisms underlying neoplasia is one of the great success stories of modern science, but this success has not been associated with parallel improvements in the treatment of malignant tumors. One possible explanation for this failure is that the most important variables that support growth of malignancies are not yet identified. Another possible explanation, however, is that multiple variables important in neoplastic progression combine to create a level of disease complexity not taken into account by current therapeutic approaches. The study of development and neoplasia in the CNS provides some of the strongest support for the latter view--a view that, if correct, would suggest that a radical rethinking of the biology of malignancy is required if we are to make progress in the treatment of this important medical condition.
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Affiliation(s)
- Mark Noble
- Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA.
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23
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Müerköster S, Weigand MA, Choi C, Walczak H, Schirrmacher V, Umansky V. Superantigen reactive Vbeta6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells. Br J Cancer 2002; 86:828-36. [PMID: 11875749 PMCID: PMC2375320 DOI: 10.1038/sj.bjc.6600104] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2001] [Revised: 11/22/2001] [Accepted: 11/23/2001] [Indexed: 12/02/2022] Open
Abstract
The endogenous viral superantigen 7 in DBA/2 mice serves as a target antigen on syngeneic ESb-MP lymphoma cells for allogeneic graft-vs-leukaemia reactive cells. Allogeneic viral superantigen 7 reactive Vbeta6+ T cells are able to transfer graft-vs-leukaemia reactivity and to kill specifically viral superantigen 7+ ESb-MP tumour cells in vitro. Here we elucidate the mechanism of this superantigen specific cell lysis. Already 10 min after co-incubation with in vitro stimulated Vbeta6+ T cells, viral superantigen 7+ ESb-MP tumour cells show an apoptotic phenotype (Annexin V-positivity, DNA-fragmentation). This extremely rapid type of cell death is not mediated by the death inducing ligands CD95L, TRAIL and TNF but by perforin and granzyme B. Surprisingly, neither mitochondria nor any of the known caspases appear to be involved in this type of tumour cell killing. In contrast, nitric oxide, released by activated macrophages and endothelial cells, induces in the same tumour cells another type of apoptosis which is much slower and involves mitochondria and caspase activation. A synergistic effect between the two different effector mechanisms of superantigen reactive donor cytotoxic T lymphocytes and nitric oxide releasing host macrophages and endothelial cells might explain the effective immune rejection of even advanced metastasised cancer in this graft-vs-leukaemia animal model.
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Affiliation(s)
- S Müerköster
- Division of Cellular Immunology, G0100, Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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24
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Abstract
This article reviews a long-standing hypothesis that metastases might be initiated through the generation of hybrids between primary tumour cells and tumour-infiltrating leucocytes such as macrophages. In this concept the hybrids become metastatic through expression of the leucocyte motility phenotype. A history of the hybrid hypothesis is presented along with recent evidence on how macrophage x tumour cell hybridization could account for some of the most defining characteristics of metastatic cells: aneuploidy, enhanced motility, aberrant glycosylation and, particularly seen in melanoma, phenotypic diversity.
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Affiliation(s)
- J M Pawelek
- Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
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25
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Schirrmacher V, Müerköster S, Bucur M, Umansky V, Rocha M. Breaking tolerance to a tumor-associated viral superantigen as a basis for graft-versus-leukemia reactivity. Int J Cancer 2000. [DOI: 10.1002/1097-0215(20000901)87:5<695::aid-ijc12>3.0.co;2-b] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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26
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Vlodavsky I, Friedmann Y, Elkin M, Aingorn H, Atzmon R, Ishai-Michaeli R, Bitan M, Pappo O, Peretz T, Michal I, Spector L, Pecker I. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat Med 1999; 5:793-802. [PMID: 10395325 DOI: 10.1038/10518] [Citation(s) in RCA: 617] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Heparan sulfate proteoglycans interact with many extracellular matrix constituents, growth factors and enzymes. Degradation of heparan sulfate by endoglycosidic heparanase cleavage affects a variety of biological processes. We have purified a 50-kDa heparanase from human hepatoma and placenta, and now report cloning of the cDNA and gene encoding this enzyme. Expression of the cloned cDNA in insect and mammalian cells yielded 65-kDa and 50-kDa recombinant heparanase proteins. The 50-kDa enzyme represents an N-terminally processed enzyme, at least 100-fold more active than the 65-kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and specimens of human breast, colon and liver carcinomas. Low metastatic murine T-lymphoma and melanoma cells transfected with the heparanase cDNA acquired a highly metastatic phenotype in vivo, reflected by a massive liver and lung colonization. This represents the first cloned mammalian heparanase, to our knowledge, and provides direct evidence for its role in tumor metastasis. Cloning of the heparanase gene enables the development of specific molecular probes for early detection and treatment of cancer metastasis and autoimmune disorders.
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MESH Headings
- Amino Acid Sequence
- Animals
- Base Sequence
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line
- Chromosome Mapping
- Chromosomes, Human, Pair 4
- Cloning, Molecular
- Disease Progression
- Enzyme Activation
- Extracellular Matrix/physiology
- Female
- Genomic Library
- Glucuronidase
- Glycoside Hydrolases/genetics
- Glycoside Hydrolases/isolation & purification
- Glycoside Hydrolases/metabolism
- Humans
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Mammals
- Mice
- Mice, Inbred DBA
- Molecular Sequence Data
- Molecular Weight
- Moths
- Neoplasm Metastasis/physiopathology
- Placenta/enzymology
- Pregnancy
- RNA, Messenger/genetics
- Recombinant Proteins/biosynthesis
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription, Genetic
- Transfection
- Tumor Cells, Cultured
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Affiliation(s)
- I Vlodavsky
- Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
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Ji Y, Ling MY, Li Y, Xie H. Effect of cell fusion on metastatic ability of mouse hepatocarcinoma cell lines. World J Gastroenterol 1999; 5:22-24. [PMID: 11819377 PMCID: PMC4688491 DOI: 10.3748/wjg.v5.i1.22] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To study the effect of cell fusion on metastatic ability of mouse hepatocarcinoma cells and the factors involved in the process of metastasis.
METHODS By the method of successively increasing the conc entrations, cell fusion and limit dilution, 8-Ag resistant cells were selected, and HGPRT-Hca-P cells and eight cloned hybridoma cells were obtained. To observe their metastatic ability, they were inoculated into mice foodtaps and the drainage lymph nodes were examined under microscope.
RESULTS The end concentration of 8-Ag which was used to select HGPRT deficient Hca-P cells was 30 mg/L. All the cells selected died in HAT culture medium in one week. Fused cells ap-peared approximately 9 days later. They were round, transparent and a little larger than their parental cells. Eight clones of hybridoma cells were obtained and named as PSH1-PSH8. The metastatic rate of HGPRT-Hca-P cells and PSH7 cells was 28.6% and 71.4% respec tively, the difference being significant (P < 0.05). The metastatic rate of other clones was no more than 20% and there was no significant difference from HGPRT-Hca-P cells (P > 0.05).
CONCLUSION In normal mice splenic lymphocytes, there are some factors that could inhibit tumor metastasis, however, there are some other factors accelerating tumor cells to metasta-size. The establishment of PSH7 provides an experimental model which could be used to study the factors involved in metastasis.
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28
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Rachkovsky M, Sodi S, Chakraborty A, Avissar Y, Bolognia J, McNiff JM, Platt J, Bermudes D, Pawelek J. Melanoma x macrophage hybrids with enhanced metastatic potential. Clin Exp Metastasis 1998; 16:299-312. [PMID: 9626809 DOI: 10.1023/a:1006557228604] [Citation(s) in RCA: 111] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Studies were conducted on the hypothesis that melanoma metastasis might be initiated through the generation of hybrids comprised of cells of the primary tumor and tumor-infiltrating leukocytes. Fusion hybrids were generated in vitro between weakly metastatic Cloudman S91 mouse melanoma cells and normal mouse or human macrophages. Hybrids were implanted s.c. in the tail and mice were monitored for metastases. Controls included parental S91 cells, autologous S91 x S91 hybrids, and B16F10 melanoma cells. Of 35 hybrids tested, most were more aggressive than the parental melanoma cells, producing metastases sooner and in more mice. A striking characteristic was heterogeneity amongst hybrids, with some lines producing no metastases and others producing metastases in up to 80% of mice. With few exceptions, hybrids with the highest metastatic potential also had the highest basal melanin content whereas those with the lowest metastatic potential were basally amelanotic, as were the parental melanoma cells. A spontaneous in vivo supermelanotic hybrid between an S91 tumor cell and DBA/2J host cell was one of the most metastatic lines. Hybrids with the highest metastatic potential also exhibited markedly higher chemotaxis to fibroblast-conditioned media. Histologically, the metastatic hybrids demonstrated vascular invasion and spread to distant organs similar to that of metastatic melanomas in mice and humans. Thus previous findings of enhanced metastasis in leukocyte x lymphoma hybrids can now be extended to include leukocyte x melanoma hybrids. Whether such hybridization is a natural cause of metastasis in vivo remains to be determined; however the fusion hybrids with genetically-matched parents described herein so closely resembled naturally-occurring metastatic melanoma cells that they could serve as useful new models for studies of this complex and deadly phenomenon.
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Affiliation(s)
- M Rachkovsky
- Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA
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29
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Fichtner KP, Schirrmacher V, Griesbach A, Hull WE. In vivo 1H-NMR microimaging with respiratory triggering for monitoring adoptive immunotherapy of metastatic mouse lymphoma. Magn Reson Med 1997; 38:440-55. [PMID: 9339446 DOI: 10.1002/mrm.1910380313] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The metastatic ESb-MP murine lymphoma in DBA/2 mice has been used as a model for investigating metastatic disease and its cure by adoptive immunotherapy (ADI) as monitored by in vivo multislice spin-echo 1H NMR microimaging at 7 T. isoflurane inhalation anesthesia facilitated long measurement sessions, and respiratory gating with a fiber-optic sensor greatly reduced motional artifacts. With T2 weighting (TR = 2 s, TE = 30 ms) mean signal-to-noise ratios of 30 and 15 for kidney and liver, respectively, were achieved in 20 min (100-micron pixels, 1-mm slices, 25-mm field of view). Without the use of contrast agents, metastases with diameters > or = 0.3 mm in the imaged plane could be detected as hyperintense lesions in kidney (contrast ratio ca. 1.4) and liver (contrast ratio ca. 2) with a confidence level of > 98%. For the first time the complete eradication of late-stage macroscopic metastases by ADI could be demonstrated noninvasively by MRI.
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Affiliation(s)
- K P Fichtner
- Central Spectroscopy Department, German Cancer Research Center, Heidelberg, Germany
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30
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Differences Between Graft-Versus-Leukemia and Graft-Versus-Host Reactivity. I. Interaction of Donor Immune T Cells With Tumor and/or Host Cells. Blood 1997. [DOI: 10.1182/blood.v89.6.2189] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractGraft-versus-leukemia (GVL) and Graft-versus-host (GVH) reactions were compared after systemic transfer of allogeneic antitumor immune T lymphocytes from B10.D2 (H-2d; MIsb) into DBA/2 (H-2d; MIsa) mice. Before immune cell transfer, recipient DBA/2 mice were sublethally irradiated with 5 Gy to prevent host-versus-graft reactivity. Recipients were either bearing syngeneic metastatic ESb lymphomas (GVL system) or were normal, non–tumor-bearing mice (GVH system). We previously reported that this adoptive immunotherapy protocol (ADI) had pronounced GVL activity and led to immune rejection of even advanced metastasized cancer. In this study, monoclonal antibodies were used for immunohistochemical analysis of native frozen tissue sections from either spleen or liver to distinguish donor from host cells, to differentiate between CD4 and CD8 T lymphocytes, and to stain sialoadhesin-positive macrophages at different time points after cell transfer. The kinetics of donor cell infiltration in spleen and liver differed in that the lymphoid organ was infiltrated earlier (days 1 to 5 after transfer) than the nonlymphoid organ (days 5 to 20). After reaching a peak, donor cell infiltration decreased gradually and was not detectable in the spleen after day 20 and in the liver after day 30. The organ-infiltrating donor immune cells were mostly T lymphocytes and stained positive for CD4 or CD8 T-cell markers. A remarkable GVL-associated observation was made with regard to a subset of macrophages bearing the adhesion molecule sialoadhesin (SER+ macrophages). In the livers of tumor-bearing mice, their numbers increased between days 1 and 12 after ADI by a factor greater than 30. Double-staining for donor cell marker and SER showed that the sialoadhesin-expressing macrophages were of host origin. The SER+ host macrophages from GVL livers were isolated by enzyme perfusion and rosetting 12 days after ADI, when they reached peak values of about 60 cells per liver lobule, and were tested, without further antigen addition, for their capacity to stimulate an antitumor CD8 T-cell response. The results of this immunologic analysis suggest that these cells in the liver function as scavengers of the destroyed metastases and as antigen-processing and -presenting cells for antitumor immune T cells.
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31
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Volpi L, Beghini A, Rossi D, Larizza L. Microsatellite instability in IVS3 of murine c-fes gene: tumor-associated rearrangement and mammalian divergence. Mamm Genome 1996; 7:682-5. [PMID: 8703122 DOI: 10.1007/s003359900205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The murine lymphomacrophage hybrids ESb, EbF1, EbF2-c4, which express c-fes constitutively, were found by Southern analysis to bear a c-fes deletion of almost 100 bp. The deleted allele was transmitted to the metastatic hybrids by their nonexpressing, poorly metastatic T-lymphoma progenitor Eb, which also has a structurally normal c-fes allele. PCR amplification and sequencing of fes cDNA spanning exons 3-5, where the deletion mapped, ruled out any involvement of coding sequences in the rearrangement. PCR amplification of the as yet unsequenced murine c-fes IVS3 and IVS4 showed they are about 50% longer than their human and feline homologs. Sequencing of IVS4 showed no difference between tumor and control DNA. Sequencing of part of the approximately 2600-bp IVS3 was guided by the restriction analysis of PCR products from control and hybrid DNAs. This showed that differences from the control appeared to be mainly located in the 900-bp HindIII-EcoRI fragment, localized in the middle of IVS3. As all three hybrids had the same restriction map, this fragment was sequenced in one of them (ESb). A run of >200 CA repeats was found in control DNA, and a reduction in the CAn microsatellite accounted for most of the c-fes deletion in the ESb hybrid. Interestingly, the 50% reduction in the size of human and feline c-fes IVS3 as compared with the murine homolog is mostly due to contraction of the same microsatellite.
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Affiliation(s)
- L Volpi
- Department of Biology and Genetics, Via Viotti 3/5, Medical Faculty, University of Milan, 20133 Milan, Italy
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32
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Spötl L, Sarti A, Dierich MP, Möst J. Cell membrane labeling with fluorescent dyes for the demonstration of cytokine-induced fusion between monocytes and tumor cells. CYTOMETRY 1995; 21:160-9. [PMID: 8582236 DOI: 10.1002/cyto.990210208] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Fusion between monocytes and tumor cells has been suggested as a cause for tumor metastasis. The aim of the present study was to establish an in vitro fusion model representing the in vivo situation as close as possible. For this purpose fusion between cells was induced by cytokine containing conditioned medium. In order to prove that hybrid formation between tumor cells and monocytes occurs, a two-color-fusion-assay based on membrane labeling with the fluorochromes PKH 2 (green) and PKH 26 (red) was established. These fusion experiments were analyzed by microscopy and, in addition, by flow cytometry. The attempt to induce fusion between monocytes and several tumor cell lines of hematopoietic origin revealed quite diverse results. The most extensive hybrid formations were seen with TALL, a T-lymphocytic tumor line. The monocytic tumor line HL60 and the B-lymphocytic tumor line BL41 also clearly yielded hybrids with monocytes but in smaller numbers. With some other hematopoietic tumor lines no evidence for hybrid formation was detected. These studies indicate that fusion of normal monocytes with certain tumor cells may be induced under conditions that may occur in comparable manner in vivo.
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Affiliation(s)
- L Spötl
- Institut für Hygiene, Leopold-Franzens-Universität Innsbruck, Austria
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Qian LW. A hypothesis on the pathogenesis of cancer: cancer might arise following an event of normal somatic cell fusing. Med Hypotheses 1993; 41:521-4. [PMID: 8183129 DOI: 10.1016/0306-9877(93)90108-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
From the analysis and comparison of biological and abnormal chromosomal behaviour between cancer and hybrid cells, I hypothesize that cancer cells might arise from a hybrid cell which comes from normal somatic cell fusion, but obtains a proliferative advantage, a poorly-differentiated state and metastatic capacity. Furthermore, I put forward the concept that the hybridization between tissue cells and the peripheral blood stem cells may be more likely to generate malignant hybrids.
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Affiliation(s)
- L W Qian
- Department of Surgery, No. 2 Affiliated Hospital of Shandong Medical University, Jinan, Shandong, P.R. China
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Abstract
Metastasis is a complex non-stochastic process that is most likely the result of genetic and epigenetic interactions of a wide variety of genes. The search for a single gene which can encompass such a pleiotropic response as to account for the observed phenotypic characteristics of metastatic tumour populations has been unsuccessful. Particular studies involving gene transfection, subtractive hybridisation and cell fusion are beginning to identify specific genes which contribute to metastasis in some cell types. However, such analyses are complicated by the inherent genetic instability and phenotypic heterogeneity present in tumour populations. A more detailed understanding of the metastatic process may require an abandoning of current generalised approaches to metastasis in favour of concentrating on key components of the metastatic cascade such as adhesion and invasion.
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Affiliation(s)
- T N Dear
- Department of Medicine, University of Sydney, Westmead Hospital, N.S.W., Australia
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35
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Bröcker EB. What's new in the local immune response in cancer? Pathol Res Pract 1989; 185:529-32. [PMID: 2602224 DOI: 10.1016/s0344-0338(89)80083-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Malignant tumors in humans are commonly associated with an inflammatory infiltrate. The mechanisms that account for the accumulation of T-lymphocytes and macrophages--these cells comprise the major components of tumor infiltrates--in the vicinity of a growing tumor are not fully understood. Tumor specific and immunogenic antigens could not be demonstrated in most solid tumors of humans, in contrast to several experimental tumor models. Thus it is not proven in human malignancies that neoantigens expressed on malignant cells are the signal which initiates an inflammatory response that, immunohistologically, is comparable to mononuclear infiltrates present in allograft rejection. A variety of nonspecific factors including lymphokines released by tumor cells may also account for the accumulation of inflammatory cells at the tumor site. The difficulties to evaluate the functional role of the "local immune response" for tumor and host are even greater. Most tumors progress in the presence of mononuclear infiltrates. Do they progress in spite of or because of the action of the local immune response? Clinical, immunopathological, and experimental data suggest that both is right, and that at least four distinct properties of tumor-associated immune reactions exist: Regression, Selection, Modulation and Progression. These distinct properties will be discussed below, using mainly the malignant melanoma of the skin as a model for a malignant tumor in humans.
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Affiliation(s)
- E B Bröcker
- Department of Dermatology, University of Münster, FRG
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The Cancer Cell. Surg Oncol 1989. [DOI: 10.1007/978-3-642-72646-0_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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De Baetselier P, Roos E, van Hecke D, Verschaeve L, Brys L, Verschueren H. Syngeneic in vivo passage of the murine BW 5147 lymphoma results in the expression of a stable metastatic phenotype. Int J Cancer 1988; 41:720-6. [PMID: 3259210 DOI: 10.1002/ijc.2910410514] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BW 5147 lymphoma cells are non-invasive tumor cells which do not generate experimental metastases following i.v. inoculation. In contrast, s.c. and intra-splenic (i.s.) growth of BW cells resulted in widespread colonization of liver and spleen. Cells derived from either s.c. tumors or metastatic lesions did generate metastases after i.v. administration. The capacity of these tumor-derived BW cells to disseminate via blood-borne cells was irreversible and stable, indicating that one in vivo passage of BW cells results in the generation of new, metastatic BW variants. Concomitantly, these variants exhibited an inherent invasive potential as manifested by their capacity to infiltrate in vitro monolayers of hepatocytes and fibroblasts. The BW variants expressed new membrane markers such as H-2 antigens, the Lyt 1.2 T-cell differentiation antigen and the MTH antigen (a newly defined membrane antigen expressed predominantly on murine metastatic T-cell lymphomas and mature T lymphocytes). This phenomenon was observed with both cloned and uncloned BW populations, suggesting that an inductive rather than a selective mechanism accounts for the transition of BW cells towards a more malignant phenotype. These observations confirm the concept that local factors at the growth site of a tumor might influence the metastatic behavior of that tumor, possibly via induction of silent differentiation programs.
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Affiliation(s)
- P De Baetselier
- Institute for Molecular Biology, Free University Brussels, Belgium
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Pohl J, Radler-Pohl A, Heicappell R, Schirrmacher V. Oncogene expression in related cancer lines differing in metastatic capacity. Clin Exp Metastasis 1988; 6:201-11. [PMID: 3280194 DOI: 10.1007/bf01782480] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Various murine tumor cell lines with different metastatic capacities were tested in vitro for oncogene expression, especially of the p21-Ha-ras protein. Small differences were seen in the expression of several distinct oncogenes in the case of a high metastatic lymphoma variant (ESb) and its low metastatic parental line (Eb). In one instance we observed a 30-fold Ha-ras gene amplification in a metastasis-derived cell line from a spontaneous mouse mammary carcinoma. In spite of this amplification we did not find an increased p21 expression in these cells.
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Affiliation(s)
- J Pohl
- Institute for Immunology and Genetics, German Cancer Research Center, Heidelberg
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Altevogt P, Heckl-Oestreicher G, Lang E, Kohl U, Kratzin H, Schirrmacher V. Murine Fc gamma receptor proteins: identification of a previously unrecognized molecule with a monoclonal antibody (12-15). Eur J Immunol 1988; 18:677-83. [PMID: 2967758 DOI: 10.1002/eji.1830180504] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Previously we studied differential expression of cell surface molecules between the metastatic murine lymphoma ESb and an adhesion variant ESb-MP. Here we describe the specificity of a monoclonal antibody (12-15) that showed strong binding to the adhesion variant and weak reactivity against ESb cells. The antibody also reacted to lymphoid but not to macrophage-derived cell lines and immunoprecipitated a molecule of approx. 60-69 kDa from ESb-MP cells. N-terminal sequencing of the antigen revealed identity to the beta protein of mouse Fc gamma receptors. Using monoclonal antibodies against Fc gamma receptors (2.4G2 and K9.361) in immunofluorescence assays and cDNA probes specific for alpha, beta 1 and beta 2 Fc receptor transcripts in Northern blot experiments the differential expression of Fc receptors in ESb and ESb-MP cells was confirmed. Biochemical analysis of endoglycosidase F-treated precipitates revealed that antibody 12-15 reacted to products of all three transcripts with molecular masses for the protein core of 38.5 kDa (beta 1), 34 kDa (beta 2) and 31 kDa alpha). In addition, an unknown protein of 37 kDa (termed beta 3) was identified by antibody 12-15 which could also be detected in ESb cells and EL4 cells. Antibodies 2.4G2 and K9.361 did not react to the beta 3 chain but reacted to varying extents to the other Fc proteins in macrophage and lymphoid cells. Comparison by peptide mapping of the novel beta 3 chain to beta 1, beta 2 and alpha proteins revealed similar, but also distinct peptides. The tissue-specific reactivity of monoclonal antibody 12-15 is likely to be due to a carbohydrate epitope associated with all Fc gamma receptors in lymphoid but not macrophage cell lines.
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Affiliation(s)
- P Altevogt
- Institut für Immunologie und Genetik, Deutsches Krebsforschungszentrum, Heidelberg, FRG
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Schirrmacher V, von Hoegen P, Heicappell R. Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1988; 233:91-6. [PMID: 3265583 DOI: 10.1007/978-1-4899-5037-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- V Schirrmacher
- Institut fur Immunologie und Genetic, Deutsches Krebforschungszentrum, Heidelberg, Federal Republic of Germany
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41
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Savagner P, Imhof BA, Yamada KM, Thiery JP. Homing of hemopoietic precursor cells to the embryonic thymus: characterization of an invasive mechanism induced by chemotactic peptides. J Biophys Biochem Cytol 1986; 103:2715-27. [PMID: 3793754 PMCID: PMC2114614 DOI: 10.1083/jcb.103.6.2715] [Citation(s) in RCA: 81] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
During embryonic development, T cell precursors migrate to the thymus, where immunocompetency is acquired. Our previous studies have shown that avian hemopoietic precursor cells are recruited to the thymus by chemotactic peptides secreted by thymic epithelial cells (Champion, S., B. A. Imhof, P. Savagner, and J. P. Thiery, 1986, Cell, 44:781-790). In this study, we have characterized the homing of these precursor cells to the thymus in vivo by electron and light microscopy. Hemopoietic precursors could be seen to extravasate from blood or lymphatic vessels, migrate in the mesenchyme, traverse the perithymic basement membrane, and finally intercalate into the thymic epithelium. Labeled hemopoietic precursors injected into the blood circulation also followed the same pathway. Migrating hemopoietic precursor cells were found to express the fibronectin receptor complex. In the presence of thymic chemotactic peptides, hemopoietic precursors traverse a human amniotic basement membrane. This invasive process was inhibited by antibodies to laminin or to fibronectin, two major glycoproteins of the amniotic membrane, by monovalent Fab' fragments of antibodies to the fibronectin receptor, and, finally by synthetic peptides that contain the cell-binding sequence Arg-Gly-Asp-Ser of fibronectin. These results indicate that hemopoietic precursors respond to thymic chemotactic peptides by invasive behavior. Direct interactions between basement membrane components and fibronectin receptors appear to be required for this developmentally regulated invasion process.
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Prindull G. Minimal residual neoplastic disease--concept, pathogenesis, and supplementary therapeutic possibilities. Cancer Treat Rev 1986; 13:177-94. [PMID: 3536089 DOI: 10.1016/0305-7372(86)90004-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Lagarde AE. Sporadic somatic fusion between MDAY-D2 murine tumor cells and DBA/2 host cells: role in metastasis. Int J Cancer 1986; 37:905-10. [PMID: 3710619 DOI: 10.1002/ijc.2910370617] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
An ouabain- and 6-thioguanine-resistant mutant (K3T103) of the metastatic MDAY-D2 murine tumor cell line was transplanted s.c. into syngeneic DBA/2 mice in order to isolate K3T103 X host cell hybrids emerging in vivo, and examine their metastatic potential. Of 10 tumor-bearing animals that were analyzed at various time intervals, only 3 developed fusion products in the primary site, present at a frequency ranging between 10(-5) and 10(-4). These hybrids survived in HAT + ouabain medium, had a lymphoblastoid morphology and a hypo-tetraploid karyotype, were non-adherent, and were as rapidly metastatic as K3T103 cells when transplanted s.c. or i.v. into DBA/2 mice. All these characteristics were shared by cloned hybrids generated in vitro following polyethylene glycol (PEG)-mediated fusion of K3T103 cells with normal DBA/2 normal splenocytes. In marked contrast, the products of K3T103 X DBA/2 normal lung fibroblast fusion displayed a fibroblastic appearance, were adherent, progressively ceased to divide and remained dormant for several weeks in culture. These results indicate: that spontaneous fusion of K3T103 cells with host cells in the course of their expansion and subsequent dissemination is a stochastic and rare event, and that since the expression of their tumorigenic and metastatic potential is retained after fusion with splenocytes, host cells of lymphoreticular origin are most likely involved in that process.
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