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Yuan J, Yang L, Zhang H, Beeraka NM, Zhang D, Wang Q, Wang M, Pr HV, Sethi G, Wang G. Decoding tumor microenvironment: EMT modulation in breast cancer metastasis and therapeutic resistance, and implications of novel immune checkpoint blockers. Biomed Pharmacother 2024; 181:117714. [PMID: 39615165 DOI: 10.1016/j.biopha.2024.117714] [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: 08/14/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 12/21/2024] Open
Abstract
Tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) play crucial roles in the initiation and progression of tumors. TME is composed of various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as non-cellular components like extracellular matrix (ECM) proteins and soluble factors. These elements interact with tumor cells through a complex network of signaling pathways involving cytokines, growth factors, metabolites, and non-coding RNA-carrying exosomes. Hypoxic conditions within the TME further modulate these interactions, collectively influencing tumor growth, metastatic potential, and response to therapy. EMT represents a dynamic and reversible process where epithelial cells undergo phenotypic changes to adopt mesenchymal characteristics in several cancers, including breast cancers. This transformation enhances cell motility and imparts stem cell-like properties, which are closely associated with increased metastatic capability and resistance to conventional cancer treatments. Thus, understanding the crosstalk between the TME and EMT is essential for unraveling the underlying mechanisms of breast cancer metastasis and therapeutic resistance. This review uniquely examines the intricate interplay between the tumor TME and epithelial-mesenchymal transition EMT in driving breast cancer metastasis and treatment resistance. It explores the therapeutic potential of targeting the TME-EMT axis, specifically through CD73-TGF-β dual-blockade, to improve outcomes in triple-negative breast cancer. Additionally, it underscores new strategies to enhance immune checkpoint blockade (ICB) responses by modulating EMT, thereby offering innovative insights for more effective cancer treatment.
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Affiliation(s)
- Jie Yuan
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Li Yang
- Department of Clinical Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Hua Zhang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Narasimha M Beeraka
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow 119991, Russia; Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Chiyyedu, Anantapuramu, Andhra Pradesh 515721, India; Department of Studies in Molecular Biology, Faculty of Science and Technology, University of Mysore, Mysore, Karnataka, 570006, India.
| | - Danfeng Zhang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Qun Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Minghua Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Hemanth Vikram Pr
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Geng Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
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Panda SK, Robinson N, Desiderio V. Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance. Biochim Biophys Acta Rev Cancer 2024; 1879:189205. [PMID: 39481663 DOI: 10.1016/j.bbcan.2024.189205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024]
Abstract
Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance. However, even with the third-generation inhibitors available, we are still far from effectively inhibiting the efflux transporters. Additionally, Cancer stem cells (CSCs) pose another significant challenge, contributing to cancer recurrence even after successful treatment. The ability of CSCs to enter dormancy and evade detection makes them almost invulnerable to chemotherapeutic drug treatment. In this review, we discuss how Mesenchymal stem cells (MSCs), one of the key components of the Tumor Microenvironment (TME), regulate both the CSCs and efflux transporters. We propose a new approach focusing on MSCs, which can be crucial to successfully address CSCs and efflux transporters.
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Affiliation(s)
- Sameer Kumar Panda
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy; Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Nirmal Robinson
- Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
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Dolatshahi M, Bahrami AR, Sheikh QI, Ghanbari M, Matin MM. Gastric cancer and mesenchymal stem cell-derived exosomes: from pro-tumorigenic effects to anti-cancer vehicles. Arch Pharm Res 2024; 47:1-19. [PMID: 38151649 DOI: 10.1007/s12272-023-01477-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 12/15/2023] [Indexed: 12/29/2023]
Abstract
Gastric cancer (GC) is one of the most prevalent malignancies in the world, with a high mortality rate in both women and men. Conventional treatments, like chemotherapy, radiotherapy and surgery, are facing some drawbacks like acquired drug resistance and various side effects, leading to cancer recurrence and increased morbidity; thus, development of novel approaches in targeted therapy would be very beneficial. Exosomes, extracellular vesicles with a size distribution of sub-150 nm, interplay in physiological and pathophysiological cell-cell communications and can pave the way for targeted cancer therapy. Accumulating pieces of evidence have indicated that exosomes derived from mesenchymal stem cells (MSC-EXs) can act as a double-edged sword in some cancers. The purpose of this review is to assess the differences between stem cell therapy and exosome therapy. Moreover, our aim is to demonstrate how naïve MSCs transform into GC-MSCs in the tumor microenvironment. Additionally, the tumorigenic and anti-proliferation effects of MSC-EXs derived from different origins were investigated. Finally, we suggest potential modifications and combination options that involve utilizing MSC-EXs from the foreskin and umbilical cord as promising sources to enhance the efficacy of gastric cancer treatment. This approach is presented in contrast to bone marrow cells, which are more heterogeneous, age-related, and are also easily affected by the patient's circulation system.
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Affiliation(s)
- Maryam Dolatshahi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
- Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Qaiser Iftikhar Sheikh
- School of Biosciences, Western Bank, Firth Court, University of Sheffield, Sheffield, S10 2TN, England, UK
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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Banerjee A, Deka D, Muralikumar M, Sun-Zhang A, Bisgin A, Christopher C, Zhang H, Sun XF, Pathak S. A concise review on miRNAs as regulators of colon cancer stem cells and associated signalling pathways. Clin Transl Oncol 2023; 25:3345-3356. [PMID: 37086351 DOI: 10.1007/s12094-023-03200-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/11/2023] [Indexed: 04/23/2023]
Abstract
Despite recent therapy advances and a better understanding of colon cancer biology, it remains one of the major causes of death. The cancer stem cells, associated with the progression, metastasis, and recurrence of colon cancer, play a major role in promoting the development of tumour and are found to be chemo resistant. The stroma of the tumour, which makes up the bulk of the tumour mass, is composed of the tumour microenvironment. With the advent of theranostic and the development of personalised medicine, miRNAs are becoming increasingly important in the context of colon malignancies. A holistic understanding of the regulatory roles of miRNAs in cancer cells and cancer stem cells will allow us to design effective strategies to regulate miRNAs, which could lead to improved clinical translation and creating a potent colon cancer treatment strategy. In this review paper, we briefly discuss the history of miRNA as well as the mechanisms of miRNA and cancer stem cells that contribute to the tumour growth, apoptosis, and advancement of colon cancer. The usefulness of miRNA in colorectal cancer theranostic is further concisely reviewed. We conclude by holding a stance in addressing the prospects and possibilities for miRNA by the disclosure of recent theranostic approaches aimed at eradicating cancer stem cells and enhancing overall cancer treatment outcomes.
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Affiliation(s)
- Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), 603103, Kelambakkam, Chennai, India.
| | - Dikshita Deka
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), 603103, Kelambakkam, Chennai, India
| | - Makalakshmi Muralikumar
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), 603103, Kelambakkam, Chennai, India
| | - Alexander Sun-Zhang
- Department of Oncology-Pathology, Karolinska Institute, 171 77, Solna, Sweden
| | - Atil Bisgin
- InfoGenom R&D Laboratories, Cukurova Technopolis, Adana, Turkey
- Medical Genetics Department of Medical Faculty, Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center), Cukurova University, Adana, Turkey
| | - Cynthia Christopher
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), 603103, Kelambakkam, Chennai, India
| | - Hong Zhang
- Department of Medical Sciences, School of Medicine, Orebro University, 701 82, Orebro, Sweden
| | - Xiao-Feng Sun
- Division of Oncology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83, Linköping, Sweden.
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), 603103, Kelambakkam, Chennai, India
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Pu Q, Gao H. The Role of the Tumor Microenvironment in Triple-Positive Breast Cancer Progression and Therapeutic Resistance. Cancers (Basel) 2023; 15:5493. [PMID: 38001753 PMCID: PMC10670777 DOI: 10.3390/cancers15225493] [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: 09/15/2023] [Revised: 10/26/2023] [Accepted: 11/18/2023] [Indexed: 11/26/2023] Open
Abstract
Breast cancer (BRCA) is a highly heterogeneous systemic disease. It is ranked first globally in the incidence of new cancer cases and has emerged as the primary cause of cancer-related death among females. Among the distinct subtypes of BRCA, triple-positive breast cancer (TPBC) has been associated with increased metastasis and invasiveness, exhibiting greater resistance to endocrine therapy involving trastuzumab. It is now understood that invasion, metastasis, and treatment resistance associated with BRCA progression are not exclusively due to breast tumor cells but are from the intricate interplay between BRCA and its tumor microenvironment (TME). Accordingly, understanding the pathogenesis and evolution of the TPBC microenvironment demands a comprehensive approach. Moreover, addressing BRCA treatment necessitates a holistic consideration of the TME, bearing significant implications for identifying novel targets for anticancer interventions. This review expounds on the relationship between critical cellular components and factors in the TPBC microenvironment and the inception, advancement, and therapeutic resistance of breast cancer to provide perspectives on the latest research on TPBC.
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Affiliation(s)
- Qian Pu
- Department of Breast Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China;
- Oncology Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China
| | - Haidong Gao
- Department of Breast Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China;
- Oncology Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China
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Hazrati A, Malekpour K, Mirsanei Z, Khosrojerdi A, Rahmani-Kukia N, Heidari N, Abbasi A, Soudi S. Cancer-associated mesenchymal stem/stromal cells: role in progression and potential targets for therapeutic approaches. Front Immunol 2023; 14:1280601. [PMID: 38022534 PMCID: PMC10655012 DOI: 10.3389/fimmu.2023.1280601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Nasim Rahmani-Kukia
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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7
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Yuan J, Yang L, Li Z, Zhang H, Wang Q, Huang J, Wang B, Mohan CD, Sethi G, Wang G. The role of the tumor microenvironment in endocrine therapy resistance in hormone receptor-positive breast cancer. Front Endocrinol (Lausanne) 2023; 14:1261283. [PMID: 37900137 PMCID: PMC10611521 DOI: 10.3389/fendo.2023.1261283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 09/29/2023] [Indexed: 10/31/2023] Open
Abstract
Endocrine therapy is the prominent strategy for the treatment of hormone-positive breast cancers. The emergence of resistance to endocrine therapy is a major health concern among hormone-positive breast cancer patients. Resistance to endocrine therapy demands the design of newer therapeutic strategies. The understanding of underlying molecular mechanisms of endocrine resistance, components of the tumor microenvironment (TME), and interaction of resistant breast cancer cells with the cellular/acellular components of the intratumoral environment are essential to formulate new therapeutic strategies for the treatment of endocrine therapy-resistant breast cancers. In the first half of the article, we have discussed the general mechanisms (including mutations in estrogen receptor gene, reregulated activation of signaling pathways, epigenetic changes, and cell cycle alteration) responsible for endocrine therapy resistance in hormone-positive breast cancers. In the latter half, we have emphasized the precise role of cellular (cancer-associated fibroblasts, immune cells, and cancer stem cells) and acellular components (collagen, fibronectin, and laminin) of TME in the development of endocrine resistance in hormone-positive breast cancers. In sum, the article provides an overview of the relationship between endocrine resistance and TME in hormone-positive breast cancers.
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Affiliation(s)
- Jie Yuan
- Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Li Yang
- Department of Clinical Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Zhi Li
- Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Hua Zhang
- Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Qun Wang
- Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Jun Huang
- Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Bei Wang
- Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Chakrabhavi Dhananjaya Mohan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore Karnataka, India
- FEST Division, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Geng Wang
- Department of Endocrine and Vascular Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China
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Gordon JAR, Evans MF, Ghule PN, Lee K, Vacek P, Sprague BL, Weaver DL, Stein GS, Stein JL. Identification of molecularly unique tumor-associated mesenchymal stromal cells in breast cancer patients. PLoS One 2023; 18:e0282473. [PMID: 36940196 PMCID: PMC10027225 DOI: 10.1371/journal.pone.0282473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/16/2023] [Indexed: 03/21/2023] Open
Abstract
The tumor microenvironment is a complex mixture of cell types that bi-directionally interact and influence tumor initiation, progression, recurrence, and patient survival. Mesenchymal stromal cells (MSCs) of the tumor microenvironment engage in crosstalk with cancer cells to mediate epigenetic control of gene expression. We identified CD90+ MSCs residing in the tumor microenvironment of patients with invasive breast cancer that exhibit a unique gene expression signature. Single-cell transcriptional analysis of these MSCs in tumor-associated stroma identified a distinct subpopulation characterized by increased expression of genes functionally related to extracellular matrix signaling. Blocking the TGFβ pathway reveals that these cells directly contribute to cancer cell proliferation. Our findings provide novel insight into communication between breast cancer cells and MSCs that are consistent with an epithelial to mesenchymal transition and acquisition of competency for compromised control of proliferation, mobility, motility, and phenotype.
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Affiliation(s)
- Jonathan A. R. Gordon
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Mark F. Evans
- Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Prachi N. Ghule
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Kyra Lee
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Pamela Vacek
- Department of Surgery, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Brian L. Sprague
- Department of Surgery, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Donald L. Weaver
- Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Gary S. Stein
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Janet L. Stein
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
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An J, Hu X, Liu F. Current understanding of cancer stem cells: Immune evasion and targeted immunotherapy in gastrointestinal malignancies. Front Oncol 2023; 13:1114621. [PMID: 36910604 PMCID: PMC9996315 DOI: 10.3389/fonc.2023.1114621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
As a relatively rare population of cancer cells existing in the tumor microenvironment, cancer stem cells (CSCs) possess properties of immune privilege to evade the attack of immune system, regulated by the microenvironment of CSCs, the so-called CSCs niche. The bidirectional interaction of CSCs with tumor microenvironment (TME) components favors an immunosuppressive shelter for CSCs' survival and maintenance. Gastrointestinal cancer stem cells (GCSCs) are broadly regarded to be intimately involved in tumor initiation, progression, metastasis and recurrence, with elevated tumor resistance to conventional therapies, which pose a major hindrance to the clinical efficacy for treated patients with gastrointestinal malignancies. Thus, a multitude of efforts have been made to combat and eradicate GCSCs within the tumor mass. Among diverse methods of targeting CSCs in gastrointestinal malignancies, immunotherapy represents a promising strategy. And the better understanding of GCSCs immunomodulation and immunoresistance mechanisms is beneficial to guide and design novel GCSCs-specific immunotherapies with enhanced immune response and clinical efficacy. In this review, we have gathered available and updated information to present an overview of the immunoevasion features harbored by cancer stem cells, and we focus on the description of immune escape strategies utilized by CSCs and microenvironmental regulations underlying CSCs immuno-suppression in the context of gastrointestinal malignancies. Importantly, this review offers deep insights into recent advances of CSC-targeting immunotherapeutic approaches in gastrointestinal cancers.
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Affiliation(s)
- Junyi An
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohua Hu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Zheng Z, Li P, Shen F, Shi Y, Shao C. Mesenchymal Stem/Stromal Cells in Cancer: from Initiation to Metastasis. Arch Med Res 2022; 53:785-793. [PMID: 36462949 DOI: 10.1016/j.arcmed.2022.11.001] [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: 10/06/2022] [Accepted: 11/02/2022] [Indexed: 12/05/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) exist in many tissues and have pleiotropic potential to self-renew and differentiate into multiple cell types. Recent research in tumor biology has focused on their low immunogenicity and tumorhoming properties. MSCs promote cancer initiation, progression, and metastasis through several different mechanisms, including epithelial-mesenchymal transition (EMT), angiogenesis, and through their interaction with immune cells. In this review, we discuss the recent advances in our understanding of the pathogenic role of MSCs in regulating tumor initiation, progression, and metastasis, thus providing a strong rationale for targeting MSCs in cancer therapy.
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Affiliation(s)
- Zhiyuan Zheng
- The Third Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine of Soochow University, Suzhou, Jiangsu, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Center, Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Peng Li
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Center, Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fangrong Shen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine of Soochow University, Suzhou, Jiangsu, China.
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine of Soochow University, Suzhou, Jiangsu, China.
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11
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Frisbie L, Buckanovich RJ, Coffman L. Carcinoma Associated Mesenchymal Stem/Stromal Cells - Architects of the Pro-tumorigenic tumor microenvironment. Stem Cells 2022; 40:705-715. [PMID: 35583414 PMCID: PMC9406606 DOI: 10.1093/stmcls/sxac036] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/12/2022] [Indexed: 11/13/2022]
Abstract
The interaction between tumor cells and non-malignant hosts cells within the tumor microenvironment (TME) is critical to the pathophysiology of cancer. These non-malignant host cells, consisting of a variety of stromal, immune and endothelial cells, engage in a complex bidirectional crosstalk with the malignant tumor cells. Mesenchymal stem/stromal cells (MSCs) are one of these host cells, and they play a critical role in directing the formation and function of the entire TME. These MSCs are epigenetically reprogrammed by cancer cells to assume a strongly pro-tumorigenic phenotype and are referred to as carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs). Studies over the last decade demonstrate that CA-MSCs not only directly interact with cancer cells to promote tumor growth and metastasis, but also orchestrate the formation of the TME. CA-MSCs can differentiate into virtually all stromal sub-lineages present in the TME, including pro-tumorigenic cancer associated fibroblasts (CAF), myofibroblasts, and adipocytes. CA-MSCs and the CAFs they produce, secrete much of the extracellular matrix in the TME. Furthermore, CA-MSC secreted factors promote angiogenesis, and recruit immunosuppressive myeloid cells effectively driving tumor immune exclusion. Thus CA-MSCs impact nearly every aspect of the TME. Despite their influence on cancer biology, as CA-MSCs represent a heterogenous population without a single definitive marker, significant confusion remains regarding the origin and proper identification CA-MSCs. This review will focus on the impact of CA-MSCs on cancer progression and metastasis and the ongoing work on CA-MSC identification, nomenclature and mechanism of action.
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Affiliation(s)
- Len Frisbie
- Department of Integrative Systems Biology, University of Pittsburgh, Pittsburgh, PA
| | - Ronald J Buckanovich
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
| | - Lan Coffman
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
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12
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Jing Y, Liang W, Zhang L, Tang J, Huang Z. The Role of Mesenchymal Stem Cells in the Induction of Cancer-Stem Cell Phenotype. Front Oncol 2022; 12:817971. [PMID: 35251985 PMCID: PMC8891610 DOI: 10.3389/fonc.2022.817971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) modify and form their microenvironment by recruiting and activating specific cell types such as mesenchymal stem cells (MSCs). Tumor-infiltrating MSCs help to establish a suitable tumor microenvironment for the restoration of CSCs and tumor progression. In addition, crosstalk between cancer cells and MSCs in the microenvironment induces a CSC phenotype in cancer cells. Many mechanisms are involved in crosstalk between CSCs/cancer cells and MSCs including cell-cell interaction, secretion of exosomes, and paracrine secretion of several molecules including inflammatory mediators, cytokines, and growth factors. Since this crosstalk may contribute to drug resistance, metastasis, and tumor growth, it is suggested that blockade of the crosstalk between MSCs and CSCs/cancer cells can provide a new avenue to improving the cancer therapeutic tools. In this review, we will discuss the role of MSCs in the induction of cancer stem cell phenotype and the restoration of CSCs. We also discuss targeting the crosstalk between MSCs and CSCs/cancer cells as a therapeutic strategy.
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Affiliation(s)
- Yuanming Jing
- Department of Gastrointestinal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Junjun Tang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
| | - Zongliang Huang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
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13
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Ghollasi M, Ghasembaglou S, Rahban D, Korani M, Motallebnezhad M, Asadi M, Zarredar H, Salimi A. Prospects for Manipulation of Mesenchymal Stem Cells in Tumor Therapy: Anti-Angiogenesis Property on the Spotlight. Int J Stem Cells 2021; 14:351-365. [PMID: 34456189 PMCID: PMC8611310 DOI: 10.15283/ijsc20146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 06/01/2021] [Accepted: 06/16/2021] [Indexed: 11/10/2022] Open
Abstract
The interactions between the tumor microenvironment and the tumor cells confers a condition that accelerate or decelerate the development of tumor. Of these cells, mesenchymal stem cells (MSCs) have the potential to modulate the tumor cells. MSCs have been established with double functions, whereby contribute to a tumorigenic or anti-tumor setting. Clinical studies have indicated the potential of MSCs to be used as tool in treating the human cancer cells. One of the advantageous features of MSCs that make them as a well-suited tool for cancer therapy is the natural tumor-trophic migration potential. A key specification of the tumor development has been stablished to be angiogenesis. As a result, manipulation of angiogenesis has become an attractive approach for cancer therapy. This review article will seek to clarify the anti-angiogenesis strategy in modulating the MSCs to treat the tumor cells.
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Affiliation(s)
- Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Shahram Ghasembaglou
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Dariush Rahban
- Department of Nanomedicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Korani
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Morteza Motallebnezhad
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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14
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Zhang W, Torres-Rojas C, Yue J, Zhu BM. Adipose-derived stem cells in ovarian cancer progression, metastasis, and chemoresistance. Exp Biol Med (Maywood) 2021; 246:1810-1815. [PMID: 34229470 DOI: 10.1177/15353702211023846] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Ovarian cancer is the deadliest gynecological malignancy due to its symptomless early stage, metastasis, and high recurrence rate. The tumor microenvironment contributes to the ovarian cancer progression, metastasis, and chemoresistance. Adipose-derived stem cell in the tumor microenvironment of ovarian cancer, as a key player, interacts with ovarian cancer cells to form the cancer-associated fibroblasts and cancer-associated adipocytes, and secretes soluble factors to activate tumor cell signaling, which can promote ovarian cancer metastasis and chemoresistance. We summarize in this review the recent progress in the studies of interactions between adipose-derived stem cell and ovarian cancer, thus, to provide some insight for ovarian cancer therapy through targeting adipose-derived stem cell.
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Affiliation(s)
- Wenjing Zhang
- Department of Genetics, Genomics & Informatics, College of Medicine, the University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Carolina Torres-Rojas
- Department of Genetics, Genomics & Informatics, College of Medicine, the University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, College of Medicine, the University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Bing-Mei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
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15
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Eiro N, Fraile M, Fernández-Francos S, Sánchez R, Costa LA, Vizoso FJ. Importance of the origin of mesenchymal (stem) stromal cells in cancer biology: "alliance" or "war" in intercellular signals. Cell Biosci 2021; 11:109. [PMID: 34112253 PMCID: PMC8194017 DOI: 10.1186/s13578-021-00620-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/31/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play a central role in the intercellular signaling within the tumor microenvironment (TME), exchanging signals with cancer cells and tumor stromal cells, such as cancer-associated fibroblasts and inflammatory mononuclear cells. Research attributes both pro-tumor and anti-tumor actions to MSCs; however, evidence indicates that MSCs specific effect on the tumor depends on the source of the MSCs and the type of tumor. There are consistent data proving that MSCs from reproductive tissues, such as the uterus, umbilical cord or placenta, have potent anti-tumor effects and tropism towards tumor tissues. More interestingly, products derived from MSCs, such as secretome or extracellular vesicles, seem to reproduce the effects of their parental cells, showing a potential advantage for clinical treatments by avoiding the drawbacks associated with cell therapy. Given these perspectives, it appears necessary new research to optimize the production, safety and antitumor potency of the products derived from the MSCs suitable for oncological therapies.
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Affiliation(s)
- Noemi Eiro
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain.
| | - Maria Fraile
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Silvia Fernández-Francos
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Rosario Sánchez
- Department of Surgery, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain
| | - Luis A Costa
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Francisco J Vizoso
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain. .,Department of Surgery, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain.
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16
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Li Y, Zhong X, Zhang Y, Lu X. Mesenchymal Stem Cells in Gastric Cancer: Vicious but Hopeful. Front Oncol 2021; 11:617677. [PMID: 34046337 PMCID: PMC8144497 DOI: 10.3389/fonc.2021.617677] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 04/22/2021] [Indexed: 12/24/2022] Open
Abstract
Tumor progression depends on the collaborative interactions between tumor cells and the surrounding stroma. First-line therapies direct against cancer cells may not reach a satisfactory outcome, such as gastric cancer (GC), with high risk of recurrence and metastasis. Therefore, novel treatments and drugs target the effects of stroma components are to be promising alternatives. Mesenchymal stem cells (MSC) represent the decisive components of tumor stroma that are found to strongly affect GC development and progression. MSC from bone marrow or adjacent normal tissues express homing profiles in timely response to GC-related inflammation signals and anchor into tumor bulks. Then the newly recruited “naïve” MSC would achieve phenotype and functional alternations and adopt the greater tumor-supporting potential under the reprogramming of GC cells. Conversely, both new-comers and tumor-resident MSC are able to modulate the tumor biology via aberrant activation of oncogenic signals, metabolic reprogramming and epithelial-to-mesenchymal transition. And they also engage in remodeling the stroma better suited for tumor progression through immunosuppression, pro-angiogenesis, as well as extracellular matrix reshaping. On the account of tumor tropism, MSC could be engineered to assist earlier diagnosis of GC and deliver tumor-killing agents precisely to the tumor microenvironment. Meanwhile, intercepting and abrogating vicious signals derived from MSC are of certain significance for the combat of GC. In this review, we mainly summarize current advances concerning the reciprocal metabolic interactions between MSC and GC and their underlying therapeutic implications in the future.
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Affiliation(s)
- Yuyi Li
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xingwei Zhong
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yunzhu Zhang
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinliang Lu
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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17
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Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int 2021; 21:158. [PMID: 33685452 PMCID: PMC7938588 DOI: 10.1186/s12935-021-01836-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/15/2021] [Indexed: 12/27/2022] Open
Abstract
A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.
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18
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Lee HY, Hong IS. Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer. Cancers (Basel) 2020; 12:cancers12102746. [PMID: 32987767 PMCID: PMC7598600 DOI: 10.3390/cancers12102746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
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Affiliation(s)
- Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, 85 Goesan-eup, Munmu-ro, Goesan-gun, Chungcheongbuk-do 367700, Korea;
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406840, Korea
- Correspondence: ; Tel.: +82-32-899-6315; Fax: +82-32-899-6350
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19
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Li JN, Li W, Cao LQ, Liu N, Zhang K. Efficacy of mesenchymal stem cells in the treatment of gastrointestinal malignancies. World J Gastrointest Oncol 2020; 12:365-382. [PMID: 32368316 PMCID: PMC7191336 DOI: 10.4251/wjgo.v12.i4.365] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/03/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs), which are a kind of stem cell, possess an immune privileged nature, tumour homing features, and multi-lineage differentiation ability. MSCs have been studied in many fields, such as tissue engineering, nervous system diseases, and cancer treatment. In recent years, an increasing number of researchers have focused on the effects of MSCs on various kinds of tumours. However, the concrete anticancer efficacy of MSCs is still controversial. Gastrointestinal (GI) malignancies are the major causes of cancer-related death worldwide. The interactions of MSCs and GI cancer cells in specific conditions have attracted increasing attention. In this review, we introduce the characteristics of MSCs and analyse the effects of MSCs on GI malignancies, including gastric cancer, hepatoma, pancreatic cancer, and colorectal cancer. In addition, we also provide our perspectives on why MSCs may play different roles in GI malignancies and further research directions to increase the treatment efficacy of MSCs on GI malignancies.
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Affiliation(s)
- Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Wei Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Lan-Qing Cao
- Department of Pathology, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Ning Liu
- Department of Central Laboratory, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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20
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Astudillo P. Wnt5a Signaling in Gastric Cancer. Front Cell Dev Biol 2020; 8:110. [PMID: 32195251 PMCID: PMC7064718 DOI: 10.3389/fcell.2020.00110] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/10/2020] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer remains an important health challenge, accounting for a significant number of cancer-related deaths worldwide. Therefore, a deeper understanding of the molecular mechanisms involved in gastric cancer establishment and progression is highly desirable. The Wnt pathway plays a fundamental role in development, homeostasis, and disease, and abnormal Wnt signaling is commonly observed in several cancer types. Wnt5a, a ligand that activates the non-canonical branch of the Wnt pathway, can play a role as a tumor suppressor or by promoting cancer cell invasion and migration, although the molecular mechanisms explaining these roles have not been fully elucidated. Wnt5a is increased in gastric cancer samples; however, most gastric cancer cell lines seem to exhibit little expression of this ligand, thus raising the question about the source of this ligand in vivo. This review summarizes available research about Wnt5a expression and signaling in gastric cancer. In gastric cancer, Wnt5a promotes invasion and migration by modulating integrin adhesion turnover. Disheveled, a scaffolding protein with crucial roles in Wnt signaling, mediates the adhesion-related effects of Wnt5a in gastric cancer cells, and several studies provide growing support for a model whereby Disheveled-interacting proteins mediates Wnt5a signaling to modulate cytoskeleton dynamics. However, Wnt5a might induce other effects in gastric cancer cells, such as cell survival and induction of gene expression. On the other hand, the available evidence suggests that Wnt5a might be expressed by cells residing in the tumor microenvironment, where feedback mechanisms sustaining Wnt5a secretion and signaling might be established. This review analyzes the possible functions of Wnt5a in this pathological context and discusses potential links to mechanosensing and YAP/TAZ signaling.
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Affiliation(s)
- Pablo Astudillo
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
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21
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Ikeda T, Nishita M, Hoshi K, Honda T, Kakeji Y, Minami Y. Mesenchymal stem cell-derived CXCL16 promotes progression of gastric cancer cells by STAT3-mediated expression of Ror1. Cancer Sci 2020; 111:1254-1265. [PMID: 32012403 PMCID: PMC7156785 DOI: 10.1111/cas.14339] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/28/2020] [Accepted: 01/28/2020] [Indexed: 12/13/2022] Open
Abstract
Bone marrow‐derived mesenchymal stem or stromal cells (MSC) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSC, and Wnt5a‐Ror2 signaling in MSC induces expression of CXCL16, which, in turn, promotes proliferation of co–cultured MKN45 gastric cancer cells via the CXCL16‐CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells. Here, we show that knockdown of CXCL16 in MSC by siRNA suppresses not only proliferation but also migration of co–cultured MKN45 cells. We also show that MSC‐derived CXCL16 or recombinant CXCL16 upregulates expression of Ror1 through activation of STAT3 in MKN45 cells, leading to promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, co–injection of MSC with MKN45 cells in nude mice promoted tumor formation in a manner dependent on expression of Ror1 in MKN45 cells, and anti–CXCL16 neutralizing antibody suppressed tumor formation of MKN45 cells co–injected with MSC. These results suggest that CXCL16 produced through Ror2‐mediated signaling in MSC within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate the CXCR6‐STAT3 pathway, which, in turn, induces expression of Ror1 in MKN45 cells, thereby promoting tumor progression.
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Affiliation(s)
- Taro Ikeda
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.,Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Michiru Nishita
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.,Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kyoka Hoshi
- Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Takashi Honda
- Department of Human Life Science, Fukushima Medical University School of Nursing, Fukushima, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Yasuhiro Minami
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
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22
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Atiya H, Frisbie L, Pressimone C, Coffman L. Mesenchymal Stem Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1234:31-42. [PMID: 32040853 DOI: 10.1007/978-3-030-37184-5_3] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The interactions between tumor cells and the non-malignant stromal and immune cells that make up the tumor microenvironment (TME) are critical to the pathophysiology of cancer. Mesenchymal stem cells (MSCs) are multipotent stromal stem cells found within most cancers and play a critical role influencing the formation and function of the TME. MSCs have been reported to support tumor growth through a variety of mechanisms including (i) differentiation into other pro-tumorigenic stromal components, (ii) suppression of the immune response, (iii) promotion of angiogenesis, (iv) enhancement of an epithelial-mesenchymal transition (EMT), (v) enrichment of cancer stem-like cells (CSC), (vi) increase in tumor cell survival, and (vii) promotion of tumor metastasis. In contrast, MSCs have also been reported to have antitumorigenic functions including (i) enhancement of the immune response, (ii) inhibition of angiogenesis, (iii) regulation of cellular signaling, and (iv) induction of tumor cell apoptosis. Although literature supporting both arguments exists, most studies point to MSCs acting in a cancer supporting role within the confines of the TME. Tumor-suppressive effects are observed when MSCs are used in higher ratios to tumor cells. Additionally, MSC function appears to be tissue type dependent and may rely on cancer education to reprogram a naïve MSC with antitumor effects into a cancer-educated or cancer-associated MSC (CA-MSC) which develops pro-tumorigenic function. Further work is required to delineate the complex crosstalk between MSCs and other components of the TME to accurately assess the impact of MSCs on cancer initiation, growth, and spread.
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Affiliation(s)
- Huda Atiya
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Leonard Frisbie
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Lan Coffman
- Division of Hematology/Oncology, Division of Gynecologic Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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23
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Rahmatizadeh F, Gholizadeh-Ghaleh Aziz S, Khodadadi K, Lale Ataei M, Ebrahimie E, Soleimani Rad J, Pashaiasl M. Bidirectional and Opposite Effects of Naïve Mesenchymal Stem Cells on Tumor Growth and Progression. Adv Pharm Bull 2019; 9:539-558. [PMID: 31857958 PMCID: PMC6912184 DOI: 10.15171/apb.2019.063] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/31/2019] [Accepted: 08/13/2019] [Indexed: 12/16/2022] Open
Abstract
Cancer has long been considered as a heterogeneous population of uncontrolled proliferation of
different transformed cell types. The recent findings concerning tumorigeneses have highlighted
the fact that tumors can progress through tight relationships among tumor cells, cellular, and
non-cellular components which are present within tumor tissues. In recent years, studies have
shown that mesenchymal stem cells (MSCs) are essential components of non-tumor cells within
the tumor tissues that can strongly affect tumor development. Several forms of MSCs have been
identified within tumor stroma. Naïve (innate) mesenchymal stem cells (N-MSCs) derived from
different sources are mostly recruited into the tumor stroma. N-MSCs exert dual and divergent
effects on tumor growth through different conditions and factors such as toll-like receptor
priming (TLR-priming), which is the primary underlying causes of opposite effects. Moreover,
MSCs also have the contrary effects by various molecular mechanisms relying on direct cellto-
cell connections and indirect communications through the autocrine, paracrine routes, and
tumor microenvironment (TME).
Overall, cell-based therapies will hold great promise to provide novel anticancer treatments.
However, the application of intact MSCs in cancer treatment can theoretically cause adverse
clinical outcomes. It is essential that to extensively analysis the effective factors and conditions
in which underlying mechanisms are adopted by MSCs when encounter with cancer.
The aim is to review the cellular and molecular mechanisms underlying the dual effects of
MSCs followed by the importance of polarization of MSCs through priming of TLRs.
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Affiliation(s)
- Faramarz Rahmatizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Khodadad Khodadadi
- Murdoch Children's Research Institute, Royal Children's Hospital, The University of Melbourne, Melbourne, Australia
| | - Maryam Lale Ataei
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Esmaeil Ebrahimie
- Adelaide Medical School, University of Adelaide, Adelaide, Australia.,School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, Australia
| | - Jafar Soleimani Rad
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran
| | - Maryam Pashaiasl
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran.,Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Javan MR, Khosrojerdi A, Moazzeni SM. New Insights Into Implementation of Mesenchymal Stem Cells in Cancer Therapy: Prospects for Anti-angiogenesis Treatment. Front Oncol 2019; 9:840. [PMID: 31555593 PMCID: PMC6722482 DOI: 10.3389/fonc.2019.00840] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor microenvironment interacts with tumor cells, establishing an atmosphere to contribute or suppress the tumor development. Among the cells which play a role in the tumor microenvironment, mesenchymal stem cells (MSCs) have been demonstrated to possess the ability to orchestrate the fate of tumor cells, drawing the attention to the field. MSCs have been considered as cells with double-bladed effects, implicating either tumorigenic or anti-tumor activity. On the other side, the promising potential of MSCs in treating human cancer cells has been observed from the clinical studies. Among the beneficial characteristics of MSCs is the natural tumor-trophic migration ability, providing facility for drug delivery and, therefore, targeted treatment to detach tumor and metastatic cells. Moreover, these cells have been the target of engineering approaches, due to their easily implemented traits, in order to obtain the desired expression of anti-angiogenic, anti-proliferative, and pro-apoptotic properties, according to the tumor type. Tumor angiogenesis is the key characteristic of tumor progression and metastasis. Manipulation of angiogenesis has become an attractive approach for cancer therapy since the introduction of the first angiogenesis inhibitor, namely bevacizumab, for metastatic colorectal cancer therapy. This review tries to conclude the approaches, with focus on anti-angiogenesis approach, in implementing the MSCs to combat against tumor cell progression.
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Affiliation(s)
- Mohammad Reza Javan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mohammad Moazzeni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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25
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Kaibuchi N, Iwata T, Onizuka S, Yano K, Tsumanuma Y, Yamato M, Okano T, Ando T. Allogeneic multipotent mesenchymal stromal cell sheet transplantation promotes healthy healing of wounds caused by zoledronate and dexamethasone in canine mandibular bones. Regen Ther 2019; 10:77-83. [PMID: 30671501 PMCID: PMC6330512 DOI: 10.1016/j.reth.2018.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/29/2018] [Accepted: 10/30/2018] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Many cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is an intractable disease, have been reported. Although a general intravenous injection of multipotent mesenchymal stromal cells (MSCs) may be effective for treating BRONJ, it has some severe problems. Therefore, our aim was to develop a treatment of locally administered MSCs. In this study, we investigated the effect of MSC sheet transplantation in the mandibular bone healing in beagle dogs, which were administered zoledronate and dexamethasone. METHODS MSCs isolated from subcutaneous fat were seeded onto temperature-responsive culture dishes to produce MSC sheets. Zoledronate and dexamethasone were administered to beagle dogs. Then, the parts of mandibular cortical bones were removed, and MSC sheets were transplanted to cover those bone defects (MSC sheet transplant side) or not (Control side). The specimens were evaluated in micro CT, histology, and immunohistochemistry. RESULTS Four weeks after surgery, redness and swellings were observed in the mucosal wounds of the control sides of 2 of 3 dogs. In contrast, the mucosal wounds of the MSC sheet transplant sides of all dogs completely healed. Histological images showed some free sequestrums and many bacterial colonies, and Immunohistological analysis showed some cathepsin K-positive multinuclear cells detached from jaw bone surfaces in the control sides. CONCLUSIONS MSC sheet transplantation promotes healthy healing of wounds caused by zoledronate and dexamethasone in canine mandibular bones. And the injured canine mandibular bones administered zoledronate and dexamethasone showed BRONJ-like findings.
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Affiliation(s)
- Nobuyuki Kaibuchi
- Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Takanori Iwata
- Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Satoru Onizuka
- Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Kosei Yano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuka Tsumanuma
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Tomohiro Ando
- Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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26
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The Role of MicroRNAs in the Regulation of Gastric Cancer Stem Cells: A Meta-Analysis of the Current Status. J Clin Med 2019; 8:jcm8050639. [PMID: 31075910 PMCID: PMC6572052 DOI: 10.3390/jcm8050639] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/04/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains one of the major causes of cancer-related mortality worldwide. As for other types of cancers, several limitations to the success of current therapeutic GC treatments may be due to cancer drug resistance that leads to tumor recurrence and metastasis. Increasing evidence suggests that cancer stem cells (CSCs) are among the major causative factors of cancer treatment failure. The research of molecular CSC mechanisms and the regulation of their properties have been intensively studied. To date, molecular gastric cancer stem cell (GCSC) characterization remains largely incomplete. Among the GCSC-targeting approaches to overcome tumor progression, recent studies have focused their attention on microRNA (miRNA). The miRNAs are short non-coding RNAs which play an important role in the regulation of numerous cellular processes through the modulation of their target gene expression. In this review, we summarize and discuss recent findings on the role of miRNAs in GCSC regulation. In addition, we perform a meta-analysis aimed to identify novel miRNAs involved in GCSC homeostasis.
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Matsuura K, Takami T, Maeda M, Hisanaga T, Fujisawa K, Saeki I, Matsumoto T, Hidaka I, Yamamoto N, Sakaida I. Evaluation of the Effects of Cultured Bone Marrow Mesenchymal Stem Cell Infusion on Hepatocarcinogenesis in Hepatocarcinogenic Mice With Liver Cirrhosis. Transplant Proc 2019; 51:925-935. [PMID: 30979485 DOI: 10.1016/j.transproceed.2019.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVES Liver transplantation remains the only curative therapy for decompensated liver cirrhosis. However, it has several limitations, and not all patients can receive liver transplants. Therefore, liver regenerative therapy without liver transplantation is considered necessary. In this study, we attempted minimally invasive liver regenerative therapy by peripheral vein infusion of bone marrow-derived mesenchymal stem cells (BMSCs) cultured from a small amount of autologous bone marrow fluid and evaluated the effects of BMSCs on hepatocarcinogenesis in a mouse model. METHODS C57BL/6 male mice were injected intraperitoneally with N-nitrosodiethylamine once at 2 weeks of age, followed by carbon tetrachloride twice a week from 6 weeks of age onwards, to create a mouse model of highly oncogenic liver cirrhosis. From 10 weeks of age, mouse isogenic green fluorescent protein-positive BMSCs (1.0 × 106/body weight) were infused once every 2 weeks, for a total of 5 times, and the effects of frequent BMSC infusion on hepatocarcinogenesis were evaluated. RESULTS In the histologic evaluation, no significant differences were observed between the controls and BMSC-administered mice in terms of incidence rate, number, or average size of foci and tumors. However, significant suppression of fibrosis and liver injury was confirmed in the group that received BMSC infusions. DISCUSSION Considering that BMSC infusion did not promote carcinogenesis, even in the state of highly oncogenic liver cirrhosis, autologous BMSC infusion might be a safe and effective therapy for human decompensated liver cirrhosis.
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Affiliation(s)
- K Matsuura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - T Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan; Center for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
| | - M Maeda
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - T Hisanaga
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan; Department of Medical Education, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - K Fujisawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan; Center for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - I Saeki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - T Matsumoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan; Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - I Hidaka
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan; Center for Liver Disease, Yamaguchi University Hospital, Yamaguchi University School of Medicine, Yamaguchi, Japan
| | - N Yamamoto
- Health Administration Center, Yamaguchi University, Yamaguchi, Japan
| | - I Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan; Center for Liver Disease, Yamaguchi University Hospital, Yamaguchi University School of Medicine, Yamaguchi, Japan
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Manzo G. Similarities Between Embryo Development and Cancer Process Suggest New Strategies for Research and Therapy of Tumors: A New Point of View. Front Cell Dev Biol 2019; 7:20. [PMID: 30899759 PMCID: PMC6416183 DOI: 10.3389/fcell.2019.00020] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 02/05/2019] [Indexed: 12/25/2022] Open
Abstract
Here, I propose that cancer stem cells (CSCs) would be equivalent to para-embryonic stem cells (p-ESCs), derived from adult cells de-re-programmed to a ground state. p-ESCs would differ from ESCs by the absence of genomic homeostasis. A p-ESC would constitute the cancer cell of origin (i-CSC or CSC0), capable of generating an initial tumor, corresponding to a pre-implantation blastocyst. In a niche with proper signals, it would engraft as a primary tumor, corresponding to a post-implantation blastocyst. i-CSC progeny would form primary pluripotent and slow self-renewing CSCs (CSC1s), blocked in an undifferentiated state, corresponding to epiblast cells; CSC1s would be tumor-initiating cells (TICs). CSC1s would generate secondary CSCs (CSC2s), corresponding to hypoblast cells; CSC2s would be tumor growth cells (TGCs). CSC1s/CSC2s would generate tertiary CSCs (CSC3s), with a mesenchymal phenotype; CSC3s would be tumor migrating cells (TMCs), corresponding to mesodermal precursors at primitive streak. CSC3s with more favorable conditions (normoxia), by asymmetrical division, would differentiate into cancer progenitor cells (CPCs), and these into cancer differentiated cells (CDCs), thus generating a defined cell hierarchy and tumor progression, mimicking somito-histo-organogenesis. CSC3s with less favorable conditions (hypoxia) would delaminate and migrate as quiescent circulating micro-metastases, mimicking mesenchymal cells in gastrula morphogenetic movements. In metastatic niches, these CSC3s would install and remain dormant in the presence of epithelial/mesenchymal transition (EMT) signals and hypoxia. But, in the presence of mesenchymal/epithelial transition (MET) signals and normoxia, they would revert to self-renewing CSC1s, reproducing the same cell hierarchy of the primary tumor as macro-metastases. Further similarities between ontogenesis and oncogenesis involving crucial factors, such as ID, HSP70, HLA-G, CD44, LIF, and STAT3, are strongly evident at molecular, physiological and immunological levels. Much experimental data about these factors led to considering the cancer process as ectopic rudimentary ontogenesis, where CSCs have privileged immunological conditions. These would consent to CSC development in an adverse environment, just like an embryo, which is tolerated, accepted and favored by the maternal organism in spite of its paternal semi-allogeneicity. From all these considerations, novel research directions, potential innovative tumor therapy and prophylaxis strategies might, theoretically, result.
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Affiliation(s)
- Giovanni Manzo
- General Pathology, “La Sapienza” University of Rome, Retired, Botrugno, Italy
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Shamai Y, Alperovich DC, Yakhini Z, Skorecki K, Tzukerman M. Reciprocal Reprogramming of Cancer Cells and Associated Mesenchymal Stem Cells in Gastric Cancer. Stem Cells 2019; 37:176-189. [PMID: 30379370 PMCID: PMC7380032 DOI: 10.1002/stem.2942] [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: 04/04/2018] [Revised: 09/25/2018] [Accepted: 10/16/2018] [Indexed: 01/01/2023]
Abstract
The interactions of cancer stem cells (CSCs) within the tumor microenvironment (TME), contribute to the overall phenomenon of intratumoral heterogeneity, which also involve CSC interactions with noncancer stromal cells. Comprehensive understanding of the tumorigenesis process requires elucidating the coordinated gene expression between cancer and tumor stromal cells for each tumor. We show that human gastric cancer cells (GSC1) subvert gene expression and cytokine production by mesenchymal stem cells (GSC-MSC), thus promoting tumor progression. Using mixed composition of human tumor xenografts, organotypic culture, and in vitro assays, we demonstrate GSC1-mediated specific reprogramming of "naïve" MSC into specialized tumor associated MSC equipped with a tumor-promoting phenotype. Although paracrine effect of GSC-MSC or primed-MSC is sufficient to enable 2D growth of GSC1, cell-cell interaction with GSC-MSC is necessary for 3D growth and in vivo tumor formation. At both the transcriptional and at the protein level, RNA-Seq and proteome analyses, respectively, revealed increased R-spondin expression in primed-MSC, and paracrine and juxtacrine mediated elevation of Lgr5 expression in GSC1, suggesting GSC-MSC-mediated support of cancer stemness in GSC1. CSC properties are sustained in vivo through the interplay between GSC1 and GSC-MSC, activating the R-spondin/Lgr5 axis and WNT/β-catenin signaling pathway. β-Catenin+ cell clusters show β-catenin nuclear localization, indicating the activation of the WNT/β-catenin signaling pathway in these cells. The β-catenin+ cluster of cells overlap the Lgr5+ cells, however, not all Lgr5+ cells express β-catenin. A predominant means to sustain the CSC contribution to tumor progression appears to be subversion of MSC in the TME by cancer cells. Stem Cells 2018 Stem Cells 2019;37:176-189.
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Affiliation(s)
| | | | - Zohar Yakhini
- Computer Science DepartmentTechnion‐Israel Institute of TechnologyHaifaIsrael
- Arazi School of Computer ScienceInterdisciplinary CenterHerzliyaIsrael
| | - Karl Skorecki
- Rambam Medical CenterHaifaIsrael
- Rappaport Faculty of Medicine and Research InstituteHaifaIsrael
- Technion‐Israel Institute of TechnologyHaifaIsrael
| | - Maty Tzukerman
- Rambam Medical CenterHaifaIsrael
- Rappaport Faculty of Medicine and Research InstituteHaifaIsrael
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Mesenchymal stem cells in suppression or progression of hematologic malignancy: current status and challenges. Leukemia 2019; 33:597-611. [PMID: 30705410 PMCID: PMC6756083 DOI: 10.1038/s41375-018-0373-9] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 12/17/2018] [Accepted: 12/23/2018] [Indexed: 12/27/2022]
Abstract
Mesenchymal stem cells (MSCs) are known for being multi-potent. However, they also possess anticancer properties, which has prompted efforts to adapt MSCs for anticancer therapies. However, MSCs have also been widely implicated in pathways that contribute to tumor growth. Numerous studies have been conducted to adapt MSCs for further clinical use; however, the results have been inconclusive, possibly due to the heterogeneity of MSC populations. Moreover, the conflicting roles of MSCs in tumor inhibition and tumor growth impede their adaptation for anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in hematologic malignancies are not as well established as they are for solid malignancies, and data comparing them are still limited. Herein the effect of MSCs on hematologic malignancies, such as leukemia and lymphoma, their mechanisms, sources of MSCs, and their effects on different types of cancer, have been discussed. This review describes how MSCs preserve both antitumorigenic and protumorigenic effects, as they tend to not only inhibit tumor growth by suppressing tumor cell proliferation but also promote tumor growth by suppressing tumor cell apoptosis. Thus clinical studies trying to adapt MSCs for anticancer therapies should consider that MSCs could actually promote hematologic cancer progression. It is necessary to take extreme care while developing MSC-based cell therapies in order to boost anticancer properties while eliminating tumor-favoring effects. This review emphasizes that research on the therapeutic applications of MSCs must consider that they exert both antitumorigenic and protumorigenic effects on hematologic malignancies.
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Wang S, Miao Z, Yang Q, Wang Y, Zhang J. The Dynamic Roles of Mesenchymal Stem Cells in Colon Cancer. Can J Gastroenterol Hepatol 2018; 2018:7628763. [PMID: 30533404 PMCID: PMC6247728 DOI: 10.1155/2018/7628763] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/23/2018] [Indexed: 12/13/2022] Open
Abstract
Colon cancer is still one of the most common causes of cancer in human and is characterized by lymphocyte infiltrates and originates from the epithelial cells found in the lining of colon or rectum of the gastrointestinal tract. Mesenchymal stem cells (MSCs) are composed of the multipotent stem cell group of stroma and can be differentiated as various cell lineages, such as fibroblasts, osteoblasts, and adipocytes. MSCs provide mechanical and structural support and have potential functions during tumor growth and metastasis. The efficacy of MSC-based therapies is partly dependent on the migration and homing of MSCs to tumors and metastatic sites. However, their migratory and engraftment potential is poorly understood. In this review, the characteristics and mechanisms of MSC's dynamic interaction with colon cancer were summarized, particularly the potential functions of MSCs on colon cancer, including its role in improving tumor growth and as a potential candidate for tumor therapy. Understanding MSC homing provides new insights into the manipulation of MSC and the improvement of their efficacy for colon cancer therapy.
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Affiliation(s)
- Shan Wang
- College of Animal Science and Veterinary Medicine, Henan institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Zhiguo Miao
- College of Animal Science and Veterinary Medicine, Henan institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Qiyuan Yang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Yimin Wang
- College of Animal Science and Veterinary Medicine, Henan institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Jinzhou Zhang
- College of Animal Science and Veterinary Medicine, Henan institute of Science and Technology, Xinxiang, Henan, 453003, China
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Dynamism, Sensitivity, and Consequences of Mesenchymal and Stem-Like Phenotype of Cancer Cells. Stem Cells Int 2018; 2018:4516454. [PMID: 30405720 PMCID: PMC6199882 DOI: 10.1155/2018/4516454] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 08/17/2018] [Indexed: 12/16/2022] Open
Abstract
There are remarkable similarities in the description of cancer stem cells (CSCs) and cancer cells with mesenchymal phenotype. Both cell types are highly tumorigenic, resistant against common anticancer treatment, and thought to cause metastatic growth. Moreover, cancer cells are able to switch between CSC and non-CSC phenotypes and vice versa, to ensure the necessary balance within the tumor. Likewise, cancer cells can switch between epithelial and mesenchymal phenotypes via well-described transition (EMT/MET) that is thought to be crucial for tumor propagation. In this review, we discuss whether, and to which extend, the CSCs and mesenchymal cancer cells are overlapping phenomena in terms of mechanisms, origin, and implication for cancer treatment. As well, we describe the dynamism of both phenotypes and involvement of the tumor microenvironment in CSC reversion and in EMT.
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Li X, Yang J, Bao M, Zeng K, Fu S, Wang C, Ye L. Wnt signaling in bone metastasis: mechanisms and therapeutic opportunities. Life Sci 2018; 208:33-45. [PMID: 29969609 DOI: 10.1016/j.lfs.2018.06.036] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 06/29/2018] [Accepted: 06/29/2018] [Indexed: 02/05/2023]
Abstract
Bone metastasis frequently occurs in advanced cancer patients, who will develop osteogenic/osteolytic bone lesions in the late stage of the disease. Wnt signaling pathway, which is mainly grouped into the β-catenin dependent pathway and β-catenin independent pathway, is a well-organized cascade that has been reported to play important roles in a variety of physiological and pathological conditions, including bone metastasis. Regulation of Wnt signaling in bone metastasis involves multiple stages, including dissemination of primary tumor cells to bone, dormancy and outgrowth of metastatic tumor cells, and tumor-induced osteogenic and osteolytic bone destruction, suggesting the importance of Wnt signaling in bone metastasis pathology. In this review, we will introduce the involvement of Wnt signaling components in specific bone metastasis stages and summarize the promising Wnt modulators that have shown potential as bone metastasis therapeutics, in the hope to maximize the therapeutic opportunities of Wnt signaling for bone metastasis.
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Affiliation(s)
- Xin Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jing Yang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Minyue Bao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Kan Zeng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shijin Fu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenglin Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Sineh Sepehr K, Razavi A, Saeidi M, Mossahebi-Mohammadi M, Abdollahpour-Alitappeh M, Hashemi SM. Development of a novel explant culture method for the isolation of mesenchymal stem cells from human breast tumor. J Immunoassay Immunochem 2018; 39:207-217. [PMID: 29741994 DOI: 10.1080/15321819.2018.1447487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) were isolated from various sources, including various types of tumors. However choosing an appropriate isolation method is an important step in obtaining cells with optimal quality and yield in companion with economical considerations. The purpose of this study was to isolate more pure MSCs from human breast tumor tissue by a modified explant culture method. METHODS AND MATERIALS The tumor tissues (n = 8) were cut into 1 to 3-mm cube-like pieces (explant). Each explant was placed in a well of 24-well format plates, cultured in Dulbecco's Modified Eagle's medium (DMEM), and maintained at 37°C with 5% humidified incubator. Morphological phenotypes of the cells were surveyed by an inverted microscope and wells with rather homogenous fibroblast-like morphology cell were considered as positive and selected for more expansion and characterization. RESULTS A total of 185 wells, 63.7% of wells were positive that were chosen for expansion. Flowcytometry analysis demonstrated that isolated cells were positive for CD73, CD44, CD29, CD105, and CD90 but negative for CD11b, CD45, CD34, and HLA‑DR. In addition, cells possessed the capability of multipotential differentiation into osteoblasts and adipocytes.
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Affiliation(s)
- Koushan Sineh Sepehr
- a Department of Immunology, School of Public Health , Tehran University of Medical Sciences , Tehran , Iran
| | - Alireza Razavi
- a Department of Immunology, School of Public Health , Tehran University of Medical Sciences , Tehran , Iran
| | - Mohsen Saeidi
- b Stem Cell Research Center , Golestan University of Medical Sciences , Gorgan , Iran
| | | | - Meghdad Abdollahpour-Alitappeh
- d Gastroenterology and Liver Diseases Research Center , Reasearch Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Seyed Mahmoud Hashemi
- e Department of Immunology, School of Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran.,f Department of Applied Cell Sciences, School of Advanced Technologies in Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran
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Yokozaki H, Koma YI, Shigeoka M, Nishio M. Cancer as a tissue: The significance of cancer-stromal interactions in the development, morphogenesis and progression of human upper digestive tract cancer. Pathol Int 2018; 68:334-352. [PMID: 29671926 DOI: 10.1111/pin.12674] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 03/19/2018] [Indexed: 12/28/2022]
Abstract
We review the significance of cancer-stromal interactions (CSIs) in the development, morphogenesis and progression of human gastric and esophageal cancer based on the data obtained from co-culture experiments. Orthotopic fibroblasts in the gastric cancer stroma not only promoted their growth by cancer cells but were also responsible for the mobility, morphogenesis and epithelial-to-mesenchymal transition (EMT) of the cancer cells through CSI. Bone marrow-derived mesenchymal stem cells could be part of the origin of cancer-associated fibroblasts (CAFs) of the gastric cancer providing an advantageous microenvironment for the restoration of cancer stem cells with the induction of the EMT. Tumor-associated macrophages (TAMs) may differentiate from bone marrow-derived monocytes/macrophages within the tumor microenvironment of esophageal cancer and participate in the growth and the progression of esophageal squamous cell carcinomas (ESCCs). Macrophages infiltrated into the intraepithelial neoplastic lesions of the esophagus may function as a biological promoter by promoting the growth and motility of squamous epithelia. Tumor cells build up "cancer as a tissue" by taking advantage of the existing network of growth factors, cytokines and chemokines through the interactions of TAMs, CAFs and cancer cells themselves.
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Affiliation(s)
- Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
| | - Yu-Ichiro Koma
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
| | - Manabu Shigeoka
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
| | - Mari Nishio
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
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36
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Zhou L, Wang M, Guo C, Zhu Y, Yu H, Zhang L, Yu P. Expression of pAkt is associated with a poor prognosis in Chinese women with invasive ductal breast cancer. Oncol Lett 2018; 15:4859-4866. [PMID: 29552125 PMCID: PMC5840663 DOI: 10.3892/ol.2018.7965] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 01/03/2018] [Indexed: 12/21/2022] Open
Abstract
Over the past three decades, numerous patients with breast cancer succumbed to cancer metastasis and recurrence, while, the exact mechanisms underlying this malignancy, and the potential biomarkers for prognosis prediction remain elusive. It was previously demonstrated that phosphorylated RAC-α serine/threonine-protein kinase (pAkt) and Beclin 1 was associated with cancer metastasis, and recurrence. Thus far, the expression patterns of pAkt and Beclin 1 in breast cancer tissues, and their associations with the prognosis of invasive ductal breast cancer remain inconclusive, which may be due to various factors, including ethnicity and pathological types. In the present study, a total of 90 Chinese female patients with invasive ductal breast cancer between June 1999 and August 2002 were enrolled at Shanghai First People's Hospital (Shanghai, China). The patients were followed up from 5 months to 13.5 years for survival analysis. The expressional levels of pAkt and Beclin 1 in invasive ductal breast cancer tissues, and the normal paracancerous tissues were measured by immunohistochemistry. Associations with prognosis following surgery were further evaluated using Cox regression analysis. In 90 invasive ductal breast cancer samples, pAkt was detected in 17 (18.9%) samples and Beclin 1 in 33 (36.7%) samples, but both were not detected in any of the paracancerous samples. Survival analysis revealed that pAkt expression carried a tendency to predict a shorter disease-free survival (DFS) in patients with invasive ductal breast cancer. Additionally, Beclin 1 expression was not significantly associated with survival. Furthermore, univariate Cox regression analysis demonstrated that pAkt expression was negatively associated with DFS and overall survival. Multivariate Cox regression analysis indicated that pAkt expression was an independent risk factor associated with poor prognosis in patients with invasive ductal breast cancer (all P<0.05). pAkt may be used as a potential prognostic biomarker in Chinese women with invasive ductal breast cancer.
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Affiliation(s)
- Ling Zhou
- Department of Surgery, Branch of Shanghai First People's Hospital, Shanghai 200081, P.R. China
| | - Min Wang
- Department of Pathology, Branch of Shanghai First People's Hospital, Shanghai 200081, P.R. China
| | - Chongyong Guo
- Department of General Surgery, Binzhou People's Hospital, Binzhou, Shandong 256600, P.R. China
| | - Ying Zhu
- Department of Pathology, Branch of Shanghai First People's Hospital, Shanghai 200081, P.R. China
| | - Hua Yu
- Department of Surgery, Branch of Shanghai First People's Hospital, Shanghai 200081, P.R. China
| | - Lu Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Pei Yu
- Department of Orthopedics, Shanghai Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 210025, P.R. China
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Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci 2018; 25:20. [PMID: 29506506 PMCID: PMC5838954 DOI: 10.1186/s12929-018-0426-4] [Citation(s) in RCA: 593] [Impact Index Per Article: 84.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 03/01/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are subpopulations of cancer cells sharing similar characteristics as normal stem or progenitor cells such as self-renewal ability and multi-lineage differentiation to drive tumour growth and heterogeneity. Throughout the cancer progression, CSC can further be induced from differentiated cancer cells via the adaptation and cross-talks with the tumour microenvironment as well as a response from therapeutic pressures, therefore contributes to their heterogeneous phenotypes. Challengingly, conventional cancer treatments target the bulk of the tumour and are unable to target CSCs due to their highly resistance nature, leading to metastasis and tumour recurrence. MAIN BODY This review highlights the roles of CSCs in tumour initiation, progression and metastasis with a focus on the cellular and molecular regulators that influence their phenotypical changes and behaviours in the different stages of cancer progression. We delineate the cross-talks between CSCs with the tumour microenvironment that support their intrinsic properties including survival, stemness, quiescence and their cellular and molecular adaptation in response to therapeutic pressure. An insight into the distinct roles of CSCs in promoting angiogenesis and metastasis has been captured based on in vitro and in vivo evidences. CONCLUSION Given dynamic cellular events along the cancer progression and contributions of resistance nature by CSCs, understanding their molecular and cellular regulatory mechanism in a heterogeneous nature, provides significant cornerstone for the development of CSC-specific therapeutics.
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Affiliation(s)
- Ain Zubaidah Ayob
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
- Cell and Molecular Laboratory (CMBL), The Dean’s Office, Faculty of Medicine, University of Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
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38
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Son B, Lee S, Youn H, Kim E, Kim W, Youn B. The role of tumor microenvironment in therapeutic resistance. Oncotarget 2018; 8:3933-3945. [PMID: 27965469 PMCID: PMC5354804 DOI: 10.18632/oncotarget.13907] [Citation(s) in RCA: 182] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 12/01/2016] [Indexed: 12/20/2022] Open
Abstract
Cancer cells undergo unlimited progression and survival owing to activation of oncogenes. However, support of the tumor microenvironment is essential to the formation of clinically relevant tumors. Recent evidence indicates that the tumor microenvironment is a critical regulator of immune escape, progression, and distant metastasis of cancer. Moreover, the tumor microenvironment is known to be involved in acquired resistance of tumors to various therapies. Despite significant advances in chemotherapy and radiotherapy, occurrence of therapeutic resistance leads to reduced efficacy. This review highlights myeloid cells, cancer-associated fibroblasts, and mesenchymal stem cells consisting of the tumor microenvironment, as well as the relevant signaling pathways that eventually render cancer cells to be therapeutically resistant.
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Affiliation(s)
- Beomseok Son
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea
| | - Sungmin Lee
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea
| | - HyeSook Youn
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea
| | - EunGi Kim
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea
| | - Wanyeon Kim
- Integrative Graduate Program of Ship and Offshore Plant Technology for Ocean Energy Resource, Pusan National University, Busan 46241, Republic of Korea.,Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - BuHyun Youn
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea.,Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea
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Abstract
Resistance to chemotherapy and cancer relapse are major clinical challenges attributed to a sub population of cancer stem cells (CSCs). The concept of CSCs has been the subject of intense research by the oncology community since evidence for their existence was first published over twenty years ago. Emerging data indicates that they are also able to evade novel therapies such as targeted agents, immunotherapies and anti-angiogenics. The inability to appropriately identify and isolate CSCs is a major hindrance to the field and novel technologies are now being utilized. Agents that target CSC-associated cell surface receptors and signaling pathways have generated promising pre-clinical results and are now entering clinical trial. Here we discuss and evaluate current therapeutic strategies to target CSCs.
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Affiliation(s)
- Stephanie Annett
- Molecular and Cellular Therapeutics, Royal College of Surgeons Ireland, Ireland
| | - Tracy Robson
- Molecular and Cellular Therapeutics, Royal College of Surgeons Ireland, Ireland.
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40
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Nuclear transport of cancer extracellular vesicle-derived biomaterials through nuclear envelope invagination-associated late endosomes. Oncotarget 2017; 8:14443-14461. [PMID: 28129640 PMCID: PMC5362417 DOI: 10.18632/oncotarget.14804] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/1969] [Accepted: 01/11/2017] [Indexed: 12/12/2022] Open
Abstract
Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication, but how the biomaterials they carry reach the target site in recipient cells is an open question. We report that subdomains of Rab7+ late endosomes and nuclear envelope invaginations come together to create a sub-nuclear compartment, where biomaterials associated with CD9+ EVs are delivered. EV-derived biomaterials were also found in the nuclei of host cells. The inhibition of nuclear import and export pathways abrogated the nuclear localization of EV-derived biomaterials or led to their accumulation therein, respectively, suggesting that their translocation is dependent on nuclear pores. Nuclear envelope invagination-associated late endosomes were observed in ex vivo biopsies in both breast carcinoma and associated stromal cells. The transcriptome of stromal cells exposed to cancer cell-derived CD9+ EVs revealed that the regulation of eleven genes, notably those involved in inflammation, relies on the nuclear translocation of EV-derived biomaterials. Our findings uncover a new cellular pathway used by EVs to reach nuclear compartment.
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41
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Avnet S, Di Pompo G, Chano T, Errani C, Ibrahim-Hashim A, Gillies RJ, Donati DM, Baldini N. Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation. Int J Cancer 2017; 140:1331-1345. [PMID: 27888521 DOI: 10.1002/ijc.30540] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 11/09/2016] [Indexed: 12/12/2022]
Abstract
The role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor of bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition that is similar to a wound setting, in which mesenchymal reactive cells are activated to release mitogenic and chemotactic factors. We therefore intended to test the hypothesis that, in OS, acid-activated MSC influence tumor cell behavior. Conditioned media or co-culture with normal MSC previously incubated with short-term acidosis (pH 6.8 for 10 hr, H+ -MSC) enhanced OS clonogenicity and invasion. This effect was mediated by NF-κB pathway activation. In fact, deep-sequencing analysis, confirmed by Real-Time PCR and ELISA, demonstrated that H+ -MSC differentially induced a tissue remodeling phenotype with increased expression of RelA, RelB and NF-κB1, and downstream, of CSF2/GM-CSF, CSF3/G-CSF and BMP2 colony-promoting factors, and of chemokines (CCL5, CXCL5 and CXCL1), and cytokines (IL6 and IL8), with an increased expression of CXCR4. An increased expression of IL6 and IL8 were found only in normal stromal cells, but not in OS cells, and this was confirmed in tumor-associated stromal cells isolated from OS tissue. Finally, H+ -MSC conditioned medium differentially promoted OS stemness (sarcosphere number, stem-associated gene expression), and chemoresistance also via IL6 secretion. Our data support the hypothesis that the acidic OS microenvironment is a key factor for MSC activation, in turn promoting the secretion of paracrine factors that influence tumor behavior, a mechanism that holds the potential for future therapeutic interventions aimed to target OS.
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Affiliation(s)
- Sofia Avnet
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Gemma Di Pompo
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Tokuhiro Chano
- Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Costantino Errani
- Orthopaedic Oncology Surgical Unit, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Arig Ibrahim-Hashim
- Department of Imaging Research, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Robert J Gillies
- Department of Imaging Research, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Davide Maria Donati
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.,Orthopaedic Oncology Surgical Unit, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Nicola Baldini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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42
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Sivanathan KN, Gronthos S, Grey ST, Rojas-Canales D, Coates PT. Immunodepletion and Hypoxia Preconditioning of Mouse Compact Bone Cells as a Novel Protocol to Isolate Highly Immunosuppressive Mesenchymal Stem Cells. Stem Cells Dev 2017; 26:512-527. [PMID: 27998209 DOI: 10.1089/scd.2016.0180] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Compact bones (CB) are major reservoirs of mouse mesenchymal stem cells (mMSC). Here, we established a protocol to isolate MSC from CB and tested their immunosuppressive potential. Collagenase type II digestion of BM-flushed CB from C57B/6 mice was performed to liberate mMSC precursors from bone surfaces to establish nondepleted mMSC. CB cells were also immunodepleted based on the expression of CD45 (leukocytes) and TER119 (erythroid cells) to eliminate hematopoietic cells. CD45-TER119- CB cells were subsequently used to generate depleted mMSC. CB nondepleted and depleted mMSC progenitors were cultured under hypoxic conditions to establish primary mMSC cultures. CB depleted mMSC compared to nondepleted mMSC showed greater cell numbers at subculturing and had increased functional ability to differentiate into adipocytes and osteoblasts. CB depleted mMSC had high purity and expressed key mMSC markers (>85% Sca-1, CD29, CD90) with no mature hematopoietic contaminating cells (<5% CD45, CD11b) when subcultured to passage 5 (P5). Nondepleted mMSC cultures, however, were less pure and heterogenous with <72% Sca-1+, CD29+, and CD90+ cells at early passages (P1 or P2), along with high percentages of contaminating CD11b+ (35.6%) and CD45+ (39.2%) cells that persisted in culture long term. Depleted and nondepleted mMSC nevertheless exhibited similar potency to suppress total (CD3+), CD4+ and CD8+ T cell proliferation, in a dendritic cell allostimulatory one-way mixed lymphocyte reaction. CB depleted mMSC, pretreated with proinflammatory cytokines IFN-γ, TNF-α, and IL-17A, showed superior suppression of CD8+ T cell, but not CD4+ T cell proliferation, relative to untreated-mMSC. In conclusion, CB depleted mMSC established under hypoxic conditions and treated with selective cytokines represent a novel source of potent immunosuppressive MSC. As these cells have enhanced immune modulatory function, they may represent a superior product for use in clinical allotransplantation.
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Affiliation(s)
- Kisha Nandini Sivanathan
- 1 School of Medicine, Faculty of Health Sciences, University of Adelaide , Adelaide, Australia .,2 Centre for Clinical and Experimental Transplantation, Royal Adelaide Hospital , Adelaide, Australia
| | - Stan Gronthos
- 3 South Australian Health and Medical Research Institute , Adelaide, Australia .,4 Mesenchymal Stem Cell Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide , Adelaide, Australia
| | - Shane T Grey
- 5 Transplantation Immunology Group, Garvan Institute of Medical Research , Sydney, Australia
| | - Darling Rojas-Canales
- 1 School of Medicine, Faculty of Health Sciences, University of Adelaide , Adelaide, Australia .,2 Centre for Clinical and Experimental Transplantation, Royal Adelaide Hospital , Adelaide, Australia
| | - Patrick T Coates
- 1 School of Medicine, Faculty of Health Sciences, University of Adelaide , Adelaide, Australia .,2 Centre for Clinical and Experimental Transplantation, Royal Adelaide Hospital , Adelaide, Australia .,6 Central Northern Adelaide Renal Transplantation Service, Royal Adelaide Hospital , Adelaide, Australia
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43
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Zhao P, Chen Y, Yue Z, Yuan Y, Wang X. Bone marrow mesenchymal stem cells regulate stemness of multiple myeloma cell lines via BTK signaling pathway. Leuk Res 2017; 57:20-26. [PMID: 28273548 DOI: 10.1016/j.leukres.2017.02.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 02/18/2017] [Accepted: 02/22/2017] [Indexed: 01/10/2023]
Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) are key components of bone marrow microenvironment. Although the importances of BM-MSCs activation in myeloma cells growth, development, progression, angiogenesis are well known, their role in the regulation of myeloma stemness is unclear. In this study, myeloma cell lines (LP-1, U266) were co-cultured with BM-MSCs, we found that BM-MSCs could up-regulate the expression of key stemness genes and proteins (OCT4, SOX2, NANOG) and increase clonogenicity. Similarly, the mechanisms underlying the BM-MSC activation of myeloma stemness remain unclear. Here, we found that PCI-32765, a Bruton tyrosine kinase (BTK) inhibitor, treatment significantly down- regulate expression of key stemness genes and proteins in vitro co-culture system. Together, our results revealed that BM-MSCs could increase myeloma stemness via activation of the BTK signal pathway.
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Affiliation(s)
- Pan Zhao
- Department of Hematology and Blood and Marrow Transplantation, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yafang Chen
- Department of Hematology and Blood and Marrow Transplantation, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhijie Yue
- Department of Hematology and Blood and Marrow Transplantation, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ying Yuan
- Department of Hematology and Blood and Marrow Transplantation, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiaofang Wang
- Department of Hematology and Blood and Marrow Transplantation, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
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44
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Yokobori T, Nishiyama M. TGF-β Signaling in Gastrointestinal Cancers: Progress in Basic and Clinical Research. J Clin Med 2017; 6:jcm6010011. [PMID: 28106769 PMCID: PMC5294964 DOI: 10.3390/jcm6010011] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/31/2016] [Accepted: 01/16/2017] [Indexed: 12/18/2022] Open
Abstract
Transforming growth factor (TGF)-β superfamily proteins have many important biological functions, including regulation of tissue differentiation, cell proliferation, and migration in both normal and cancer cells. Many studies have reported that TGF-β signaling is associated with disease progression and therapeutic resistance in several cancers. Similarly, TGF-β-induced protein (TGFBI)—a downstream component of the TGF-β signaling pathway—has been shown to promote and/or inhibit cancer. Here, we review the state of basic and clinical research on the roles of TGF-β and TGFBI in gastrointestinal cancers.
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Affiliation(s)
- Takehiko Yokobori
- Research Program for Omics-based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
| | - Masahiko Nishiyama
- Research Program for Omics-based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
- Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
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45
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Bruna F, Arango-Rodríguez M, Plaza A, Espinoza I, Conget P. The administration of multipotent stromal cells at precancerous stage precludes tumor growth and epithelial dedifferentiation of oral squamous cell carcinoma. Stem Cell Res 2016; 18:5-13. [PMID: 27939557 DOI: 10.1016/j.scr.2016.11.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 11/01/2016] [Accepted: 11/22/2016] [Indexed: 02/06/2023] Open
Abstract
Multipotent stromal cells (MSCs) are envisioned as a powerful therapeutic tool. As they home into tumors, secrete trophic and vasculogenic factors, and suppress immune response their role in carcinogenesis is a matter of controversy. Worldwide oral squamous cell carcinoma (OSCC) is the fifth most common epithelial cancer. Our aim was to determine whether MSC administration at precancerous stage modifies the natural progression of OSCC. OSCC was induced in Syrian hamsters by topical application of DMBA in the buccal pouch. At papilloma stage, the vehicle or 3×106 allogenic bone marrow-derived MSCs were locally administered. Four weeks later, the lesions were studied according to: volume, stratification (histology), proliferation (Ki-67), apoptosis (Caspase 3 cleaved), vasculature (ASMA), inflammation (Leukocyte infiltrate), differentiation (CK1 and CK4) and gene expression profile (mRNA). Tumors found in individuals that received MSCs were smaller than those presented in the vehicle group (87±80 versus 54±62mm3, p<0.05). The rate of proliferation was two times lower and the apoptosis was 2.5 times higher in lesions treated with MSCs than in untreated ones. While the laters presented dedifferentiated cells, the former maintained differentiated cells (cytokeratin and gene expression profile similar to normal tissue). Thus, MSC administration at papilloma stage precludes tumor growth and epithelial dedifferentiation of OSCC.
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Affiliation(s)
- Flavia Bruna
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
| | - Martha Arango-Rodríguez
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Anita Plaza
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Iris Espinoza
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Paulette Conget
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
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46
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Lu JH, Wei HJ, Peng BY, Chou HH, Chen WH, Liu HY, Deng WP. Adipose-Derived Stem Cells Enhance Cancer Stem Cell Property and Tumor Formation Capacity in Lewis Lung Carcinoma Cells Through an Interleukin-6 Paracrine Circuit. Stem Cells Dev 2016; 25:1833-1842. [PMID: 27596042 DOI: 10.1089/scd.2016.0163] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention and emerged as therapeutic approaches in several medical fields. Although current knowledge of the biological impacts of ADSCs in cancer research is greatly improved, the underlying effects of ADSCs in tumor development remain controversial and cause the safety concerns in clinical utilization. Hence, we isolated primary ADSCs from the abdominal fat of mice and conducted interaction of ADSCs with Lewis lung carcinoma cells in culture and in mice to investigate the impacts of ADSCs on tumor development. Cytokine array and neutralizing antibody were further utilized to identify the key regulator and downstream signaling pathway. In this study, we demonstrated that ADSCs enhance the malignant characteristics of LLC1 cells, including cell growth ability and especially cancer stem cell property. ADSCs were then identified to promote tumor formation and growth in mice. We further determined that ADSC interaction with LLC1 cells stimulates increased secretion of interleukin-6 mainly from ADSCs, which then act in a paracrine manner on LLC1 cells to enhance their malignant characteristics. Interleukin-6 was also identified to regulate genes related to cell proliferation and cancer stem cell, as well as to activate JAK2/STAT3, a predominant interleukin-6-activated pathway, in LLC1 cells. Collectively, we demonstrated that ADSCs play a pro-malignant role in tumor development of Lewis lung carcinoma cells by particularly promoting cancer stem cell property through interleukin-6 paracrine circuit, which is important for safety considerations regarding the clinical application of ADSCs.
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Affiliation(s)
- Jui-Hua Lu
- 1 Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University , Taipei City, Taiwan
| | - Hong-Jian Wei
- 1 Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University , Taipei City, Taiwan .,2 Stem Cell Research Center, Taipei Medical University , Taipei City, Taiwan
| | - Bou-Yue Peng
- 3 Department of Dentistry, Taipei Medical University Hospital , Taipei City, Taiwan .,4 School of Dentistry, College of Oral Medicine, Taipei Medical University , Taipei City, Taiwan
| | - Hsin-Hua Chou
- 4 School of Dentistry, College of Oral Medicine, Taipei Medical University , Taipei City, Taiwan
| | - Wei-Hong Chen
- 2 Stem Cell Research Center, Taipei Medical University , Taipei City, Taiwan
| | - Hen-Yu Liu
- 2 Stem Cell Research Center, Taipei Medical University , Taipei City, Taiwan
| | - Win-Ping Deng
- 1 Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University , Taipei City, Taiwan .,2 Stem Cell Research Center, Taipei Medical University , Taipei City, Taiwan .,5 College of Medicine, Fu Jen Catholic University , New Taipei City, Taiwan
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47
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Sheng XL, Yuan R, Liu ZM. Effect of mesenchymal stem cells on proliferation and chemotherapeutic resistance of human gastric cancer cells SGC7901 in vivo. Shijie Huaren Xiaohua Zazhi 2016; 24:3877-3883. [DOI: 10.11569/wcjd.v24.i27.3877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of bone marrow mesenchymal stem cells (MSCs) on the proliferation and chemotherapeutic resistance of gastric cancer cells SGC7901.
METHODS SGC7901 cells and primary bone marrow MSCs were cultured in vitro. Nude mice were divided into two groups and received subcutaneous injection of SGC7901cells alone and SGC7901 cells plus bone marrow MSCs, respectively. After the tumors grew up to 250-400 mm3, each group was further randomly divided into two groups and received intraperitoneal injection of 5-fluorouridine (5-Fu) and normal saline (NS), respectively. The four groups were as follows: SGC7901 + NS (group A), SGC7901 + MSCs + NS (group B), SGC7901 + Fu (group C), and SGC7901 + MSCs + Fu (group D). All the nude mice were sacrificed on days 18 after 9 intraperitoneal injections. Tumor volume, tumor weight, and net weight of nude mice were measured at the end of the experiment, and pathological changes of tumors were detected under an inverted microscope.
RESULTS The differences in tumor volume, tumor weight, and net weight of mice were significant between each group. MSCs increased the proliferation ability and 5-Fu resistance of SGC7901 cells, but under the same conditions (5-Fu+/-), the net weight of nude mice in the SGC7901 + MSC group was significantly more than that of the SGC7901 group.
CONCLUSION MSC can not only enhance the proliferation and 5-Fu resistance of transplanted SGC7901 cells, but also improve the nutritional condition of nude mice simultaneously.
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Multipotent mesenchymal stromal cell sheet therapy for bisphosphonate-related osteonecrosis of the jaw in a rat model. Acta Biomater 2016; 42:400-410. [PMID: 27326918 DOI: 10.1016/j.actbio.2016.06.022] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 06/03/2016] [Accepted: 06/16/2016] [Indexed: 12/21/2022]
Abstract
UNLABELLED Bisphosphonates (BPs) inhibit bone resorption and are frequently used to treat osteoporosis, bone metastasis, and other conditions that result in bone fragility. However, numerous studies have reported that BPs are closely related to the development of osteonecrosis of the jaw (BRONJ), which is an intractable disease. Recent studies have demonstrated that intravenous infusion of multipotent mesenchymal stromal cells (MSCs) is effective for the treatment of BRONJ-like disease models. However, the stability of injected MSCs is relatively low. In this study, the protein level of vascular endothelial growth factor in BP-treated MSCs was significantly lower than untreated-MSCs. The mRNA expression levels of receptor activator of nuclear factor κ-B ligand and osteoprotegerin were significantly decreased in BP-treated MSCs. We developed a tissue-engineered cell sheet of allogeneic enhanced green fluorescent protein (EGFP)-labeled MSCs and investigated the effect of MSC sheet transplantation in a BRONJ-like rat model. The MSC sheet group showed wound healing in most cases compared with the control group and MSC intravenous injection group (occurrence of bone exposure: 12.5% compared with 80% and 100%, respectively). Immunofluorescence staining revealed that EGFP-positive cells were localized around newly formed blood vessels in the transplanted sub-mucosa at 2weeks after transplantation. Blood vessels were significantly observed in the MSC sheet group compared to in the control group and MSC intravenous injection group (106±9.6 compared with 40±5.3 and 62±10.2 vessels/mm(2), respectively). These results suggest that allogeneic MSC sheet transplantation is a promising alternative approach for treating BRONJ. STATEMENT OF SIGNIFICANCE Bisphosphonates are frequently used to treat osteoporosis, bone metastasis of various cancers, and other diseases. However, bisphosphonate related-osteonecrosis of the jaw (BRONJ) is an intractable disease because it often recurs after surgery or is exacerbated following conservative treatment. Therefore, an alternative approach for treating BRONJ is needed. In this study, we developed a bone marrow-derived multipotent mesenchymal stromal cell (MSC) sheet to treat BRONJ and investigated the effect of MSC sheet transplantation in a rat model of BRONJ-like disease. The MSC sheet transplantation group showed wound healing in most cases, while only minimal healing was observed in the control group and MSC intravenous injection group. Our results suggest that the MSC sheet is a promising alternative approach for the treatment of BRONJ.
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Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2016; 16:225-38. [PMID: 25748930 DOI: 10.1016/j.stem.2015.02.015] [Citation(s) in RCA: 1156] [Impact Index Per Article: 128.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity, and clonal long-term repopulation potential. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system, and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets.
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Affiliation(s)
- Vicki Plaks
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA
| | - Niwen Kong
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA
| | - Zena Werb
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA.
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Berger L, Shamai Y, Skorecki KL, Tzukerman M. Tumor Specific Recruitment and Reprogramming of Mesenchymal Stem Cells in Tumorigenesis. Stem Cells 2015; 34:1011-26. [PMID: 26676563 DOI: 10.1002/stem.2269] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 11/19/2015] [Accepted: 11/29/2015] [Indexed: 01/14/2023]
Abstract
Non-neoplastic stromal cells harvested from patient tumors were identified as tumor-derived mesenchymal stem cells (MSCs) by their multipotential capacity to differentiate into adipocytes, osteoblasts, and chondrocytes and by the expression of MSC specific cell surface markers. These procedures yielded also epithelial cancer cells and their counterpart MSC from gastric carcinoma (GSC1) and lung carcinoma (LC2). While the LC2 cancer cell growth is independent of their LC-MSC, the GSC1 cancer cell growth is critically dependent on the presence of their counterpart GSC-MSC or their conditioned medium (CM). The fact that none of the various other tumor-derived MSCs was able to restore the specific effect of GSC-MSC on GSC1 cancer cell growth suggests specificity of tumor-derived MSC, which are specifically recruited and "educated"/reprogrammed by the cancer cells to support tumor growth. Using cytokine array analysis, we were able to demonstrate that GSC1 cell growth is mediated through hepatocyte growth factor (HGF)/c-MET signaling pathway which is activated exclusively by HGF secreted from GSC-MSC. An innovative approach demonstrates GSC1-mediated specific tropism of "naïve" MSC from the adjacent tissue in a tumor specific manner to support tumor progression. The results suggest that specific tumor tropic "naïve" MSC are reprogrammed in a tumor-specific manner to support gastric tumor progression. Understanding the mechanisms involved in the interactions of the tumor cancer cells and tumor-derived MSC will constitute the basis for developing multimodal anticancer therapeutic strategies that will also take into account the specific tumor tropism properties of MSC and their reprogramming.
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Affiliation(s)
- Liron Berger
- Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel
| | - Yeela Shamai
- Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel
| | - Karl L Skorecki
- Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.,Rambam Medical Center, Haifa, Israel
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