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Liu C, Gao J, Cheng Y, Zhang S, Fu C. Homologous-adhering/targeting cell membrane- and cell-mediated delivery systems: a cancer-catch-cancer strategy in cancer therapy. Regen Biomater 2024; 12:rbae135. [PMID: 39811105 PMCID: PMC11729729 DOI: 10.1093/rb/rbae135] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/09/2024] [Accepted: 11/06/2024] [Indexed: 01/16/2025] Open
Abstract
Low tumor enrichment remains a serious and urgent problem for drug delivery in cancer therapy. Accurate targeting of tumor sites is still a critical aim in cancer therapy. Though there have been a variety of delivery strategies to improve the tumor targeting and enrichment, biological barriers still cause most delivered guests to fail or be excreted before they work. Recently, cell membrane-based systems have attracted a huge amount of attention due to their advantages such as easy access, good biocompatibility and immune escape, which contribute to their biomimetic structures and specific surface proteins. Furthermore, cancer cell membrane-based delivery systems are referred to as homologous-targeting function in which they exhibit significantly high adhesion and internalization to homologous-type tumor sites or cells even though the exact mechanism is not entirely revealed. Here, we summarize the sources and characterizations of cancer cell membrane systems, including reconstructed single or hybrid membrane-based nano-/microcarriers, as well as engineered cancer cells. Additionally, advanced applications of these cancer cell membrane systems in cancer therapy are categorized and summarized according to the components of membranes. The potential factors related to homologous targeting of cancer cell membrane-based systems are also discussed. By discussing the applications, challenges and opportunities, we expect the cancer cell membrane-based homologous-targeting systems to have a far-reaching development in preclinic or clinics.
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Affiliation(s)
- Chenguang Liu
- Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China
| | - Jingjie Gao
- Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China
| | - Yuying Cheng
- Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China
| | - Shanshan Zhang
- Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P. R. China
| | - Caiyun Fu
- Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China
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Zhang Y, Fan M, Zhang Y. Revolutionizing bone defect healing: the power of mesenchymal stem cells as seeds. Front Bioeng Biotechnol 2024; 12:1421674. [PMID: 39497791 PMCID: PMC11532096 DOI: 10.3389/fbioe.2024.1421674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 10/10/2024] [Indexed: 11/07/2024] Open
Abstract
Bone defects can arise from trauma or pathological factors, resulting in compromised bone integrity and the loss or absence of bone tissue. As we are all aware, repairing bone defects is a core problem in bone tissue engineering. While minor bone defects can self-repair if the periosteum remains intact and normal osteogenesis occurs, significant defects or conditions such as congenital osteogenesis imperfecta present substantial challenges to self-healing. As research on mesenchymal stem cell (MSC) advances, new fields of application have emerged; however, their application in orthopedics remains one of the most established and clinically valuable directions. This review aims to provide a comprehensive overview of the research progress regarding MSCs in the treatment of diverse bone defects. MSCs, as multipotent stem cells, offer significant advantages due to their immunomodulatory properties and ability to undergo osteogenic differentiation. The review will encompass the characteristics of MSCs within the osteogenic microenvironment and summarize the research progress of MSCs in different types of bone defects, ranging from their fundamental characteristics and animal studies to clinical applications.
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Affiliation(s)
- Yueyao Zhang
- Trauma Emergency Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Biomechanics of Hebei Province, Orthopaedic Research Institution of Hebei Province, Shijiazhuang, China
| | - Mengke Fan
- Trauma Emergency Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Biomechanics of Hebei Province, Orthopaedic Research Institution of Hebei Province, Shijiazhuang, China
| | - Yingze Zhang
- Trauma Emergency Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Biomechanics of Hebei Province, Orthopaedic Research Institution of Hebei Province, Shijiazhuang, China
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3
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Hass R, von der Ohe J, Luo T. Human mesenchymal stroma/stem-like cell-derived taxol-loaded EVs/exosomes transfer anti-tumor microRNA signatures and express enhanced SDF-1-mediated tumor tropism. Cell Commun Signal 2024; 22:506. [PMID: 39420354 PMCID: PMC11488203 DOI: 10.1186/s12964-024-01886-2] [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: 02/21/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND The release of extracellular vesicles (EVs) including exosomes from human mesenchymal stroma/stem-like cells (MSC) represents valuable cell-free carriers for the delivery of regenerative and medicinal compounds. METHODS EVs/exosomes were isolated by differential centrifugation from four individual MSC as controls and after treatment with a sub-lethal concentration of 10 mM taxol for 24 h, respectively. The isolated EVs/exosomes were characterized and quantified by nano-tracking-analysis and by Western blots. MicroRNAs (miRs) were isolated from the different EVs/exosome populations and expression levels were quantified by qPCR using 1246 miR templates. Cytotoxic effects of the different MSC-derived taxol-loaded EVs/exosomes were determined in five different GFP-transduced cancer cell lines and quantified by a fluoroscan assay with a GFP-detecting fluorimeter. The presence of stroma cell-derived factor 1 (SDF-1) in MSC-derived EVs/exosomes and its enhanced expression in the vesicles after taxol treatment of MSC was quantified by a specific ELISA. RESULTS EVs/exosomes isolated from four individual taxol-treated MSC displayed a larger size and higher yields as the control EVs/exosomes and were used as anti-tumor therapeutic vehicles. Application of each of the four MSC-derived taxol-loaded EVs/exosome populations revealed significant cytotoxic effects in cell lines of five different tumor entities (carcinomas of lung, breast, ovar, colon, astrocytoma) in a concentration-dependent manner. Expression analysis of 1246 miRs in these taxol-loaded EVs/exosomes as compared to the corresponding MSC-derived control EVs/exosomes unraveled a taxol-mediated up-regulation of 11 miRs with predominantly anti-tumorigenic properties. Moreover, various constitutively expressed protein levels were unanimously altered in the MSC cultures. Taxol treatment of the different MSC revealed an up-regulation of tetraspanins and a 2.2-fold to 5.4-fold increased expression of SDF-1 among others. Treatment of cancer cells with MSC-derived taxol-loaded EVs/exosomes in the presence of a neutralizing SDF-1 antibody significantly abolished the cytotoxic effects between 20.3% and 27%. CONCLUSIONS These findings suggested a taxol-mediated increase of anti-cancer properties in MSC that enhance the tropism of derived EVs/exosomes to tumors, thereby specifically focusing the therapeutic effects of the delivered products.
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Affiliation(s)
- Ralf Hass
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany.
| | - Juliane von der Ohe
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany
| | - Tianjiao Luo
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany
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Xiao D, Xiong M, Wang X, Lyu M, Sun H, Cui Y, Chen C, Jiang Z, Sun F. Regulation of the Function and Expression of EpCAM. Biomedicines 2024; 12:1129. [PMID: 38791091 PMCID: PMC11117676 DOI: 10.3390/biomedicines12051129] [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: 04/09/2024] [Revised: 05/11/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein on the cell surface. Given its strong expression on epithelial cells and epithelial cell-derived tumors, EpCAM has been identified as a biomarker for circulating tumor cells (CTCs) and exosomes and a target for cancer therapy. As a cell adhesion molecule, EpCAM has a crystal structure that indicates that it forms a cis-dimer first and then probably a trans-tetramer to mediate intercellular adhesion. Through regulated intramembrane proteolysis (RIP), EpCAM and its proteolytic fragments are also able to regulate multiple signaling pathways, Wnt signaling in particular. Although great progress has been made, increasingly more findings have revealed the context-specific expression and function patterns of EpCAM and their regulation processes, which necessitates further studies to determine the structure, function, and expression of EpCAM under both physiological and pathological conditions, broadening its application in basic and translational cancer research.
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Affiliation(s)
- Di Xiao
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Mingrui Xiong
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Xin Wang
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Mengqing Lyu
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Hanxiang Sun
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Yeting Cui
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Chen Chen
- Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China;
| | - Ziyu Jiang
- Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China;
| | - Fan Sun
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430081, China; (D.X.); (M.X.); (X.W.); (M.L.); (H.S.); (Y.C.)
- Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan 430081, China
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Noubissi FK, Odubanjo OV, Ogle BM, Tchounwou PB. Mechanisms of Cell Fusion in Cancer. Results Probl Cell Differ 2024; 71:407-432. [PMID: 37996688 PMCID: PMC10893907 DOI: 10.1007/978-3-031-37936-9_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2023]
Abstract
Cell-cell fusion is a normal physiological mechanism that requires a well-orchestrated regulation of intracellular and extracellular factors. Dysregulation of this process could lead to diseases such as osteoporosis, malformation of muscles, difficulties in pregnancy, and cancer. Extensive literature demonstrates that fusion occurs between cancer cells and other cell types to potentially promote cancer progression and metastasis. However, the mechanisms governing this process in cancer initiation, promotion, and progression are less well-studied. Fusogens involved in normal physiological processes such as syncytins and associated factors such as phosphatidylserine and annexins have been observed to be critical in cancer cell fusion as well. Some of the extracellular factors associated with cancer cell fusion include chronic inflammation and inflammatory cytokines, hypoxia, and viral infection. The interaction between these extracellular factors and cell's intrinsic factors potentially modulates actin dynamics to drive the fusion of cancer cells. In this review, we have discussed the different mechanisms that have been identified or postulated to drive cancer cell fusion.
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Affiliation(s)
- Felicite K Noubissi
- Department of Biology, Jackson State University, Jackson, MS, USA.
- Research Centers in Minority Institutions (RCMI), Center for Health Disparity Research (RCMI-CHDR), Jackson State University, Jackson, MS, USA.
| | - Oluwatoyin V Odubanjo
- Department of Biology, Jackson State University, Jackson, MS, USA
- Research Centers in Minority Institutions (RCMI), Center for Health Disparity Research (RCMI-CHDR), Jackson State University, Jackson, MS, USA
| | - Brenda M Ogle
- Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, MN, USA
- Department of Pediatrics, University of Minnesota-Twin Cities, Minneapolis, MN, USA
- Stem Cell Institute, University of Minnesota-Twin Cities, Minneapolis, MN, USA
| | - Paul B Tchounwou
- Department of Biology, Jackson State University, Jackson, MS, USA
- Research Centers in Minority Institutions (RCMI), Center for Health Disparity Research (RCMI-CHDR), Jackson State University, Jackson, MS, USA
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Jahangiri B, Khalaj-Kondori M, Asadollahi E, Kian Saei A, Sadeghizadeh M. Dual impacts of mesenchymal stem cell-derived exosomes on cancer cells: unravelling complex interactions. J Cell Commun Signal 2023:10.1007/s12079-023-00794-3. [PMID: 37973719 DOI: 10.1007/s12079-023-00794-3] [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: 06/10/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent, self-renewing stromal cells found in a variety of adult tissues. MSCs possess a remarkable ability to migrate towards tumor sites, known as homing. This homing process is mediated by various factors, including chemokines, growth factors, and extracellular matrix components present in the tumor microenvironment. MSCs release extracellular vesicles known as exosomes (MSC-Exos), which have been suggested to serve a key role in mediating a wide variety of MSC activities. Through cell-cell communication, MSC-Exos have been shown to alter recipient cell phenotype or function and play as a novel cell-free alternative for MSC-based cell therapy. However, MSC recruitment to tumors allows for their interaction with cancer cells and subsequent regulation of tumor behavior. MSC-Exos act as tumor niche modulators via transferring exosomal contents, such as specific proteins or genetic materials, to the nearby cancer cells, leading to either promotion or suppression of tumorigenesis, angiogenesis, and metastasis, depending on the specific microenvironmental cues and recipient cell characteristics. Consequently, there is still a debate about the precise relationship between tumor cells and MSC-Exos, and it is unclear how MSC-Exos impacts tumor cells. Although the dysregulation of miRNAs is caused by the progression of cancer, they also play a direct role in either promoting or inhibiting tumor growth as they act as either oncogenes or tumor suppressors. The utilization of MSC-Exos may prove to be an effective method for restoring miRNA as a means of treating cancer. This review aimed to present the existing understanding of the impact that MSC-Exos could have on cancer. To begin with, we presented a brief explanation of exosomes, MSCs, and MSC-Exos. Following this, we delved into the impact of MSC-Exos on cancer growth, EMT, metastasis, angiogenesis, resistance to chemotherapy and radiotherapy, and modulation of the immune system. Opposing effects of mesenchymal stem cells-derived exosomes on cancer cells.
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Affiliation(s)
- Babak Jahangiri
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Elahe Asadollahi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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7
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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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Slama Y, Ah-Pine F, Khettab M, Arcambal A, Begue M, Dutheil F, Gasque P. The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential. Int J Mol Sci 2023; 24:13511. [PMID: 37686315 PMCID: PMC10488262 DOI: 10.3390/ijms241713511] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.
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Affiliation(s)
- Youssef Slama
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Franck Ah-Pine
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Mohamed Khettab
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Angelique Arcambal
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Mickael Begue
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Fabien Dutheil
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Philippe Gasque
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
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9
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Wieder R. Fibroblasts as Turned Agents in Cancer Progression. Cancers (Basel) 2023; 15:2014. [PMID: 37046676 PMCID: PMC10093070 DOI: 10.3390/cancers15072014] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/19/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer "wounds" the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches.
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Affiliation(s)
- Robert Wieder
- Rutgers New Jersey Medical School and the Cancer Institute of New Jersey, Newark, NJ 07103, USA
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10
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Alipour R, Hashemibeni B, Asgari V, Bahramian H. Time- and Concentration-Dependent Effects of the Stem Cells Derived from Human Exfoliated Deciduous Teeth on Osteosarcoma Cells. Adv Biomed Res 2023; 12:81. [PMID: 37200742 PMCID: PMC10186045 DOI: 10.4103/abr.abr_277_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/14/2021] [Accepted: 10/11/2021] [Indexed: 05/20/2023] Open
Abstract
Background Stem cells have been proposed to be one of the potent sources for treatment applications. Among diverse types of stem cells, stem cells derived from human exfoliated deciduous teeth (SHEDs) are known as the immature stem cell population, which are easily isolated, fast, and without ethical implications. SHEDs could induce pluripotent stem cells and show differentiation in chondrocytes, adipocytes, osteoblasts, neural cells, hepatocytes, myocytes, odontoblasts, and skin cells. Materials and Methods In the current study, we investigated the effects of SHED on osteosarcoma cells (Saos-II) following 3 and 5 days indirect coculture. Results Our results showed that indirect coculture of SHED with Saos-II cells could promote or inhibit Saos-II cells' growth in a concentration (the number of SHED vs. Saos-II cells) and time (days of indirect co-culture) dependent manner. Conclusion Our findings suggested that, indirectly, SHED co-culture with the Soas-II cells might functions as a tumor suppressor where a higher number of SHEDs are used in the culture in comparison with the one cultured in the absence of/or fewer SHED incubation.
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Affiliation(s)
- Razieh Alipour
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Batool Hashemibeni
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Vajihe Asgari
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Bahramian
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Address for correspondence: Dr. Hamid Bahramian, Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran. E-mail:
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11
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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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Műzes G, Sipos F. Mesenchymal Stem Cell-Derived Secretome: A Potential Therapeutic Option for Autoimmune and Immune-Mediated Inflammatory Diseases. Cells 2022; 11:2300. [PMID: 35892597 PMCID: PMC9367576 DOI: 10.3390/cells11152300] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/16/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Immune-mediated inflammatory diseases (IMIDs) encompass several entities such as "classic" autoimmune disorders or immune-mediated diseases with autoinflammatory characteristics. Adult stem cells including mesenchymal stem cells (MSCs) are by far the most commonly used type in clinical practice. However, due to the possible side effects of MSC-based treatments, there is an increase in interest in the MSC-secretome (containing large extracellular vesicles, microvesicles, and exosomes) as an alternative therapeutic option in IMIDs. A wide spectrum of MSC-secretome-related biological activities has been proven thus far including anti-inflammatory, anti-apoptotic, and immunomodulatory properties. In comparison with MSCs, the secretome is less immunogenic but exerts similar biological actions, so it can be considered as an ideal cell-free therapeutic alternative. Additionally, since the composition of the MSC-secretome can be engineered, for a future perspective, it could also be viewed as part of a potential delivery system within nanomedicine, allowing us to specifically target dysfunctional cells or tissues. Although many encouraging results from pre-clinical studies have recently been obtained that strongly support the application of the MSC-secretome in IMIDs, human studies with MSC-secretome administration are still in their infancy. This article reviews the immunomodulatory effects of the MSC-secretome in IMIDs and provides insight into the interpretation of its beneficial biological actions.
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Affiliation(s)
- Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, Szentkirályi Street 46, 1088 Budapest, Hungary;
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Sipos F, Műzes G. Disagreements in the therapeutic use of mesenchymal stem cell-derived secretome. World J Stem Cells 2022; 14:365-371. [PMID: 35949398 PMCID: PMC9244954 DOI: 10.4252/wjsc.v14.i6.365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/15/2022] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
In a recent article, the authors provide a detailed summary of the characteristics and biological functions of mesenchymal stem cells (MSCs), as well as a discussion on the potential mechanisms of action of MSC-based therapies. They describe the morphology, biogenesis, and current isolation techniques of exosomes, one of the most important fractions of the MSC-derived secretome. They also summarize the characteristics of MSC-derived exosomes and highlight their functions and therapeutic potential for tissue/organ regeneration and for kidney, liver, cardiovascular, neurological, and musculoskeletal diseases, as well as cutaneous wound healing. Despite the fact that MSCs are regarded as an important pillar of regenerative medicine, their regenerative potential has been demonstrated to be limited in a number of pathological conditions. The negative effects of MSC-based cell therapy have heightened interest in the therapeutic use of MSC-derived secretome. On the other hand, MSC-derived exosomes and microvesicles possess the potential to have a significant impact on disease development, including cancer. MSCs can interact with tumor cells and promote mutual exchange and induction of cellular markers by exchanging secretome. Furthermore, enzymes secreted into and activated within exosomes can result in tumor cells acquiring new properties. As a result, therapeutic applications of MSC-derived secretomes must be approached with extreme caution.
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Affiliation(s)
- Ferenc Sipos
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary.
| | - Györgyi Műzes
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary
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14
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Bladder Cancer Cells Exert Pleiotropic Effects on Human Adipose-Derived Stem Cells. Life (Basel) 2022; 12:life12040549. [PMID: 35455040 PMCID: PMC9025060 DOI: 10.3390/life12040549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/29/2022] [Accepted: 04/05/2022] [Indexed: 12/12/2022] Open
Abstract
Stem cell-based therapies are considered one of the most promising disciplines in biomedicine. Bladder cancer patients could benefit from therapies directed to promote healing after invasive surgeries or to lessen urinary incontinence, a common side effect of both cancer itself and the treatment. However, the local delivery of cells producing large amounts of paracrine factors may alter interactions within the microenvironment. For this reason, reconstructive cellular therapies for patients with a history of cancer carry a potential risk of tumor reactivation. We used an indirect co-culture model to characterize the interplay between adipose-derived stem cells and bladder cancer cells. Incubation with ASCs increased MCP-1 secretion by bladder cancer cells (from 2.1-fold to 8.1-fold, depending on the cell line). Cancer cell-derived factors altered ASC morphology. Cells with atypical shapes and significantly enlarged volumes appeared within the monolayer. Incubation in a conditioned medium (CM) containing soluble mediators secreted by 5637 and HB-CLS-1 bladder cancer cell lines decreased ASC numbers by 47.5% and 45.7%. A significant increase in adhesion to ECM components, accompanied by reduced motility and sheet migration, was also observed after incubation in CM from 5637 and HB-CLS-1 cells. No differences were observed when ASCs were co-cultured with HT-1376 cells. Our previous and present results indicate that soluble mediators secreted by ASCs and bladder cancer cells induce opposite effects influencing cells that represent the non-muscle-invasive urinary bladder.
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SIPOS FERENC, MŰZES GYÖRGYI. Controversies in therapeutic application of mesenchymal stem cell-derived secretome. BIOCELL 2022; 46:903-906. [DOI: 10.32604/biocell.2022.018200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/30/2021] [Indexed: 02/05/2023]
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Liao CM, Luo T, von der Ohe J, de Juan Mora B, Schmitt R, Hass R. Human MSC-Derived Exosomes Reduce Cellular Senescence in Renal Epithelial Cells. Int J Mol Sci 2021; 22:13562. [PMID: 34948355 PMCID: PMC8709122 DOI: 10.3390/ijms222413562] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/10/2021] [Accepted: 12/14/2021] [Indexed: 12/23/2022] Open
Abstract
Cellular senescence of renal tubular cells is associated with chronic diseases and age-related kidney disorders. Therapies to antagonize senescence are, therefore, explored as novel approaches in nephropathy. Exosomes derived from human mesenchymal stroma-/stem-like cells (MSC) entail the transfer of multiple bioactive molecules, exhibiting profound regenerative potential in various tissues, including therapeutic effects in kidney diseases. Here, we first demonstrate that exosomes promote proliferation and reduce senescence in aged MSC cultures. For potential therapeutic perspectives in organ rejuvenation, we used MSC-derived exosomes to antagonize senescence in murine kidney primary tubular epithelial cells (PTEC). Exosome treatment efficiently reduced senescence while diminishing the transcription of senescence markers and senescence-associated secretory phenotype (SASP) factors. Concomitantly, we observed less DNA damage foci and more proliferating cells. These data provide new information regarding the therapeutic property of MSC exosomes in the development of renal senescence, suggesting a contribution to a new chapter of regenerative vehicles in senotherapy.
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Affiliation(s)
- Chieh Ming Liao
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (C.M.L.); (B.d.J.M.); (R.S.)
| | - Tianjiao Luo
- Biochemistry and Tumor Biology Lab, Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
| | - Blanca de Juan Mora
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (C.M.L.); (B.d.J.M.); (R.S.)
| | - Roland Schmitt
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (C.M.L.); (B.d.J.M.); (R.S.)
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
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Luo T, von der Ohe J, Hass R. MSC-Derived Extracellular Vesicles in Tumors and Therapy. Cancers (Basel) 2021; 13:5212. [PMID: 34680359 PMCID: PMC8533755 DOI: 10.3390/cancers13205212] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022] Open
Abstract
Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem cell niches, beneficial regenerative effects in various diseases, and reduction of senescence. However, the mode of action in MSC-derived exosomes strongly depends on the biological content like different regulatory microRNAs that are determined by the tissue origin of MSCs. In tumors, MSCs use indirect and direct pathways in a communication network to interact with cancer cells. This leads to mutual functional changes with the acquisition of an aberrant tumor-associated MSC phenotype accompanied by altered cargo in the exosomes. Consequently, MSC-derived exosomes either from normal tissue-originating MSCs or from aberrant tumor-associated MSCs can confer different actions on tumor development. These processes exhibiting tumor-inhibitory and tumor-supportive effects with a focus on exosome microRNA content will be discriminated and discussed within this review.
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Affiliation(s)
| | | | - Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
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Ji X, Sun T, Xie S, Qian H, Song L, Wang L, Liu H, Feng Q. Upregulation of CPNE7 in mesenchymal stromal cells promotes oral squamous cell carcinoma metastasis through the NF-κB pathway. Cell Death Discov 2021; 7:294. [PMID: 34650058 PMCID: PMC8516970 DOI: 10.1038/s41420-021-00684-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 09/01/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
A remarkable shift in Mesenchymal stromal cells (MSCs) plays an important role in cancer metastasis, but the molecular mechanism is still unclear. CPNE7, a calcium-dependent phospholipid-binding protein, mediates signal transduction and metastasis in many tumours. Here, we demonstrated that MSCs derived from OSCC (OSCC-MSCs) promoted the metastasis of OSCC cells by transwell assay and animal models through epithelial to mesenchymal transition (EMT) (p < 0.05). RNA-sequencing, ELISA, neutralizing antibody and CXCR2 inhibitor assay confirmed that CXCL8 secreted by OSCC-MSCs was associated with the upregulated expression of CPNE7 by immunohistochemical and western blotting (p < 0.05). This is mechanistically linked to the activation of CPNE7 to NF-κB pathway-induced metastasis, including phosphorylated p65 and IκBa. CPNE7 silencing inhibited metastatic abilities and the expression of CXCL8, phosphorylated p65, IκBa, and p65 nuclear translocation by western blotting and immunofluorescence, while CPNE7 overexpression markedly promoted these events (p < 0.05). We also identified that Nucleolin could be bind CPNE7 and IκBa by co-immunoprecipitation. Together, our results suggest that upregulation of CPNE7 in MSCs interacted with surface receptor -Nucleolin and then combined with IκBa to promoted phosphorylated IκBa and p65 nuclear translocation to active NF-κB pathway, and then regulates CXCL8 secretion to promote the metastasis of OSCC cells. Therefore, CPNE7 in MSCs could be promising therapeutic targets in OSCC.
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Affiliation(s)
- Xiaoli Ji
- Department of Stomatology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, No.105 Jiefang Road, Jinan, 250013, Shandong, China. .,Department of Oral Mucosal Diseases, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China. .,Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China.
| | - Tianyong Sun
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China
| | - Shang Xie
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian, Beijing, 100081, China
| | - Hua Qian
- Department of Stomatology, The Second Hospital of Shandong University, No. 247 Beiyuan Road, Jinan, 250033, China
| | - Lixiang Song
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China
| | - Lihua Wang
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China
| | - Hongwei Liu
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian, Beijing, 100081, China.
| | - Qiang Feng
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, 250012, Shandong, China. .,NHC Key Laboratory of Otorhinolaryngology (Shandong University), No.44-1 Wenhua Road West, Jinan, Shandong, China, 250012.
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Böckelmann LC, Felix T, Calabrò S, Schumacher U. YKL-40 protein expression in human tumor samples and human tumor cell line xenografts: implications for its use in tumor models. Cell Oncol (Dordr) 2021; 44:1183-1195. [PMID: 34432260 PMCID: PMC8516773 DOI: 10.1007/s13402-021-00630-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND YKL-40, also known as non-enzymatic chitinase-3 like-protein-1 (CHI3L1), is a glycoprotein expressed and secreted mainly by inflammatory cells and tumor cells. Accordingly, several studies demonstrated elevated YKL-40 serum levels in cancer patients and found YKL-40 to be correlated with a poor prognosis and disease severity in some tumor entities. YKL-40 was suggested to be involved in angiogenesis and extracellular matrix remodeling. As yet, however, its precise biological function remains elusive. METHODS As YKL-40 protein expression has only been investigated in few malignancies, we employed immunohistochemical detection in a large multi-tumor tissue microarray consisting of 2,310 samples from 72 different tumor entities. In addition, YKL-40 protein expression was determined in primary mouse xenograft tumors derived from human cancer cell lines. RESULTS YKL-40 could be detected in almost all cancer entities and was differently expressed depending on tumor stage and subtype (e.g., thyroid cancer, colorectal cancer, gastric cancer and ovarian cancer). While YKL-40 was absent in in vitro grown human cancer cell lines, YKL-40 expression was upregulated in xenograft tumor tissues in vivo. CONCLUSIONS These data provide new insights into YKL-40 expression at the protein level in various tumor entities and its regulation in tumor models. Our data suggest that upregulation of YKL-40 expression is a common feature in vivo and is finely regulated by tumor cell-microenvironment interactions.
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Affiliation(s)
- Lukas Clemens Böckelmann
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Theresa Felix
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simona Calabrò
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Hass R, von der Ohe J, Dittmar T. Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP). Cancers (Basel) 2021; 13:4636. [PMID: 34572863 PMCID: PMC8470238 DOI: 10.3390/cancers13184636] [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: 08/17/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022] Open
Abstract
Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. 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. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells.
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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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21
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Melzer C, von der Ohe J, Luo T, Hass R. Spontaneous Fusion of MSC with Breast Cancer Cells Can Generate Tumor Dormancy. Int J Mol Sci 2021; 22:5930. [PMID: 34072967 PMCID: PMC8198754 DOI: 10.3390/ijms22115930] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/02/2020] [Accepted: 05/26/2021] [Indexed: 12/22/2022] Open
Abstract
Direct cellular interactions of MDA-MB-231cherry breast cancer cells with GFP-transduced human mesenchymal stroma/stem-like cells (MSCGFP) in a co-culture model resulted in spontaneous cell fusion by the generation of MDA-MSC-hyb5cherry GFP breast cancer hybrid cells. The proliferative capacity of MDA-MSC-hyb5 cells was enhanced about 1.8-fold when compared to the parental MDA-MB-231cherry breast cancer cells. In contrast to a spontaneous MDA-MB-231cherry induced tumor development in vivo within 18.8 days, the MDA-MSC-hyb5 cells initially remained quiescent in a dormancy-like state. At distinct time points after injection, NODscid mice started to develop MDA-MSC-hyb5 cell-induced tumors up to about a half year later. Following tumor initiation, however, tumor growth and formation of metastases in various different organs occurred rapidly within about 10.5 days. Changes in gene expression levels were evaluated by RNA-microarray analysis and revealed certain increase in dormancy-associated transcripts in MDA-MSC-hyb5. Chemotherapeutic responsiveness of MDA-MSC-hyb5 cells was partially enhanced when compared to MDA-MB-231 cells. However, some resistance, e.g., for taxol was detectable in cancer hybrid cells. Moreover, drug response partially changed during the tumor development of MDA-MSC-hyb5 cells; this suggests the presence of unstable in vivo phenotypes of MDA-hyb5 cells with increased tumor heterogeneity.
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Affiliation(s)
| | | | | | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (C.M.); (J.v.d.O.); (T.L.)
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Ivolgin DA, Kudlay DA. Mesenchymal multipotent stromal cells and cancer safety: two sides of the same coin or a double-edged sword (review of foreign literature). RUSSIAN JOURNAL OF PEDIATRIC HEMATOLOGY AND ONCOLOGY 2021; 8:64-84. [DOI: 10.21682/2311-1267-2021-8-1-64-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Knowledge about the mechanisms of action of mesenchymal multipotent stromal cells (MSC) has undergone a significant evolution since their discovery. From the first attempts to use the remarkable properties of MSC in restoring the functions of organs and tissues, the most important question arose – how safe their use would be? One of the aspects of safety of the use of such biomaterial is tumorogenicity and oncogenicity. Numerous studies have shown that the mechanisms by which MSC realize their regenerative potential can, in principle, have a stimulating effect on tumor cells. This review presents specific mechanisms that have a potentially pro-tumor effect, which include the homing of MSC to the tumor site, support for replicative and proliferative signaling of both cancer cells and cancer stem cells, angiogenesis, and effects on the epithelial-mesenchymal transition. Along with pro-tumor mechanisms, the mechanisms of possible antitumor action are also described – direct suppression of tumor growth, loading and transportation of chemotherapeutic agents, oncolytic viruses, genetic modifications for targeting cancer, delivery of “suicide genes” to the tumor. Also, in conclusion, a small review of the current clinical trials of MSC as antitumor agents for malignant neoplasms of various localization (gastrointestinal tract, lungs, ovaries) is given.
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Affiliation(s)
- D. A. Ivolgin
- I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia
| | - D. A. Kudlay
- JSC “GENERIUM”;
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University);
National Research Center – Institute of Immunology Federal Medical-Biological Agency of Russia
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Endoglin in the Spotlight to Treat Cancer. Int J Mol Sci 2021; 22:ijms22063186. [PMID: 33804796 PMCID: PMC8003971 DOI: 10.3390/ijms22063186] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/06/2021] [Accepted: 03/17/2021] [Indexed: 01/02/2023] Open
Abstract
A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFβ pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy.
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Trogocytosis between Non-Immune Cells for Cell Clearance, and among Immune-Related Cells for Modulating Immune Responses and Autoimmunity. Int J Mol Sci 2021; 22:ijms22052236. [PMID: 33668117 PMCID: PMC7956485 DOI: 10.3390/ijms22052236] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/21/2021] [Accepted: 02/21/2021] [Indexed: 12/21/2022] Open
Abstract
The term trogocytosis refers to a rapid bidirectional and active transfer of surface membrane fragment and associated proteins between cells. The trogocytosis requires cell-cell contact, and exhibits fast kinetics and the limited lifetime of the transferred molecules on the surface of the acceptor cells. The biological actions of trogocytosis include information exchange, cell clearance of unwanted tissues in embryonic development, immunoregulation, cancer surveillance/evasion, allogeneic cell survival and infectious pathogen killing or intercellular transmission. In the present review, we will extensively review all these aspects. In addition to its biological significance, aberrant trogocytosis in the immune system leading to autoimmunity and immune-mediated inflammatory diseases will also be discussed. Finally, the prospective investigations for further understanding the molecular basis of trogocytosis and its clinical applications will also be proposed.
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Hass R, von der Ohe J, Ungefroren H. Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness. Cancers (Basel) 2020; 12:3716. [PMID: 33322354 PMCID: PMC7764513 DOI: 10.3390/cancers12123716] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor heterogeneity is considered the major cause of treatment failure in current cancer therapies. This feature of solid tumors is not only the result of clonal outgrowth of cells with genetic mutations, but also of epigenetic alterations induced by physical and chemical signals from the tumor microenvironment (TME). Besides fibroblasts, endothelial and immune cells, mesenchymal stroma/stem-like cells (MSCs) and tumor-associated macrophages (TAMs) intimately crosstalk with cancer cells and can exhibit both anti- and pro-tumorigenic effects. MSCs can alter cancer cellular phenotypes to increase cancer cell plasticity, eventually resulting in the generation of cancer stem cells (CSCs). The shift between different phenotypic states (phenotype switching) of CSCs is controlled via both genetic programs, such as epithelial-mesenchymal transdifferentiation or retrodifferentiation, and epigenetic alterations triggered by signals from the TME, like hypoxia, spatial heterogeneity or stromal cell-derived chemokines. Finally, we highlight the role of spontaneous cancer cell fusion with various types of stromal cells. i.e., MSCs in shaping CSC plasticity. A better understanding of cell plasticity and phenotype shifting in CSCs is a prerequisite for exploiting this phenomenon to reduce tumor heterogeneity, thereby improving the chance for therapy success.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany;
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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ComŞa Ş, CeauȘu AR, Popescu R, SÂrb S, CÎmpean AM, Raica M. The MSC-MCF-7 Duet Playing Tumor Vasculogenesis and Angiogenesis onto the Chick Embryo Chorioallantoic Membrane. In Vivo 2020; 34:3315-3325. [PMID: 33144439 PMCID: PMC7811630 DOI: 10.21873/invivo.12170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/10/2020] [Accepted: 07/16/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIM Human mesenchymal stem cells (hMSC) represent a versatile cell population, able to modulate the tumor microenvironment. Our aim was to recreate an open scene for the in vivo interaction between hMSC and the MCF-7 breast cancer cells (MCF-7), in order to enlighten the intimate involvement of hMSC in tumor vasculogenesis and angiogenesis. MATERIALS AND METHODS hMSC and MCF-7 were seeded onto the chick embryo chorioallantoic membrane (CAM) and incubated for 7 days. Consecutively, the morphology and the immunohistochemical profile of CAM were assessed. RESULTS Following this complex interaction, MCF-7 acquired a more aggressive phenotype, hMSC switched to a vascular precursor phenotype, while CAM underwent a major reset to an earlier stage, with hotspots of angiogenesis, vasculogenesis and hematopoiesis. CONCLUSION The hallmark of this study was the establishment of a veritable in vivo experimental model of MSC involvement in tumor vasculogenesis and angiogenesis, allowing further analysis in the field.
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Affiliation(s)
- Şerban ComŞa
- Department of Microscopic Morphology/Histology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
- Angiogenesis Research Center, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
| | - Amalia-Raluca CeauȘu
- Department of Microscopic Morphology/Histology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
- Angiogenesis Research Center, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
| | - Roxana Popescu
- Department of Microscopic Morphology/Cell and Molecular Biology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
| | - Simona SÂrb
- Department of Microscopic Morphology/Histology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
| | - Anca-Maria CÎmpean
- Department of Microscopic Morphology/Histology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
- Angiogenesis Research Center, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
| | - Marius Raica
- Department of Microscopic Morphology/Histology, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
- Angiogenesis Research Center, "Victor Babeş" University of Medicine and Pharmacy, Timişoara, Romania
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Melzer C, von der Ohe J, Hass R. Anti-Tumor Effects of Exosomes Derived from Drug-Incubated Permanently Growing Human MSC. Int J Mol Sci 2020; 21:7311. [PMID: 33023058 PMCID: PMC7582671 DOI: 10.3390/ijms21197311] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
Similar to growth-limited human primary cultures of mesenchymal stroma/stem-like cells (MSC), the continuously proliferating human MSC544 cell line produced extracellular vesicles as characterized by expression of the tetraspanin molecules CD9, CD63, and CD81. Release of these particles was predominantly detectable during continuous cell growth of MSC544 in contrast to confluency-mediated transient growth arrest. For therapeutic use, these particles were isolated from proliferating MSC544 after taxol treatment and applied to different cancer cell cultures. A pronounced cytotoxicity of lung, ovarian, and breast cancer cells was observed primarily with taxol-loaded exosomes, similar to the effects displayed by application of taxol substance. While these findings suggested pronounced cancer cell targeting of MSC544 exosomes, a tumor therapeutic approach was performed using a mouse in vivo breast cancer model. Thus, intravenous injection of taxol-loaded MSC544 exosomes displayed superior tumor-reducing capabilities as compared to application of taxol exosomes by oral gavage. To broaden this therapeutic spectrum, epirubicin was applied to MSC544, and the derived exosomes likewise exhibited significant cytotoxic effects in different cancer cell cultures. These findings suggest an unlimited source for large-scale exosome production with reproducible quality to enable variable drug targeting of tumors or other diseases.
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Affiliation(s)
| | | | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (C.M.); (J.v.d.O.)
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28
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Hass R. Role of MSC in the Tumor Microenvironment. Cancers (Basel) 2020; 12:2107. [PMID: 32751163 PMCID: PMC7464647 DOI: 10.3390/cancers12082107] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/24/2020] [Accepted: 07/25/2020] [Indexed: 12/24/2022] Open
Abstract
The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor's metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany
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29
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Melzer C, Jacobs R, Dittmar T, Pich A, von der Ohe J, Yang Y, Hass R. Reversible Growth-Arrest of a Spontaneously-Derived Human MSC-Like Cell Line. Int J Mol Sci 2020; 21:4752. [PMID: 32635395 PMCID: PMC7369918 DOI: 10.3390/ijms21134752] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022] Open
Abstract
Life cycle limitation hampers the production of high amounts of primary human mesenchymal stroma-/stem-like cells (MSC) and limits cell source reproducibility for clinical applications. The characterization of permanently growing MSC544 revealed some differentiation capacity and the simultaneous presence of known MSC markers CD73, CD90, and CD105 even after continuous long-term culture for more than one year and 32 passages. The expression of CD13, CD29, CD44, and CD166 were identified as further surface proteins, all of which were also simultaneously detectable in various other types of primary MSC populations derived from the umbilical cord, bone marrow, and placenta suggesting MSC-like properties in the cell line. Proliferating steady state MSC544 exhibited immune-modulatory activity similar to a subpopulation of long-term growth-inhibited MSC544 after 189d of continuous culture in confluency. This confluent connective cell layer with fibroblast-like morphology can spontaneously contract and the generated space is subsequently occupied by new cells with regained proliferative capacity. Accordingly, the confluent and senescence-associated beta-galactosidase-positive MSC544 culture with about 95% G0/G1 growth-arrest resumed re-entry into the proliferative cell cycle within 3d after sub-confluent culture. The MSC544 cells remained viable during confluency and throughout this transition which was accompanied by marked changes in the release of proteins. Thus, expression of proliferation-associated genes was down-modulated in confluent MSC544 and re-expressed following sub-confluent conditions whilst telomerase (hTERT) transcripts remained detectable at similar levels in both, confluent growth-arrested and proliferating MSC544. Together with the capability of connective cell layer formation for potential therapeutic approaches, MSC544 provide a long term reproducible human cell source with constant properties.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (C.M.); (J.v.d.O.); (Y.Y.)
| | - Roland Jacobs
- Department of Rheumatology and Clinical Immunology, Hannover Medical School, 30625 Hannover, Germany;
| | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58453 Witten, Germany;
| | - Andreas Pich
- Department of Toxicology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (C.M.); (J.v.d.O.); (Y.Y.)
| | - Yuanyuan Yang
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (C.M.); (J.v.d.O.); (Y.Y.)
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (C.M.); (J.v.d.O.); (Y.Y.)
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30
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Saleh M, Taher M, Sohrabpour AA, Vaezi AA, Nasiri Toosi M, Kavianpour M, Ghazvinian Z, Abdolahi S, Verdi J. Perspective of placenta derived mesenchymal stem cells in acute liver failure. Cell Biosci 2020; 10:71. [PMID: 32483484 PMCID: PMC7245988 DOI: 10.1186/s13578-020-00433-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 05/16/2020] [Indexed: 02/07/2023] Open
Abstract
Acute Liver failure (ALF) is a life-threatening disease and is determined by coagulopathy (with INR ≥ 1.5) and hepatic encephalopathy as a result of severe liver injury in patients without preexisting liver disease. Since there are problems with liver transplantation including lack of donors, use of immunosuppressive drugs, and high costs of this process, new therapeutic approaches alongside current treatments are needed. The placenta is a tissue that is normally discarded after childbirth. On the other hand, human placenta is a rich source of mesenchymal stem cells (MSCs), which is easily available, without moral problems, and its derived cells are less affected by age and environmental factors. Therefore, placenta-derived mesenchymal stem cells (PD-MSCs) can be considered as an allogeneic source for liver disease. Considering the studies on MSCs and their effects on various diseases, it can be stated that MSCs are among the most important agents to be used for novel future therapies of liver diseases. In this paper, we will investigate the effects of mesenchymal stem cells through migration and immigration to the site of injury, cell-to-cell contact, immunomodulatory effects, and secretory factors in ALF.
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Affiliation(s)
- Mahshid Saleh
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taher
- 2Gastroenterology and Hepatology, Tehran University of Medical Sciences, Imam Hospital Complex, Tehran, Iran
| | - Amir Ali Sohrabpour
- 3Gastroenterology and Hepatology, School of Medicine Shariati Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Amir Abbas Vaezi
- 4Department of Internal Medicine, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Mohsen Nasiri Toosi
- 5Internal Medicine, School of Medicine Liver Transplantation Research Center Imam, Khomeini Hospital Tehran University of Medical Sciences, Tehran, Iran
| | - Maria Kavianpour
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Ghazvinian
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahrokh Abdolahi
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Verdi
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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31
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The voltage-gated proton channel hHv1 is functionally expressed in human chorion-derived mesenchymal stem cells. Sci Rep 2020; 10:7100. [PMID: 32346069 PMCID: PMC7188850 DOI: 10.1038/s41598-020-63517-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 04/01/2020] [Indexed: 01/08/2023] Open
Abstract
The voltage-gated proton channel Hv1 is widely expressed, among others, in immune and cancer cells, it provides an efficient cytosolic H+extrusion mechanism and regulates vital functions such as oxidative burst, migration and proliferation. Here we demonstrate the presence of human Hv1 (hHv1) in the placenta/chorion-derived mesenchymal stem cells (cMSCs) using RT-PCR. The voltage- and pH-dependent gating of the current is similar to that of hHv1 expressed in cell lines and that the current is blocked by 5-chloro-2-guanidinobenzimidazole (ClGBI) and activated by arachidonic acid (AA). Inhibition of hHv1 by ClGBI significantly decreases mineral matrix production of cMSCs induced by conditions mimicking physiological or pathological (inorganic phosphate, Pi) induction of osteogenesis. Wound healing assay and single cell motility analysis show that ClGBI significantly inhibits the migration of cMSCs. Thus, seminal functions of cMSCs are modulated by hHv1 which makes this channel as an attractive target for controlling advantages/disadvantages of MSCs therapy.
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32
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Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, Cui H. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther 2020; 5:8. [PMID: 32296030 PMCID: PMC7005297 DOI: 10.1038/s41392-020-0110-5] [Citation(s) in RCA: 1170] [Impact Index Per Article: 234.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 12/15/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022] Open
Abstract
Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.
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Affiliation(s)
- Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Pengfei Shi
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Gaichao Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jie Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Wen Peng
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jiayi Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Guanghui Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Xiaowen Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Fei Chen
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China.
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China.
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Hass R, von der Ohe J, Ungefroren H. Potential Role of MSC/Cancer Cell Fusion and EMT for Breast Cancer Stem Cell Formation. Cancers (Basel) 2019; 11:1432. [PMID: 31557960 PMCID: PMC6826868 DOI: 10.3390/cancers11101432] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/20/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023] Open
Abstract
Solid tumors comprise of maturated cancer cells and self-renewing cancer stem-like cells (CSCs), which are associated with various other nontumorigenic cell populations in the tumor microenvironment. In addition to immune cells, endothelial cells, fibroblasts, and further cell types, mesenchymal stroma/stem-like cells (MSC) represent an important cell population recruited to tumor sites and predominantly interacting with the different cancer cells. Breast cancer models were among the first to reveal distinct properties of CSCs, however, the cellular process(es) through which these cells are generated, maintained, and expanded within neoplastic tissues remains incompletely understood. Here, we discuss several possible scenarios that are not mutually exclusive but may even act synergistically: fusion of cancer cells with MSC to yield hybrid cells and/or the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells by MSC, which can relay signals for retrodifferentiation and eventually, the generation of breast CSCs (BCSCs). In either case, the consequences may be promotion of self-renewal capacity, tumor cell plasticity and heterogeneity, an increase in the cancer cells' invasive and metastatic potential, and the acquisition of resistance mechanisms towards chemo- or radiotherapy. While specific signaling mechanisms involved in each of these properties remain to be elucidated, the present review article focusses on a potential involvement of cancer cell fusion and EMT in the development of breast cancer stem cells.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany.
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
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Gu ZW, He YF, Wang WJ, Tian Q, Di W. MiR-1180 from bone marrow-derived mesenchymal stem cells induces glycolysis and chemoresistance in ovarian cancer cells by upregulating the Wnt signaling pathway. J Zhejiang Univ Sci B 2019; 20:219-237. [PMID: 30829010 DOI: 10.1631/jzus.b1800190] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Bone marrow-derived mesenchymal stem cells (BM-MSCs) play an important role in cancer development and progression. However, the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown. METHODS Conditioned media of BM-MSCs (BM-MSC-CM) were analyzed using a technique based on microRNA arrays. The most highly expressed microRNAs were selected for testing their effects on glycolysis and chemoresistance in SKOV3 and COC1 ovarian cancer cells. The targeted gene and related signaling pathway were investigated using in silico analysis and in vitro cancer cell models. Kaplan-Merier survival analysis was performed on a population of 59 patients enrolled to analyze the clinical significance of microRNA findings in the prognosis of ovarian cancer. RESULTS MiR-1180 was the most abundant microRNA detected in BM-MSC-CM, which simultaneously induces glycolysis and chemoresistance (against cisplatin) in ovarian cancer cells. The secreted frizzled-related protein 1 (SFRP1) gene was identified as a major target of miR-1180. The overexpression of miR-1180 led to the activation of Wnt signaling and its downstream components, namely Wnt5a, β-catenin, c-Myc, and CyclinD1, which are responsible for glycolysis-induced chemoresistance. The miR-1180 level was inversely correlated with SFRP1 mRNA expression in ovarian cancer tissue. The overexpressed miR-1180 was associated with a poor prognosis for the long-term (96-month) survival of ovarian cancer patients. CONCLUSIONS BM-MSCs enhance the chemoresistance of ovarian cancer by releasing miR-1180. The released miR-1180 activates the Wnt signaling pathway in cancer cells by targeting SFRP1. The enhanced Wnt signaling upregulates the glycolytic level (i.e. Warburg effect), which reinforces the chemoresistance property of ovarian cancer cells.
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Affiliation(s)
- Zhuo-Wei Gu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yi-Feng He
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wen-Jing Wang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Qi Tian
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wen Di
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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35
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Melzer C, Rehn V, Yang Y, Bähre H, von der Ohe J, Hass R. Taxol-Loaded MSC-Derived Exosomes Provide a Therapeutic Vehicle to Target Metastatic Breast Cancer and Other Carcinoma Cells. Cancers (Basel) 2019; 11:798. [PMID: 31181850 PMCID: PMC6627807 DOI: 10.3390/cancers11060798] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 06/01/2019] [Accepted: 06/04/2019] [Indexed: 02/06/2023] Open
Abstract
MSC-derived exosomes display, among others, an efficient biocompatibility and a reduced intrinsic immunogenicity, representing a valuable vehicle for drug delivery in a tumor-therapeutic approach. Following treatment of several human mesenchymal stroma/stem-like cell (MSC) populations with sub-lethal concentrations of taxol for 24 h, exosomes were isolated and applied to different human cancer populations including A549 lung cancer, SK-OV-3 ovarian cancer, and MDA-hyb1 breast cancer cells. While MSC control exosomes revealed little if any growth inhibition on the tumor cells, exposure to taxol-loaded MSC-derived exosomes was associated with 80-90% cytotoxicity. A similar application of taxol-loaded exosomes from HuVEC displayed much fewer effects. Quantification by LC-MS/MS analysis demonstrated a 7.6-fold reduced taxol concentration in MSC exosomes when compared to equivalent cytotoxic in vitro effects achieved with taxol substances, indicating a specific and more efficient tumor-targeting property. Consequently, MSC-derived taxol exosomes were tested in vivo. Highly metastatic MDA-hyb1 breast tumors were induced in NODscid mice, and systemic intravenous application of MSC-derived taxol exosomes revealed a more than 60% reduction of subcutaneous primary tumors. Moreover, the amount of distant organ metastases observed at least in lung, liver, spleen, and kidney was reduced by 50% with MSC taxol exosomes, similar to the effects observed with taxol, although the concentration of taxol in exosomes was about 1000-fold reduced. Together, these findings in different cancer cell populations and in vivo provide promising future perspectives for drug-loaded MSC-derived exosomes in efficiently targeting primary tumors and metastases by reducing side effects.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Vanessa Rehn
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Yuanyuan Yang
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
- Tongji Hospital Affiliated Tongji University, Shanghai 200065, China.
| | - Heike Bähre
- Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
- Research Core Unit Metabolomics, Hannover Medical School, 30625 Hannover, Germany.
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
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Melzer C, von der Ohe J, Otterbein H, Ungefroren H, Hass R. Changes in uPA, PAI-1, and TGF-β Production during Breast Cancer Cell Interaction with Human Mesenchymal Stroma/Stem-Like Cells (MSC). Int J Mol Sci 2019; 20:2630. [PMID: 31142059 PMCID: PMC6600334 DOI: 10.3390/ijms20112630] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/17/2019] [Accepted: 05/24/2019] [Indexed: 02/06/2023] Open
Abstract
The interactions of cancer cells with neighboring non-malignant cells in the microenvironment play an important role for progressive neoplastic development and metastasis. Long-term direct co-culture of human MDA-MB-231cherry breast cancer cells with benign human mesenchymal stroma/stem-like cells (MSC) MSC544GFP stably expressing mCherry and eGFP fluorescence proteins, respectively, was associated with the formation of three-dimensional (3D) tumor spheroids in vitro. The quantification of the breast tumor marker urokinase plasminogen activator (uPA) in mono-cultured MDA-MB-231 cells revealed an approximately 14-fold enhanced expression when compared to five different normal human MSC mono-cultures. Moreover, uPA levels in 3D tumor spheroids remained elevated 9.4-fold above the average of five different human MSC cultures. In contrast, the expression of the corresponding plasminogen activator inhibitor type-1 (PAI-1) declined by 2.6-fold in the breast cancer cells and was even further reduced by 3.2-fold in the MDA-MB-231cherry/MSC544GFP 3D co-culture spheroids when compared to the various MSC populations. The supportive data were obtained for the production of TGF-β1, which is an important growth factor in the regulation of tumor growth and metastasis formation. Whereas, TGF-β1 release in MDA-MB-231cherry/MSC544GFP co-cultures was elevated by 1.56-fold as compared to MSC544 mono-cultures after 24 h; this ratio further increased to 2.19-fold after 72 h. Quantitative PCR analyses in MSC544 and MDA-MB-231 cells revealed that MSC, rather than the breast cancer cells, are responsible for TGF-β1 synthesis and that TGF-β1 contributes to its own synthesis in these cells. These findings suggested potential synergistic effects in the expression/secretion of uPA, PAI-1, and TGF-β during the co-culture of breast cancer cells with MSC.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Hannah Otterbein
- First Department of Medicine, UKSH, Campus Lübeck, 23538 Lübeck, Germany.
| | - Hendrik Ungefroren
- First Department of Medicine, UKSH, Campus Lübeck, 23538 Lübeck, Germany.
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, UKSH, Campus Kiel, 24105 Kiel, Germany.
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
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Avnet S, Lemma S, Cortini M, Di Pompo G, Perut F, Baldini N. Pre-clinical Models for Studying the Interaction Between Mesenchymal Stromal Cells and Cancer Cells and the Induction of Stemness. Front Oncol 2019; 9:305. [PMID: 31114753 PMCID: PMC6502984 DOI: 10.3389/fonc.2019.00305] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 04/02/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have essential functions in building and supporting the tumour microenvironment, providing metastatic niches, and maintaining cancer hallmarks, and it is increasingly evident that the study of the role of MSC in cancer is crucial for paving the way to clinical opportunities for novel anti-cancer therapies. To date, the vast majority of preclinical models that have been used for studying the effect of reactive MSC on cancer growth, metastasis, and response to therapy has been mainly based on in vitro flat biology, including the co-culturing with cell compartmentalization or with cell-to-cell contact, and on in vivo cancer models with different routes of MSC inoculation. More complex in vitro 3D models based on spheroid structures that are formed by intermingled MSC and tumour cells are also capturing the interest in cancer research. These are innovative culture systems tailored on the specific tumour type and that can be combined with a synthetic extracellular matrix, or included in in silico technologies, to more properly mimic the in vivo biological, spatial, biochemical, and biophysical features of tumour tissues. In this review, we summarized the most popular and currently available preclinical models for evaluating the role of MSC in cancer and their specific suitability, for example, in assaying the MSC-driven induction of epithelial-to-mesenchymal transition or of stem-like traits in cancer cells. Finally, we enlightened the need to carefully consider those parameters that might unintentionally strongly affect the secretome in MSC-cancer interplay and introduce confounding variables for the interpretation of results.
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Affiliation(s)
- Sofia Avnet
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Silvia Lemma
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Margherita Cortini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Gemma Di Pompo
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Francesca Perut
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Nicola Baldini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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Hu J, Zhao W, Huang Y, Wang Z, Jiang T, Wang L. MiR-1180 from bone marrow MSCs promotes cell proliferation and glycolysis in ovarian cancer cells via SFRP1/Wnt pathway. Cancer Cell Int 2019; 19:66. [PMID: 30936781 PMCID: PMC6427852 DOI: 10.1186/s12935-019-0751-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 02/08/2019] [Indexed: 02/08/2023] Open
Abstract
Background The ovarian cancer microenvironment is responsible for cancer cell growth and disease relapse. Bone marrow mesenchymal stem cells (BM-MSCs) play important roles in ovarian cancer, however, the mechanism of BM-MSCs inducing cell proliferation and glycolysis needs further research. Methods miRNA array was used to analyze the significant miRNAs. RT-qPCR was used to examine the level of miR-1180 and SFRP1. The western blotting was used to detect the protein level of SFRP1 and Wnt signal pathway. We utilized luciferase reporter assay to confirm the direct interaction of SFRP1 with miR-1180. MTT assay were employed to investigate the proliferation of ovarian cancer cells. ECAR, ATP assay were used to measure the glycolysis state of ovarian cancer cells. Results It was demonstrated that BM-MSCs promoted ovarian cancer cell proliferation and glycolysis. The miRNA profile from the BM-MSCs indicated that miR-1180 was up-regulated in the conditioned medium of BM-MSCs. MiR-1180 could accelerate ovarian cancer cell proliferation and glycolysis. We also found that up-regulation of miR-1180 activated Wnt signaling by targeting SFRP1 in ovarian cancer cells. Conclusion The study demonstrated that miR-1180 was a critical miRNA mediating BM-MSCs induced cell proliferation and glycolysis and could be a new target in ovarian cancer therapy.
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Affiliation(s)
- Jinghui Hu
- 1Department of Gynaecology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003 China
| | - Wei Zhao
- 1Department of Gynaecology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003 China
| | - Yujie Huang
- 1Department of Gynaecology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003 China
| | - Zhe Wang
- 1Department of Gynaecology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003 China
| | - Tingting Jiang
- 1Department of Gynaecology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003 China
| | - Li Wang
- 2Department of Gynaecology and Obstetrics, Changzhou Maternal and Child Health Care Hospital Affiliated Nanjing Medical University, Changzhou, China
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Ávila-Ibarra LR, Mora-García MDL, García-Rocha R, Hernández-Montes J, Weiss-Steider B, Montesinos JJ, Lizano Soberon M, García-López P, López CAD, Torres-Pineda DB, Chacón-Salinas R, Vallejo-Castillo L, Pérez-Tapia SM, Monroy-García A. Mesenchymal Stromal Cells Derived from Normal Cervix and Cervical Cancer Tumors Increase CD73 Expression in Cervical Cancer Cells Through TGF-β1 Production. Stem Cells Dev 2019; 28:477-488. [PMID: 30696359 DOI: 10.1089/scd.2018.0183] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) in the tumor microenvironment (TME) participate together with tumor cells to suppress antitumor effector cells through the production of immunosuppressive factors, such as transforming growth factor-beta 1 (TGF-β1). Furthermore, TGF-β1 can induce 5'-nucleotidase (CD73) expression in various cell types; this functional activity is associated with the production of adenosine (Ado), which is an immunosuppressive nucleoside. In this study, we provide evidence that coculture of MSCs derived from cervical tumors (CeCa-MSC) with CeCa tumor cells increases CD73 expression in tumor cells and the capacity of these cells to generate Ado in a MSC ratio-dependent manner. Interestingly, the increase in CD73 in the CeCa cell membrane corresponded to an increase in the TGF-β1 expression level in the tumor cells and the TGF-β1 content in the supernatants of the CeCa/CeCa-MSC cocultures. The addition of anti-hTGF-β neutralizing antibodies strongly reversed CD73 expression in the tumor cells. This phenomenon was not exclusive to CeCa-MSCs; coculture of MSCs derived from the normal cervix with CeCa cells produced similar results. These results suggest that the interaction of MSCs with CeCa tumor cells in the TME may condition higher TGF-β1 production to maintain an immunosuppressive status not only through the activity of this cytokine per se but also through its ability to induce CD73 expression in tumor cells and generate an immunosuppressive microenvironment rich in Ado.
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Affiliation(s)
- Luis Roberto Ávila-Ibarra
- 1 Laboratorio de Inmunología y Cáncer, Unidad de Investigación Médica en Enfermedades Oncológicas, CMN SXXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.,2 Laboratorio de Inmunobiología, UIDCC-UMIEZ, FES-Zaragoza, UNAM, Ciudad de México, México.,3 Programa de Posgrado en Ciencias Biológicas, UNAM, Ciudad de México, México
| | | | - Rosario García-Rocha
- 2 Laboratorio de Inmunobiología, UIDCC-UMIEZ, FES-Zaragoza, UNAM, Ciudad de México, México
| | - Jorge Hernández-Montes
- 2 Laboratorio de Inmunobiología, UIDCC-UMIEZ, FES-Zaragoza, UNAM, Ciudad de México, México
| | - Benny Weiss-Steider
- 2 Laboratorio de Inmunobiología, UIDCC-UMIEZ, FES-Zaragoza, UNAM, Ciudad de México, México
| | - Juan José Montesinos
- 4 Laboratorio de Células Troncales Mesenquimales, Unidad de Investigación Médica en Enfermedades Oncológicas, CMN SXXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Marcela Lizano Soberon
- 5 Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, UNAM, Ciudad de México, México
| | - Patricia García-López
- 6 Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, México
| | | | - Daniela Berenice Torres-Pineda
- 1 Laboratorio de Inmunología y Cáncer, Unidad de Investigación Médica en Enfermedades Oncológicas, CMN SXXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.,3 Programa de Posgrado en Ciencias Biológicas, UNAM, Ciudad de México, México
| | - Rommel Chacón-Salinas
- 7 Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Instituto Politécnico Nacional, Ciudad de México, México.,8 Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Ciudad de México, México
| | - Luis Vallejo-Castillo
- 7 Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Instituto Politécnico Nacional, Ciudad de México, México.,9 Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav-IPN), Ciudad de México, México
| | - Sonia Mayra Pérez-Tapia
- 7 Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Instituto Politécnico Nacional, Ciudad de México, México.,8 Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Ciudad de México, México
| | - Alberto Monroy-García
- 1 Laboratorio de Inmunología y Cáncer, Unidad de Investigación Médica en Enfermedades Oncológicas, CMN SXXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.,2 Laboratorio de Inmunobiología, UIDCC-UMIEZ, FES-Zaragoza, UNAM, Ciudad de México, México
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Melzer C, von der Ohe J, Hass R. Involvement of Actin Cytoskeletal Components in Breast Cancer Cell Fusion with Human Mesenchymal Stroma/Stem-Like Cells. Int J Mol Sci 2019; 20:876. [PMID: 30781614 PMCID: PMC6412741 DOI: 10.3390/ijms20040876] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/14/2019] [Accepted: 02/15/2019] [Indexed: 12/13/2022] Open
Abstract
Cell fusion as a rare event was observed following the co-culture of human MDA-MB-231cherry breast cancer cells or benign neoplastic MCF10Acherry breast epithelial cells together with different mesenchymal stroma/stem-like cells (MSCGFP) cultures, respectively, resulting in the generation of double-fluorescing hybrid cells. Analysis of potential molecular mechanisms for the formation of cancer hybrid cells revealed cytoskeletal components, including F-actin. Thus, a sub-lethal concentration of cytochalasin D, which blocks elongation of actin filaments, was able to significantly reduce cancer hybrid cell formation. Simultaneously, cell cycle progression of the different co-cultures remained unaffected following treatment with cytochalasin D, indicating continued proliferation. Moreover, exposure to 50 nM cytochalasin D revealed little if any effect on the expression of various integrins and cell adhesion molecules in the different co-cultures. However, LC-MS proteome analysis of the different control co-cultures compared to corresponding cytochalasin-treated co-cultures demonstrated predominant differences in the expression of actin-associated cytoskeletal proteins. In addition, the requirement of structured actin to provide an appropriate cytoskeletal network for enabling subsequent fusion processes was also substantiated by the actin filament disrupting latrunculin B, which inhibits the fusion process between the breast cancer populations and mesenchymal stroma/stem-like cells (MSC). Together, these findings suggest an important role of distinct actin structures and associated cytoskeletal components during cell fusion and the formation of breast cancer hybrid cells.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
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Melzer C, von der Ohe J, Hass R. In Vivo Cell Fusion between Mesenchymal Stroma/Stem-Like Cells and Breast Cancer Cells. Cancers (Basel) 2019; 11:185. [PMID: 30764554 PMCID: PMC6406489 DOI: 10.3390/cancers11020185] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/21/2019] [Accepted: 01/21/2019] [Indexed: 12/13/2022] Open
Abstract
Cellular communication within the tumor microenvironment enables important interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem-like cells (MSC). These interactions were monitored in vivo following co-injection of GFP-labeled human MSC together with mcherry-labeled MDA-MB-231 breast cancer cells in NODscid mice. Within 14 days of tumor development the number of initially co-injected MSC had significantly declined and spontaneous formation of breast cancer/MSC hybrid cells was observed by the appearance of double fluorescing cells. This in vivo fusion displayed a rare event and occurred in less than 0.5% of the tumor cell population. Similar findings were observed in a parallel in vitro co-culture. Characterization of the new cell fusion products obtained after two consecutive flow cytometry cell sorting and single cell cloning revealed two populations, termed MDA-hyb3 and MDA-hyb4. The breast cancer fusion cells expressed both, GFP and mcherry and displayed more characteristics of the MDA-MB-231 cells than of the parental MSC. While little if any differences were determined in the proliferative capacity, a significant delay of MDA-hyb3 cells in tumor formation was observed when compared to the parental MDA-MB-231 cells. Moreover, MDA-hyb3 cells developed an altered pattern of distant organ metastases. These findings demonstrated dynamic tumor changes by in vivo and in vitro fusion with the development of new breast cancer hybrid cells carrying altered tumorigenic properties. Consequently, cancer cell fusion contributes to progressively increasing tumor heterogeneity which complicates a therapeutic regimen.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
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Melzer C, von der Ohe J, Hass R. MSC stimulate ovarian tumor growth during intercellular communication but reduce tumorigenicity after fusion with ovarian cancer cells. Cell Commun Signal 2018; 16:67. [PMID: 30316300 PMCID: PMC6186086 DOI: 10.1186/s12964-018-0279-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/01/2018] [Indexed: 12/15/2022] Open
Abstract
The tumor microenvironment enables important cellular interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem cells (MSC). In vivo cellular interactions of primary human MSC in co-culture with human SK-OV-3 ovarian cancer cells revealed an increased tumor growth as compared to mono-cultures of the ovarian cancer cells. Moreover, the presence of MSC stimulated formation of liver metastases. Further interactions of MSC with the ovarian cancer cells resulted in the formation of hybrid cells by cell fusion. Isolation and single cell cloning of these hybrid cells revealed two differentially fused ovarian cancer cell populations termed SK-hyb1 and SK-hyb2. RNA microarray analysis demonstrated expression profiles from both parental partners whereby SK-hyb1 were attributed with more SK-OV-3 like properties and SK-hyb2 cells displayed more similarities to MSC. Both ovarian cancer hybrid populations exhibited reduced proliferative capacity compared to the parental SK-OV-3 cells. Moreover, the fused populations failed to develop tumors in NODscid mice. Together, these data suggested certain stimulatory effects on ovarian tumor growth in the presence of MSC. Conversely, fusion of MSC with SK-OV-3 cells contributed to the generation of new cancer hybrid populations displaying a significantly reduced tumorigenicity.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology (OE 6410), Hannover Medical School, Carl-Neuberg-Str. 1, D –30625 Hannover, Germany
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology (OE 6410), Hannover Medical School, Carl-Neuberg-Str. 1, D –30625 Hannover, Germany
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology (OE 6410), Hannover Medical School, Carl-Neuberg-Str. 1, D –30625 Hannover, Germany
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Exosomes Regulate the Transformation of Cancer Cells in Cancer Stem Cell Homeostasis. Stem Cells Int 2018; 2018:4837370. [PMID: 30344611 PMCID: PMC6174755 DOI: 10.1155/2018/4837370] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 07/31/2018] [Indexed: 02/07/2023] Open
Abstract
In different biological model systems, exosomes are considered mediators of cell-cell communication between different cell populations. Exosomes, as extracellular vesicles, participate in physiological and pathological processes by transmitting signaling molecules such as proteins, nucleic acids, and lipids. The tumor's microenvironment consists of many types of cells, including cancer stem cells and mesenchymal cells. It is well known that these cells communicate with each other and thereby regulate the progression of the tumor. Recent studies have provided evidence that exosomes mediate the interactions between different types of cells in the tumor microenvironment, providing further insight into how these cells interact through exosome signaling. Cancer stem cells are a small kind of heterogeneous cells that existed in tumor tissues or cancer cell lines. These cells possess a stemness phenotype with a self-renewal ability and multipotential differentiation which was considered the reason for the failure of conventional cancer therapies and tumor recurrence. However, a highly dynamic equilibrium was found between cancer stem cells and cancer cells, and this indicates that cancer stem cells are no more special target and blocking the transformation of cancer stem cells and cancer cells seem to be a more significant therapy strategy. Whether exosomes, as an information transforming carrier between cells, regulated cancer cell transformation in cancer stem cell dynamic equilibrium and targeting exosome signaling attenuated the formation of cancer stem cells and finally cure cancers is worthy of further study.
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Chitwood CA, Dietzsch C, Jacobs G, McArdle T, Freeman BT, Banga A, Noubissi FK, Ogle BM. Breast tumor cell hybrids form spontaneously in vivo and contribute to breast tumor metastases. APL Bioeng 2018; 2:031907. [PMID: 31069316 PMCID: PMC6324215 DOI: 10.1063/1.5024744] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 07/18/2018] [Indexed: 12/15/2022] Open
Abstract
Cancer cell fusion was suggested as a mechanism of metastasis about a century ago. Since then, many additional modes of material transfer (i.e., tunneling nanotubes, and exosomes) to generate cell hybrids have been identified. However, studies documenting spontaneous tumor hybrid formation in vivo as a mechanism that enables metastasis are still lacking. Here, we tested whether spontaneous hybrid formation in vivo contributes to bona fide metastatic tumors. We first used single cell RNASeq to analyze the gene expression profile of spontaneously formed cancer cell-stromal hybrids, and results revealed that hybrids exhibit a clustering pattern that is distinct from either parental cell and suggestive of substantial diversity of individual hybrids. Despite the newly gained diversity, hybrids can retain expression of critical genes of each parental cell. To assess the biological impact of cancer cell hybrids in vivo, we transfected murine mammary tumor cells, isolated from FVB/N-Tg(MMTV-PyVT)634Mul/J mice (PyVT) with Cre recombinase prior to injection to the murine fat pad of FVB.129S6(B6)-Gt(ROSA)26Sortm1(Luc)Kael/J mice such that luciferase expression is induced with hybrid formation; luciferase expression was tracked for up to four months. We observed that hybrid formation occurs spontaneously in vivo and that a significantly higher number of hybrids reside in metastases compared to the primary tumor, supporting the possibility that hybrids can emerge from the primary tumor and proliferate to help create a new tumor at a distant site. Additional studies are now warranted to delineate the mechanisms of cancer cell hybrid transit to metastases since drugs to inhibit hybrid formation might prevent metastatic spread.
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Affiliation(s)
| | | | | | | | | | | | - Felicite K Noubissi
- Department of Biology/RCMI, Jackson State University, Jackson, Mississippi 39217, USA
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45
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García-Olmo DC, Picazo MG, García-Olmo D. Melanoma transplants in “green” mice: Fluorescent cells in tumors are not equivalent to host-derived cells. ELECTRON J BIOTECHN 2018. [DOI: 10.1016/j.ejbt.2018.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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Melzer C, von der Ohe J, Hass R. Concise Review: Crosstalk of Mesenchymal Stroma/Stem-Like Cells with Cancer Cells Provides Therapeutic Potential. Stem Cells 2018; 36:951-968. [PMID: 29603861 DOI: 10.1002/stem.2829] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 02/26/2018] [Accepted: 03/19/2018] [Indexed: 12/21/2022]
Abstract
Various direct and indirect cellular interactions between multi-functional mesenchymal stroma/stem-like cells (MSCs) and cancer cells contribute to increasing plasticity within the tumor tissue and its microenvironment. Direct and tight communication between MSC and cancer cells is based on membrane protein interactions and the exchange of large plasma membrane fragments also known as trogocytosis. An ultimate but rare direct interaction resumes in fusion of these two cellular partners resulting in the formation of new cancer hybrid cell populations. Alternatively, indirect interactions are displayed by the release of membranous vesicle-encapsulated microRNAs and proteins or soluble components such as molecular growth factors, hormones, chemo-/cytokines, and metabolites. Released single molecules as well as multivesicular bodies including exosomes and microvesicles can form local concentration gradients within the tumor microenvironment and are incorporated not only by adjacent neighboring cells but also affect distant target cells. The present Review will focus on vesicle-mediated indirect communication and on cancer cell fusion with direct contact between MSC and cancer cells. These different types of interaction are accompanied by functional interference and mutual acquisition of new cellular properties. Consequently, alterations in cancer cell functionalities paralleled by the capability to reorganize the tumor stroma can trigger changes in metastatic behavior and promote retrodifferentiation to develop new cancer stem-like cells. However, exosomes and microvesicles acting over long distances may also provide a tool with therapeutic potential when loaded with anti-tumor cargo. Stem Cells 2018;36:951-968.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
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Melzer C, von der Ohe J, Hass R. In Vitro Fusion of Normal and Neoplastic Breast Epithelial Cells with Human Mesenchymal Stroma/Stem Cells Partially Involves Tumor Necrosis Factor Receptor Signaling. Stem Cells 2018; 36:977-989. [PMID: 29569804 DOI: 10.1002/stem.2819] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 02/05/2018] [Accepted: 02/24/2018] [Indexed: 12/12/2022]
Abstract
Formation of hybrid cells by "accidental cell fusion" of normal and neoplastic breast epithelial cells with local tissue-associated mesenchymal stroma/stem-like cells (MSC) in an inflammatory microenvironment can generate new cancer cell populations whereby molecular signaling mechanisms of this process remain unclear. Fusions of lentiviral enhanced green fluorescent protein-labeled MSC with mcherry-labeled breast epithelial cells were quantified and effects of tumor necrosis factor alpha (TNF-α) and receptor downstream signaling were investigated. Cocultures of MSC with normal human mammary epithelial cells, with neoplastic MCF10A, or with MDA-MB-231 or MCF7 breast cancer cells demonstrated hybrid cell formation between 0.1% and about 2% of the populations within 72 hours, whereby the fusion process occurred in less than 5 minutes. Addition of the pro-inflammatory cytokine TNF-α significantly enhanced MCF10A-MSC cell fusion. Small-interfering RNA (siRNA) knockdown experiments revealed an involvement of tumor necrosis factor (TNF) receptor-1 and -2 in this process. This was also substantiated by siRNA knockdown of tumor necrosis factor receptor type 1-associated death domain which abolished TNF-α-stimulated fusion. While TNF receptor signaling can be relayed via the Mitogen-activated protein kinase 8 (MAPK8), NF-κB or cell death pathways, examination of further downstream signaling exhibited little if any effects of MAPK8 or RelA (p65) on TNF-α-mediated cell fusion, respectively. These data suggested that cell fusion between MSC and MCF10A breast epithelial cells can be stimulated by TNF-α involving TNF receptor-activated cell death pathways or additional NF-κB signaling. Stem Cells 2018;36:977-989.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
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Ranganath SH. Bioengineered cellular and cell membrane-derived vehicles for actively targeted drug delivery: So near and yet so far. Adv Drug Deliv Rev 2018; 132:57-80. [PMID: 29935987 DOI: 10.1016/j.addr.2018.06.012] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/31/2018] [Accepted: 06/18/2018] [Indexed: 12/16/2022]
Abstract
Cellular carriers for drug delivery are attractive alternatives to synthetic nanoparticles owing to their innate homing/targeting abilities. Here, we review molecular interactions involved in the homing of Mesenchymal stem cells (MSCs) and other cell types to understand the process of designing and engineering highly efficient, actively targeting cellular vehicles. In addition, we comprehensively discuss various genetic and non-genetic strategies and propose futuristic approaches of engineering MSC homing using micro/nanotechnology and high throughput small molecule screening. Most of the targeting abilities of a cell come from its plasma membrane, thus, efforts to harness cell membranes as drug delivery vehicles are gaining importance and are highlighted here. We also recognize and report the lack of detailed characterization of cell membranes in terms of safety, structural integrity, targeting functionality, and drug transport. Finally, we provide insights on future development of bioengineered cellular and cell membrane-derived vesicles for successful clinical translation.
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Affiliation(s)
- Sudhir H Ranganath
- Bio-INvENT Lab, Department of Chemical Engineering, Siddaganga Institute of Technology, B.H. Road, Tumakuru, 572103, Karnataka, India.
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Poggi A, Varesano S, Zocchi MR. How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive. Front Immunol 2018; 9:262. [PMID: 29515580 PMCID: PMC5825917 DOI: 10.3389/fimmu.2018.00262] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 01/30/2018] [Indexed: 12/17/2022] Open
Abstract
Experimental evidence indicates that mesenchymal stromal cells (MSCs) may regulate tumor microenvironment (TME). It is conceivable that the interaction with MSC can influence neoplastic cell functional behavior, remodeling TME and generating a tumor cell niche that supports tissue neovascularization, tumor invasion and metastasization. In addition, MSC can release transforming growth factor-beta that is involved in the epithelial-mesenchymal transition of carcinoma cells; this transition is essential to give rise to aggressive tumor cells and favor cancer progression. Also, MSC can both affect the anti-tumor immune response and limit drug availability surrounding tumor cells, thus creating a sort of barrier. This mechanism, in principle, should limit tumor expansion but, on the contrary, often leads to the impairment of the immune system-mediated recognition of tumor cells. Furthermore, the cross-talk between MSC and anti-tumor lymphocytes of the innate and adaptive arms of the immune system strongly drives TME to become immunosuppressive. Indeed, MSC can trigger the generation of several types of regulatory cells which block immune response and eventually impair the elimination of tumor cells. Based on these considerations, it should be possible to favor the anti-tumor immune response acting on TME. First, we will review the molecular mechanisms involved in MSC-mediated regulation of immune response. Second, we will focus on the experimental data supporting that it is possible to convert TME from immunosuppressive to immunostimulant, specifically targeting MSC.
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Affiliation(s)
- Alessandro Poggi
- Molecular Oncology and Angiogenesis Unit, Policlinico San Martino, Genoa, Italy
| | - Serena Varesano
- Molecular Oncology and Angiogenesis Unit, Policlinico San Martino, Genoa, Italy
| | - Maria Raffaella Zocchi
- Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
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Melzer C, von der Ohe J, Hass R. Enhanced metastatic capacity of breast cancer cells after interaction and hybrid formation with mesenchymal stroma/stem cells (MSC). Cell Commun Signal 2018; 16:2. [PMID: 29329589 PMCID: PMC5795285 DOI: 10.1186/s12964-018-0215-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 01/02/2018] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Fusion of breast cancer cells with tumor-associated populations of the microenvironment including mesenchymal stroma/stem-like cells (MSC) represents a rare event in cell communication whereby the metastatic capacity of those hybrid cells remains unclear. METHODS Functional changes were investigated in vitro and in vivo following spontaneous fusion and hybrid cell formation between primary human MSC and human MDA-MB-231 breast cancer cells. Thus, lentiviral eGFP-labeled MSC and breast cancer cells labeled with mcherry resulted in dual-fluorescing hybrid cells after co-culture. RESULTS Double FACS sorting and single cell cloning revealed two different aneuploid male hybrid populations (MDA-hyb1 and MDA-hyb2) with different STR profiles, pronounced telomerase activities, and enhanced proliferative capacities as compared to the parental cells. Microarray-based mRNA profiling demonstrated marked regulation of genes involved in epithelial-mesenchymal transition and increased expression of metastasis-associated genes including S100A4. In vivo studies following subcutaneous injection of the breast cancer and the two hybrid populations substantiated the in vitro findings by a significantly elevated tumor growth of the hybrid cells. Moreover, both hybrid populations developed various distant organ metastases in a much shorter period of time than the parental breast cancer cells. CONCLUSION Together, these data demonstrate spontaneous development of new tumor cell populations exhibiting different parental properties after close interaction and subsequent fusion of MSC with breast cancer cells. This formation of tumor hybrids contributes to continuously increasing tumor heterogeneity and elevated metastatic capacities.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, D-30625, Germany
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, D-30625, Germany
| | - Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, D-30625, Germany.
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