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1
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Sencha LM, Karpova MA, Dobrynina OE, Balalaeva IV. Cell-type dependent effect of 3D collagen matrix on cancer cell resistance to suboptimal conditions: the case of serum deprivation, glucose starvation, and hypoxia. Tissue Cell 2025; 93:102719. [PMID: 39823703 DOI: 10.1016/j.tice.2024.102719] [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: 09/03/2024] [Revised: 12/13/2024] [Accepted: 12/29/2024] [Indexed: 01/20/2025]
Abstract
The extracellular matrix (ECM) and its primary chemical components, including collagen, play a pivotal role in carcinogenesis and tumor progression. The ECM actively regulates cell proliferation, migration, and, importantly, resistance to various adverse factors. It is widely recognized as a key factor in modifying the resistance of tumor cells to various treatment modalities and cytotoxic compounds. However, the role of the ECM in tumor cell adaptation to nutritional deficiencies and hypoxic conditions remains significantly less studied. Since it is generally accepted that tumor cells resistance increases when cultured in a three-dimensional matrix, we sought to experimentally test the universality of this statement. In this work, we analyzed the responses of tumor cells with varying origins and proliferative activities, including human bladder carcinoma, epidermoid carcinoma, and ovarian carcinoma, to deprivation of serum, glucose and oxygen. We compared cell resistance to suboptimal conditions when cultured in a monolayer on tissue culture (TC)-treated polystyrene, on collagen-coated surfaces, or within a three-dimensional hydrogel composed of collagen type I. All three cell lines were stably transfected with fluorescent protein genes. To register the cell growth dynamics, we used a fluorescence-based technique that allows long-term quantitative observations without disrupting the hydrogel. The analyzed cell lines demonstrated different patterns of relative sensitivity to suboptimal conditions. We revealed that the direction and intensity of the collagen matrix effect depend on the cell type. Slowly proliferating ovarian carcinoma cells showed no noticeable changes in their behavior when cultured in a gel compared to a monolayer. In the case of bladder carcinoma, we registered predominantly resistance-stimulating effect of the collagen matrix, but it was significant only under serum deprivation. The most pronounced effect of collagen was registered for epidermoid carcinoma. Importantly, this effect was ambivalent: gel-embedded cells demonstrated significantly enhanced resistance to serum deprivation, but, at the same time, they were more responsive to glucose starvation and hypoxic conditions. We attribute the registered phenomenon to the individual characteristics of tumor cells with different origins and metabolic activities.
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Affiliation(s)
- Ludmila M Sencha
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Maria A Karpova
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Olga E Dobrynina
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Irina V Balalaeva
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia.
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2
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Mohseni A, Salehi F, Rostami S, Hadiloo K, Hashemi M, Baridjavadi Z, Ahangari F, Karami N, Samani F, Tahmasebi S, Farahani N, Taheriazam A. Harnessing the power of exosomes for diagnosis, prognosis, and treatment of hematological malignancies. Stem Cell Res Ther 2025; 16:6. [PMID: 39773361 PMCID: PMC11708188 DOI: 10.1186/s13287-024-04125-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025] Open
Abstract
Exosomes are small extracellular vesicles of endocytic origin released by various cell types. They consist of lipid bilayers containing macromolecules such as lipids, proteins, microRNAs, growth factors, cytokines, and carbohydrates. Exosomes play a critical role in the diagnosis and treatment of various diseases. For instance, exosome contents have been utilized as biomarkers in body fluids (urine, saliva, serum) to identify cancers, autoimmune diseases, and inflammatory conditions such as sepsis. Due to their small size and ability to reach tumor microenvironments, exosomes are also used as carriers for chemotherapeutic drugs in drug delivery systems. Furthermore, evidence indicates that malignant cells release exosomes into the tumor microenvironment, influencing immune cells in a paracrine manner. Additionally, immune cell-derived exosomes, such as those from Natural Killer (NK) cells or cytotoxic T lymphocytes (CTLs), show potential as therapeutic agents in treating malignancies like leukemia. This review discusses the diagnostic role of exosomes in various hematological malignancies and explores the therapeutic potential of immune cell-derived exosomes in these diseases.
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Affiliation(s)
- Amirata Mohseni
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Fatemeh Salehi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Samaneh Rostami
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Kaveh Hadiloo
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zahra Baridjavadi
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Ahangari
- Department of Immunology, Pasteur Institue of Iran, Tehran, Iran
| | - Najibeh Karami
- Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Samani
- Blood Transfusion Research Center, High Institute for Research and Education in transfusion medicine, Iranian Blood Transfusion Organization (IBTO), Tehran, Iran
| | - Safa Tahmasebi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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3
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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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4
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Poddar MS, Chu YD, Pendharkar G, Liu CH, Yeh CT. Exploring cancer-associated fibroblast-induced resistance to tyrosine kinase inhibitors in hepatoma cells using a liver-on-a-chip model. LAB ON A CHIP 2024; 24:5043-5054. [PMID: 39356081 DOI: 10.1039/d4lc00624k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2024]
Abstract
Liver cancer is a significant global contributor to cancer-related mortality. Despite available targeted therapies, resistance to tyrosine kinase inhibitors (TKIs) like sorafenib and lenvatinib poses a formidable challenge. The tumor microenvironment (TME), inhabited by cancer-associated fibroblasts (CAFs), profoundly influences this resistance. To uncover the mechanisms, a 3D microfluidic chip replicating liver architecture was fabricated to probe the intricate mechanisms of TKI resistance. The chip design mirrors the hexagonal structure of liver lobules, situating liver cancer cells at the core, encircled by fibroblasts, with rigorous assessments confirming biocompatibility and consistent cell growth. After determining the IC50 values of sorafenib and lenvatinib in 2D co-culture, a transwell setup revealed drug resistance development in co-cultured cells. Within the 3D microfluidic chip, live/dead assays highlighted elevated viability under drug exposure, emphasizing fibroblast-driven drug resistance. The study identifies AHSG and CLEC3B as potential mediators of drug resistance in co-culture, significantly upregulated in the co-cultured medium. Functional tests confirmed their roles, as introducing recombinant AHSG and CLEC3B enhanced liver cancer cell resistance to sorafenib and lenvatinib in both 2D and 3D scenarios. In conclusion, by replicating the complex TME using microfluidic technology, this study sheds light on the roles of AHSG and CLEC3B as well as possible approaches for improving the effectiveness of liver cancer treatment.
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Affiliation(s)
- Madhu Shree Poddar
- Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu, 30044, Taiwan, R.O.C..
| | - Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C..
| | - Gaurav Pendharkar
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 30044, Taiwan, R.O.C
| | - Cheng-Hsien Liu
- Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu, 30044, Taiwan, R.O.C..
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 30044, Taiwan, R.O.C
- College of Semiconductor Research, National Tsing Hua University, Hsinchu 30044, Taiwan, R.O.C
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C..
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
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5
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Wang KH, Chang YH, Ding DC. Bone Marrow Mesenchymal Stem Cells Promote Ovarian Cancer Cell Proliferation via Cytokine Interactions. Int J Mol Sci 2024; 25:6746. [PMID: 38928452 PMCID: PMC11203416 DOI: 10.3390/ijms25126746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) are key players in promoting ovarian cancer cell proliferation, orchestrated by the dynamic interplay between cytokines and their interactions with immune cells; however, the intricate crosstalk among BMSCs and cytokines has not yet been elucidated. Here, we aimed to investigate interactions between BMSCs and ovarian cancer cells. We established BMSCs with a characterized morphology, surface marker expression, and tri-lineage differentiation potential. Ovarian cancer cells (SKOV3) cultured with conditioned medium from BMSCs showed increased migration, invasion, and colony formation, indicating the role of the tumor microenvironment in influencing cancer cell behavior. BMSCs promoted SKOV3 tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice, increasing tumor growth. The co-injection of BMSCs increased the phosphorylation of p38 MAPK and GSK-3β in SKOV3 tumors. Co-culturing SKOV3 cells with BMSCs led to an increase in the expression of cytokines, especially MCP-1 and IL-6. These findings highlight the influence of BMSCs on ovarian cancer cell behavior and the potential involvement of specific cytokines in mediating these effects. Understanding these mechanisms will highlight potential therapeutic avenues that may halt ovarian cancer progression.
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Affiliation(s)
- Kai-Hung Wang
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan;
| | - Yu-Hsun Chang
- Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan;
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
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6
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Yi Y, Qin G, Yang H, Jia H, Zeng Q, Zheng D, Ye S, Zhang Z, Liu TM, Luo KQ, Deng CX, Xu RH. Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNβ-HLA. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400888. [PMID: 38638003 PMCID: PMC11151078 DOI: 10.1002/advs.202400888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/17/2024] [Indexed: 04/20/2024]
Abstract
Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-β (IFNβ) by MSCs. IFNβ reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.
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Affiliation(s)
- Ye Yi
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Guihui Qin
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Hongmei Yang
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Hao Jia
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Qibing Zeng
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Dejin Zheng
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Sen Ye
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Zhiming Zhang
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Tzu-Ming Liu
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao SAR, 999078, China
| | - Kathy Qian Luo
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao SAR, 999078, China
| | - Chu-Xia Deng
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao SAR, 999078, China
| | - Ren-He Xu
- Center of Reproduction, Development and Aging, Cancer Center, and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao SAR, 999078, China
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7
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Kaviani M, Soleimanian S, Keshtkar S, Azarpira N, Asvar Z, Pakbaz S. Molecular Prospective on Malignant Transformation of Mesenchymal Stem Cells: An Issue in Cell Therapy. Cell Reprogram 2024; 26:96-106. [PMID: 38917438 DOI: 10.1089/cell.2024.0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2024] Open
Abstract
Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are multipotent stem cells that can be isolated from various tissues and could self-renew and differentiate. They secrete cytokines and trophic factors that create a regenerative microenvironment and have immunomodulatory properties. Although clinical trials have been conducted with MSCs in various diseases, concerns regarding the possibility of malignant transformation of these cells have been raised. The studies showed a higher rate of hematological malignancy and carcinogenesis in experimental models after MSC transplantation. The mechanisms underlying malignant transformation of MSCs are complex and not fully understood, but they are believed to involve the presence of special signaling molecules and alterations in cell behavior regulation pathways. Possible pathways that lead to MSCs' oncogenic transformation occur through two mechanisms: spontaneous and stimulated malignant transformation, including cell fusion, fusion proteins, and the tumor microenvironment. MSC-based therapies have the potential to revolutionize medicine, and addressing the issue of malignancy is crucial to ensure their safety and efficacy. Therefore, the purpose of the present review is to summarize the potential mechanisms of the malignant transformation of MSCs. [Figure: see text].
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Affiliation(s)
- Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeede Soleimanian
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Keshtkar
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Asvar
- Nanotechnology School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, Mount Sinai Hospital, Toronto, ON, Canada
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8
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Buruiană A, Gheban BA, Gheban-Roșca IA, Georgiu C, Crișan D, Crișan M. The Tumor Stroma of Squamous Cell Carcinoma: A Complex Environment That Fuels Cancer Progression. Cancers (Basel) 2024; 16:1727. [PMID: 38730679 PMCID: PMC11083853 DOI: 10.3390/cancers16091727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 04/25/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
The tumor microenvironment (TME), a complex assembly of cellular and extracellular matrix (ECM) components, plays a crucial role in driving tumor progression, shaping treatment responses, and influencing metastasis. This narrative review focuses on the cutaneous squamous cell carcinoma (cSCC) tumor stroma, highlighting its key constituents and their dynamic contributions. We examine how significant changes within the cSCC ECM-specifically, alterations in fibronectin, hyaluronic acid, laminins, proteoglycans, and collagens-promote cancer progression, metastasis, and drug resistance. The cellular composition of the cSCC TME is also explored, detailing the intricate interplay of cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, pericytes, adipocytes, and various immune cell populations. These diverse players modulate tumor development, angiogenesis, and immune responses. Finally, we emphasize the TME's potential as a therapeutic target. Emerging strategies discussed in this review include harnessing the immune system (adoptive cell transfer, checkpoint blockade), hindering tumor angiogenesis, disrupting CAF activity, and manipulating ECM components. These approaches underscore the vital role that deciphering TME interactions plays in advancing cSCC therapy. Further research illuminating these complex relationships will uncover new avenues for developing more effective treatments for cSCC.
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Affiliation(s)
- Alexandra Buruiană
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Bogdan-Alexandru Gheban
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Emergency Clinical County Hospital, 400347 Cluj-Napoca, Romania
| | - Ioana-Andreea Gheban-Roșca
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, 400129 Cluj-Napoca, Romania;
| | - Carmen Georgiu
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Doința Crișan
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Maria Crișan
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
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9
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Khan C, Rusan NM. Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer. Trends Cancer 2024; 10:289-311. [PMID: 38350736 PMCID: PMC11008779 DOI: 10.1016/j.trecan.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 02/15/2024]
Abstract
Cancer metastasis causes over 90% of cancer patient fatalities. Poor prognosis is determined by tumor type, the tumor microenvironment (TME), organ-specific biology, and animal physiology. While model organisms do not fully mimic the complexity of humans, many processes can be studied efficiently owing to the ease of genetic, developmental, and cell biology studies. For decades, Drosophila has been instrumental in identifying basic mechanisms controlling tumor growth and metastasis. The ability to generate clonal populations of distinct genotypes in otherwise wild-type animals makes Drosophila a powerful system to study tumor-host interactions at the local and global scales. This review discusses advancements in tumor biology, highlighting the strength of Drosophila for modeling TMEs and systemic responses in driving tumor progression and metastasis.
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Affiliation(s)
- Chaitali Khan
- Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Nasser M Rusan
- Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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10
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Zhou L, Zhao H, Zhang C, Chen Z, Li D, Qian G. Study on the mechanism of CXCL12/CXCR4-axis-mediated upregulation of IL-8 and IL-6 on the biological function of acute T lymphocyte leukaemia cells. Cytotechnology 2024; 76:97-111. [PMID: 38304623 PMCID: PMC10828134 DOI: 10.1007/s10616-023-00600-3] [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: 11/24/2022] [Accepted: 10/11/2023] [Indexed: 02/03/2024] Open
Abstract
Blocking the CXCL12/CXCR4 axis can alter the biological functions of leukaemia cells. We hypothesise that interleukin (IL)-8 and IL-6 play an important role in this process. To test this hypothesis, we established a co-culture model of leukaemia cells and bone marrow stromal cells. Treatment of cells with AMD3100, a CXCR4 antagonist, and G-CSF blocked the CXCL12/CXCR4 axis, inducing biological changes in the leukaemia cells and altering IL-8 and IL-6 levels. Subsequently, after stimulating the CXCL12/CXCR4 axis, specific pathway blockers were employed to assess the role of four candidate signalling pathways in this process. ELISA results confirmed that MG-132 (10 μm) inhibits IL-8 expression and that the NF-κB signalling pathway contributes to this effect. Moreover, treatment with Perifosine, an AKT inhibitor, inhibited IL-6 expression. In addition, changes in the NF-κB signalling pathway inhibited IL-8 expression. Treatment with SP600125, a Jun N-terminal kinase inhibitor, and Perifosine also inhibited IL-8 expression; however, this effect occurred later. IL-6 expression was also lower in the Perifosine group; hence, inhibiting the PI3K/AKT signalling pathway can reduce IL-6 expression. This process requires the participation of multiple signalling pathways to regulate IL-8 and IL-6 expression. Therefore, the associated mechanism is likely to be highly intricate, with potential cross-effects that may impact leukaemia pathogenesis. IL-6 and IL-8 are physiologically regulated by the CXCL12/CXCR4 axis, while the NF-κB and JNK/AP-1 pathways are required for IL-8 expression in T-cell acute lymphoblastic leukaemia. Accordingly, by upregulating IL-8, the bone marrow microenvironment and CXCL12/CXCR4 axis may contribute to T-cell acute lymphoblastic leukaemia pathogenesis.
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Affiliation(s)
- Liping Zhou
- Department of Pediatrics, The People’s Hospital of Zhangqiu District, Jinan, 250200 Shandong People’s Republic of China
| | - Hui Zhao
- Department of Pediatrics, The People’s Hospital of Zhangqiu District, Jinan, 250200 Shandong People’s Republic of China
| | - Chao Zhang
- Department of Nephrology, The People’s Hospital of Zhangqiu District, Jinan, 250200 Shandong People’s Republic of China
| | - Zhe Chen
- Health and Family Planning Inspection Agency of Zhangqiu District, Jinan, 250200 Shandong People’s Republic of China
| | - Dong Li
- Cryomedicine Laboratory, Qilu Hospital of Shandong University, Jinan, 250012 Shandong People’s Republic of China
| | - Guanglei Qian
- Department of Pediatrics, The People’s Hospital of Zhangqiu District, Jinan, 250200 Shandong People’s Republic of China
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11
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Chauhan A, Agarwal S, Masih M, Gautam PK. The Multifunction Role of Tumor-Associated Mesenchymal Stem Cells and Their Interaction with Immune Cells in Breast Cancer. Immunol Invest 2023; 52:856-878. [PMID: 37615117 DOI: 10.1080/08820139.2023.2249025] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Mesenchymal stem cells (MSCs) are a heterogeneous group of progenitor cells that play a multifunctional role including tissue regeneration, self-renewal properties, and differentiate into cells of mesodermal lineage such as adipocytes, osteoblasts, and chondrocytes. MSCs come into contact with tumor microenvironment (TME) and differentiate into tumor-associated MSCs (TA-MSCs). Various substances such as chemokines, cytokines, growth factors, and others are released by tumor cells to recruit MSCs. TA-MSCs induced epithelial-mesenchymal transition (EMT) program which mediates tumor growth progression, migration, and invasion. Role of MSCs in the tumor progression, stemness, malignancy, and treatment resistance in the breast cancer TME. Immunomodulation by MSCs is mediated by a combination of cell contact-dependent mechanisms and soluble substances. Monocytes/macrophages, dendritic cells, T cells, B cells, and NK cells all show signs of MSCs' immunomodulatory capability. In a complicated interplay initiated by MSCs, anti-inflammatory monocytes/macrophages and regulatory T cells (Tregs) play a key role, as they unveil their full immunomodulatory potential. MSC- secreted cytokines are commonly blamed for the interaction between MSCs, monocytes, and Tregs. Here, we review the current knowledge of cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the role MSCs play in breast cancer progression and its TME.Abbreviation MSC: Mesenchymal Stem Cells; TME: Tumor Microenvironment; TAMS; Tumour-associated Macrophages; ECM: Extracellular matrix; CAFs: Cancer-associated Fibroblasts; CFUs: Colony-forming unit Fibroblasts; Tregs: T regulatory cells; Bregs; Regulatory B cells; IFN-γ: Interferon-gamma; TNF-α: Tumour Necrosis Factor-alpha; IL: Interleukin; TGF-β: transforming growth factorβ; PGE2: Prostaglandin E2; CXCR: Chemokine Receptor; Blimp-1; B lymphocyte-induced maturation protein-1; CCL: Chemokine motif ligand; EMT: Epithelial-mesenchymal transition.
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Affiliation(s)
- Anita Chauhan
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Sonam Agarwal
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Marilyn Masih
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
| | - Pramod Kumar Gautam
- Department of Biochemistry, AII India Institute of Medical Sciences, New Delhi, India
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Nethi SK, Li X, Bhatnagar S, Prabha S. Enhancing Anticancer Efficacy of Chemotherapeutics Using Targeting Ligand-Functionalized Synthetic Antigen Receptor-Mesenchymal Stem Cells. Pharmaceutics 2023; 15:1742. [PMID: 37376189 DOI: 10.3390/pharmaceutics15061742] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/08/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been studied for their potential in facilitating tumor-targeted delivery of chemotherapeutics due to their tumor-homing characteristics. We hypothesized that targeting effectiveness of MSCs can be further enhanced by incorporating tumor-targeting ligands on MSC surfaces that will allow for enhanced arrest and binding within the tumor tissue. We utilized a unique strategy of modifying MSCs with synthetic antigen receptors (SARs), targeting specific antigens overexpressed on cancer cells. MSCs were surface-functionalized by first incorporating recombinant protein G (PG) on the surface, followed by binding of the targeting antibody to the PG handle. We functionalized MSCs with antibodies targeting a tyrosine kinase transmembrane receptor protein, epidermal growth factor receptor (EGFR), overexpressed in non-small-cell lung cancer (NSCLC). The efficacy of MSCs functionalized with anti-EGFR antibodies (cetuximab and D8) was determined in murine models of NSCLC. Cetuximab-functionalized MSCs demonstrated improved binding to EGFR protein and to EGFR overexpressing A549 lung adenocarcinoma cells. Further, cetuximab-functionalized MSCs loaded with paclitaxel nanoparticles were efficient in slowing orthotopic A549 tumor growth and improving the overall survival relative to that of other controls. Biodistribution studies revealed a six-fold higher retention of EGFR-targeted MSCs than non-targeted MSCs. Based on these results, we conclude that targeting ligand functionalization could be used to enhance the concentration of therapeutic MSC constructs at the tumor tissue and to achieve improved antitumor response.
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Affiliation(s)
- Susheel Kumar Nethi
- Fels Cancer Institute for Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Xiaolei Li
- Fels Cancer Institute for Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | | | - Swayam Prabha
- Fels Cancer Institute for Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Molecular Therapeutics Program, Fox Chase Cancer Center, Temple University, Philadelphia, PA 19111, USA
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Mandal D, Kushwaha K, Gupta J. Emerging nano-strategies against tumour microenvironment (TME): a review. OPENNANO 2023. [DOI: 10.1016/j.onano.2022.100112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Johnson B, Zhuang L, Rath EM, Yuen ML, Cheng NC, Shi H, Kao S, Reid G, Cheng YY. Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response. Cancers (Basel) 2022; 14:cancers14194784. [PMID: 36230710 PMCID: PMC9564288 DOI: 10.3390/cancers14194784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 09/27/2022] [Indexed: 12/23/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a deadly thoracic malignancy and existing treatment options are limited. Chemotherapy remains the most widely used first-line treatment regimen for patients with unresectable MPM, but is hampered by drug resistance issues. The current study demonstrated a modest enhancement of MPM cell sensitivity to chemotherapy drug treatment following microRNA (miRNA) transfection in MPM cell lines, albeit not for all tested miRNAs. This effect was more pronounced for FAK (PND-1186) small molecule inhibitor treatment; consistent with previously published data. We previously established that MPM response to survivin (YM155) small molecule inhibitor treatment is unrelated to basal survivin expression. Here, we showed that MPM response to YM155 treatment is enhanced following miRNA transfection of YM155-resistant MPM cells. We determined that YM155-resistant MPM cells secrete a higher level of exosomes in comparison to YM155-sensitive MPM cells. Despite this, an exosome inhibitor (GW4896) did not enhance MPM cell sensitivity to YM155. Additionally, our study showed no evidence of a correlation between the mRNA expression of inhibitor of apoptosis (IAP) gene family members and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in the MPM cell lines and correlated with poor sensitivity to YM155.
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Affiliation(s)
- Ben Johnson
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
- Correspondence: ; Tel.: +61-976-79869
| | - Ling Zhuang
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
| | - Emma M. Rath
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
- Giannoulatou Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Man Lee Yuen
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
| | - Ngan Ching Cheng
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
| | - Huaikai Shi
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
| | - Steven Kao
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
- Chris O’Brien Life House, Sydney, NSW 2050, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
| | - Glen Reid
- Department of Pathology, Otago Medical School, University of Otago, Dunedin 9016, New Zealand
| | - Yuen Yee Cheng
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
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Ramuta TŽ, Kreft ME. Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells. Cancers (Basel) 2022; 14:cancers14153761. [PMID: 35954425 PMCID: PMC9367361 DOI: 10.3390/cancers14153761] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Tumours consist of different cell types and an extracellular matrix, all of which together form a complex microenvironment. The tumour microenvironment plays a critical role in various aspects of tumour development and progression. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that have a tri-lineage differentiation capacity and are one of the key stromal cells in the tumour microenvironment. Following the interaction with cancer cells, they are transformed from naïve MSCs to tumour-associated MSCs, which substantially affect tumour growth and progression as well as the development of chemoresistance in cancer cells. The aim of this review article is to provide an overview of studies that have investigated how MSCs affect the susceptibility of cancer cells to chemotherapeutics. Their results show that MSCs protect cancer cells from chemotherapeutics by influencing several signalling pathways. This knowledge is crucial for the development of new treatment approaches that will lead to improved treatment outcomes. Abstract The tumour microenvironment, which is comprised of various cell types and the extracellular matrix, substantially impacts tumour initiation, progression, and metastasis. Mesenchymal stem/stromal cells (MSCs) are one of the key stromal cells in the tumour microenvironment, and their interaction with cancer cells results in the transformation of naïve MSCs to tumour-associated MSCs. The latter has an important impact on tumour growth and progression. Recently, it has been shown that they can also contribute to the development of chemoresistance in cancer cells. This review provides an overview of 42 studies published between 1 January 2001 and 1 January 2022 that examined the effect of MSCs on the susceptibility of cancer cells to chemotherapeutics. The studies showed that MSCs affect various signalling pathways in cancer cells, leading to protection against chemotherapy-induced damage. Promising results emerged from the use of inhibitors of various signalling pathways that are affected in cancer cells due to interactions with MSCs in the tumour microenvironment. These studies present a good starting point for the investigation of novel treatment approaches and demonstrate the importance of targeting the stroma in the tumour microenvironment to improve treatment outcomes.
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The effect of mesenchymal stromal cells ın the microenvironment on cancer development. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:114. [PMID: 35674854 DOI: 10.1007/s12032-022-01703-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/01/2022] [Indexed: 10/18/2022]
Abstract
Inflammatory signals secreted from the tumor microenvironment are thought to promote tumor growth and survival. It has been reported that stromal cells in the tumor microenvironment have similar characteristics to tumor-associated cells. In addition miRNAs play critical roles in various diseases, including cancer. In this study, we aimed to investigate the effects of co-culture of cancer cells and stromal cells isolated from normal and malignant breast tissue on each other and the possible effects of miRNAs on these interactions. The characterized stromal cells were co-cultured with an MDA-MB-231 cancer cell line. The proliferation capacity of the experimental groups was evaluated using the WST-1 assay. The expression of breast cancer-specific miRNAs and related genes were assessed by real-time PCR. ELISA assay was performed to determine the concentration of some cytokines and chemokines. We found that the microenvironment plays an important role in the development of cancer, confirming the changes in the expression of oncogenic and tumor suppressor miRNA and their target genes after co-culture with malignant stromal cells. As a result of the studies, specific gene expressions of related signaling pathways were detected in correlation with miRNA changes and the effects of tumor microenvironment on tumorigenesis were revealed in detail. miRNAs have been shown to play an important role in cancer development in recent studies. The idea that these small molecules can be used in diagnosis and treatment is becoming stronger day by day. We believe that new treatment approaches involving the tumor microenvironment and using miRNAs as markers are promising.
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17
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Zhao LX, Zhang K, Shen BB, Li JN. Mesenchymal stem cell-derived exosomes for gastrointestinal cancer. World J Gastrointest Oncol 2021; 13:1981-1996. [PMID: 35070036 PMCID: PMC8713327 DOI: 10.4251/wjgo.v13.i12.1981] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/15/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) malignancies, a series of malignant conditions originating from the digestive system, include gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. GI cancers have been regarded as the leading cancer-related cause of death in recent years. Therefore, it is essential to develop effective treatment strategies for GI malignancies. Mesenchymal stem cells (MSCs), a type of distinct non-hematopoietic stem cells and an important component of the tumor microenvironment, play important roles in regulating GI cancer development and progression through multiple mechanisms, such as secreting cytokines and direct interactions. Currently, studies are focusing on the anti-cancer effect of MSCs on GI malignancies. However, the effects and functional mechanisms of MSC-derived exosomes on GI cancer are less studied. MSC-derived exosomes can regulate GI tumor growth, drug response, metastasis, and invasion through transplanting proteins and miRNA to tumor cells to activate the specific signal pathway. Besides, the MSC-derived exosomes are also seen as an important drug delivery system and have shown potential in anti-cancer treatment. This study aims to summarize the effect and biological functions of MSC-derived exosomes on the development of GI cancers and discuss their possible clinical applications for the treatment of GI malignancies.
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Affiliation(s)
- Lin-Xian Zhao
- Department of General Surgery, 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
| | - Bing-Bing Shen
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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18
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Karimi-Shahri M, Javid H, Sharbaf Mashhad A, Yazdani S, Hashemy SI. Mesenchymal stem cells in cancer therapy; the art of harnessing a foe to a friend. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1307-1323. [PMID: 35096289 PMCID: PMC8769515 DOI: 10.22038/ijbms.2021.58227.12934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/04/2021] [Indexed: 12/09/2022]
Abstract
For a long time, mesenchymal stem cells (MSCs) were discussed only as stem cells which could give rise to different types of cells. However, when it became clear that their presence in the tumor microenvironment (TME) was like a green light for tumorigenesis, they emerged from the ashes. This review was arranged to provide a comprehensive and precise description of MSCs' role in regulating tumorigenesis and to discuss the dark and the bright sides of cancer treatment strategies using MSCs. To gather the details about MSCs, we made an intensive literature review using keywords, including MSCs, tumor microenvironment, tumorigenesis, and targeted therapy. Through transferring cytokines, growth factors, and microRNAs, MSCs maintain the cancer stem cell population, increase angiogenesis, provide a facility for cancer metastasis, and shut down the anti-tumor activity of the immune system. Although MSCs progress tumorigenesis, there is a consensus that these cells could be used as a vehicle to transfer anti-cancer agents into the tumor milieu. This feature opened a new chapter in MSCs biology, this time from the therapeutic perspective. Although the data are not sufficient, the advent of new genetic engineering methods might make it possible to engage these cells as Trojan horses to eliminate the malignant population. So many years of investigation showed that MSCs are an important group of cells, residing in the TME, studying the function of which not only could add a delicate series of information to the process of tumorigenesis but also could revolutionize cancer treatment strategies.
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Affiliation(s)
- Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Sharbaf Mashhad
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shaghayegh Yazdani
- Department of Medical Laboratory Sciences, Ilam Institute for Medical Sciences, Ilam, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Rat Adipose-Derived Stromal Cells (ADSCs) Increases the Glioblastoma Growth and Decreases the Animal Survival. Stem Cell Rev Rep 2021; 18:1495-1509. [PMID: 34403074 DOI: 10.1007/s12015-021-10227-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2021] [Indexed: 12/22/2022]
Abstract
Many studies have shown that mesenchymal stromal cells (MSCs) and their secreted factors may modulate the biology of tumor cells. However, how these interactions happen in vivo remains unclear. In the present study, we investigated the effects of rat adipose-derived stromal cells (ADSCs) and their conditioned medium (ADSC-CM) in glioma tumor growth and malignancy in vivo. Our results showed that when we co-injected C6 cells plus ADSCs into the rat brains, the tumors generated were larger and the animals exhibited shorter survival, when compared with tumors of the animals that received only C6 cells or C6 cells pre-treated with ADSC-CM. We further showed that the animals that received C6 plus ADSC did not present enhanced expression of CD73 (a gene highly expressed in ADSCs), indicating that the tumor volume observed in these animals was not a mere consequence of the higher density of cells administered in this group. Finally, we showed that the animals that received C6 + ADSC presented tumors with larger necrosis areas and greater infiltration of immune cells. These results indicate that the immunoregulatory properties of ADSCs and its contribution to tumor stroma can support tumor growth leading to larger zones of necrosis, recruitment of immune cells, thus facilitating tumor progression. Our data provide new insights into the way by which ADSCs and tumor cells interact and highlight the importance of understanding the fate and roles of MSCs in tumor sites in vivo, as well as their intricate crosstalk with cancer cells.
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20
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Omori H, Shan Q, Takabatake K, Nakano K, Kawai H, Sukegawa S, Tsujigiwa H, Nagatsuka H. The Origin of Stroma Influences the Biological Characteristics of Oral Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13143491. [PMID: 34298705 PMCID: PMC8305380 DOI: 10.3390/cancers13143491] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Normal stromal cells play a significant role in the progression of cancers but are poorly investigated in oral squamous cell carcinoma (OSCC). In this study, we found that stromal cells derived from the gingival and periodontal ligament tissues could inhibit differentiation and promote the proliferation, invasion, and migration of OSCC both in vitro and in vivo. Furthermore, microarray data suggested that genes, such as CDK1, BUB1B, TOP2A, DLGAP5, BUB1, and CCNB2, probably play a role in influencing the different effects of gingival stromal tissue cells (G-SCs) and periodontal ligament stromal cells (P-SCs) on the progression of OSCC. Therefore, both G-SCs and P-SCs could promote the progression of OSCC, which could be a potential regulatory mechanism in the progression of OSCC. Abstract Normal stromal cells surrounding the tumor parenchyma, such as the extracellular matrix (ECM), normal fibroblasts, mesenchymal stromal cells, and osteoblasts, play a significant role in the progression of cancers. However, the role of gingival and periodontal ligament tissue-derived stromal cells in OSCC progression is unclear. In this study, the effect of G-SCs and P-SCs on the differentiation, proliferation, invasion, and migration of OSCC cells in vitro was examined by Giemsa staining, Immunofluorescence (IF), (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS), invasion, and migration assays. Furthermore, the effect of G-SCs and P-SCs on the differentiation, proliferation, and bone invasion by OSCC cells in vivo was examined by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), and tartrate-resistant acid phosphatase (TRAP) staining, respectively. Finally, microarray data and bioinformatics analyses identified potential genes that caused the different effects of G-SCs and P-SCs on OSCC progression. The results showed that both G-SCs and P-SCs inhibited the differentiation and promoted the proliferation, invasion, and migration of OSCC in vitro and in vivo. In addition, genes, including CDK1, BUB1B, TOP2A, DLGAP5, BUB1, and CCNB2, are probably involved in causing the different effects of G-SCs and P-SCs on OSCC progression. Therefore, as a potential regulatory mechanism, both G-SCs and P-SCs can promote OSCC progression.
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Affiliation(s)
- Haruka Omori
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
| | - Qiusheng Shan
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
- Correspondence:
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
| | - Shintaro Sukegawa
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
- Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Kagawa 760-0065, Japan
| | - Hidetsugu Tsujigiwa
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
- Department of Life Science, Faculty of Science, Okayama University of Science, Okayama 700-0005, Japan
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8525, Japan; (H.O.); (Q.S.); (K.N.); (H.K.); (S.S.); (H.T.); (H.N.)
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Balaji S, Kim U, Muthukkaruppan V, Vanniarajan A. Emerging role of tumor microenvironment derived exosomes in therapeutic resistance and metastasis through epithelial-to-mesenchymal transition. Life Sci 2021; 280:119750. [PMID: 34171378 DOI: 10.1016/j.lfs.2021.119750] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment (TME) constitutes multiple cell types including cancerous and non-cancerous cells. The intercellular communication between these cells through TME derived exosomes may either enhance or suppress the tumorigenic processes. The tumor-derived exosomes could convert an anti-tumor environment into a pro-tumor environment by inducing the differentiation of stromal cells into tumor-associated cells. The exosomes from tumor-associated stromal cells reciprocally trigger epithelial-to-mesenchymal transition (EMT) in tumor cells, which impose therapeutic resistance and metastasis. It is well known that these exosomes contain the signals of EMT, but how these signals execute chemoresistance and metastasis in tumors remains elusive. Understanding the significance and molecular signatures of exosomes transmitting EMT signals would aid in developing appropriate methods of inhibiting them. In this review, we focus on molecular signatures of exosomes that shuttle between cancer cells and their stromal populations in TME to explicate their impact on therapeutic resistance and metastasis through EMT. Especially Wnt signaling is found to be involved in multiple ways of exosomal transport and hence we decipher the biomolecules of Wnt signaling trafficked through exosomes and their potential in serving as therapeutic targets.
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Affiliation(s)
- Sekaran Balaji
- Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu 625 020, India
| | - Usha Kim
- Department of Orbit, Oculoplasty and Ocular Oncology, Aravind Eye Hospital, Madurai, Tamil Nadu 625 020, India
| | - Veerappan Muthukkaruppan
- Department of Immunology and Stem Cell Biology, Aravind Medical Research Foundation, Madurai, Tamil Nadu 625 020, India
| | - Ayyasamy Vanniarajan
- Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, Tamil Nadu 625 020, India.
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Yang S, An J, Park S, Lee J, Chae H, Lee K, Song W, Youn H. Enhanced expression of cyclooxygenase-2 related multi-drug resistance gene in melanoma and osteosarcoma cell lines by TSG-6 secreted from canine adipose-derived mesenchymal stem/stromal cells. Vet Med Sci 2021; 7:968-978. [PMID: 33570264 PMCID: PMC8136926 DOI: 10.1002/vms3.442] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 12/09/2020] [Accepted: 01/16/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Multiple drug resistance (MDR) of cancer cells is the main cause of intrinsic or acquired desensitization to chemotherapy in many cancers. A number of studies have found high expression of COX-2 to be a factor for expression of MDR gene in several cancer. Furthermore, adipose tissue derived mesenchymal stem/stromal cells (ADSC) have been found to increase cyclo-oxygenase-2 (COX-2) expression in some tumour cells. The mechanism for this, however, is not yet clear and needs further study. OBJECTIVE The purpose of this study was to determine whether tumour necrosis factor-alpha stimulated gene/protein 6 (TSG-6) secreted from ADSCs is associated with an increase in MDR genes by inducing COX-2 gene expression in melanoma and osteosarcoma cell lines. METHODS ADSCs were transfected with TSG-6 siRNA or Control RNA respected, and cancer cell line were transfected with COX-2 siRNA or Control RNA respected. Using trans well coculture system, the interactions of ADSCs with tumour cells were investigated. RESULTS Increased COX-2 expression was observed in cancer cell co-cultured with ADSCs. Additionally, we identified that COX-2 expression was related to drug resistance genes (P-glycoprotein, multidrug resistance-associated protein). Transfecting canine ADSCs with small interfering RNA, TSG-6 secreted from ADSCs was found to be a major factor in the regulation of COX-2 expression and drug resistance genes in osteosarcoma and melanoma cell lines. CONCLUSION TSG-6 mediated COX-2 up-regulation is a possible mechanism of chemoresistance development induced by ADSCs. These findings provide better understanding about the mechanism associated with ADSC-induced chemoresistance in cancer.
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Affiliation(s)
- Se‐Jin Yang
- Laboratory of Veterinary Internal MedicineDepartment of Veterinary Clinical ScienceCollege of Veterinary MedicineSeoul National UniversitySeoulRepublic of Korea
| | - Ju‐Hyun An
- Laboratory of Veterinary Internal MedicineDepartment of Veterinary Clinical ScienceCollege of Veterinary MedicineSeoul National UniversitySeoulRepublic of Korea
| | - Su‐Min Park
- Laboratory of Veterinary Internal MedicineDepartment of Veterinary Clinical ScienceCollege of Veterinary MedicineSeoul National UniversitySeoulRepublic of Korea
| | - Jeong‐Hwa Lee
- Laboratory of Veterinary Internal MedicineDepartment of Veterinary Clinical ScienceCollege of Veterinary MedicineSeoul National UniversitySeoulRepublic of Korea
| | - Hyung‐Kyu Chae
- Laboratory of Veterinary Internal MedicineDepartment of Veterinary Clinical ScienceCollege of Veterinary MedicineSeoul National UniversitySeoulRepublic of Korea
| | - Kyung‐Mi Lee
- Laboratory of Veterinary Internal MedicineDepartment of Veterinary Clinical ScienceCollege of Veterinary MedicineSeoul National UniversitySeoulRepublic of Korea
| | - Woo‐Jin Song
- Department of Veterinary Internal MedicineCollege of Veterinary MedicineJeju National UniversityJeju‐SiKorea
| | - Hwa‐Young Youn
- Laboratory of Veterinary Internal MedicineDepartment of Veterinary Clinical ScienceCollege of Veterinary MedicineSeoul National UniversitySeoulRepublic of Korea
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Microvesicles mediate sorafenib resistance in liver cancer cells through attenuating p53 and enhancing FOXM1 expression. Life Sci 2021; 271:119149. [PMID: 33549596 DOI: 10.1016/j.lfs.2021.119149] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 12/15/2022]
Abstract
Drug resistance in cancer, still poses therapeutic challenges and tumor microenvironment plays a critical role in it. Microvesicles (MVs) are effective transporters of the molecular information between cells and regulate the tumor microenvironment. They contribute to the drug resistance by transferring functional molecules between cells. Herein we report the effects of liver cancer cell-secreted MVs on sorafenib resistance in liver cancer cells HepG2 and Huh7 both in vitro and in vivo. In our study, these cancer cell-secreted MVs affected the anti-proliferative effect of sorafenib in a dose- and time-dependent manner and also inhibited the sorafenib induced apoptosis in vitro. Further, in in-vivo xenograft mice models, liver cancer cell-secreted MVs increased the tumor volume even after sorafenib treatment. Further, HGF, also got elevated in liver cancer cell-secreted MVs treatment group and activated Ras protein expression. miR-25 in the cancer cell-secreted MVs was transferred to their host cells HepG2 and Huh7 cells and reversed the sorafenib induced expression of tumor suppressor p53. This in turn induced the expression of FOXM1, a key regulator of cell cycle progression and thus affected the anti-proliferative effect of sorafenib. Therefore, this study reveals that liver cancer cell-derived MVs can mediate sorafenib resistance in the liver cancer cells, suggesting that these MVs may not be utilized as vehicles for anti-cancer drug delivery in liver cancer treatments.
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Zigman-Hoffman E, Sredni B, Meilik B, Naparstek E, Tartakovsky B. Tellurium compound provides pro-apoptotic signaling in drug resistant multiple myeloma. Leuk Lymphoma 2020; 62:1146-1156. [PMID: 33334225 DOI: 10.1080/10428194.2020.1858292] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Multiple Myeloma, effectively treated by chemotherapeutic drugs, relapses due to drug resistance. We tested here the capacity of mesenchymal stromal cells, from the bone marrow of patients or from adipose tissue of healthy individuals, to induce drug resistance in Myeloma cell lines. We show that drug resistance can be achieved by factors secreted by the various MSC's. Mass spectrometry analysis of MSC's conditioned media revealed that fibronectin, was particularly instrumental in providing anti-apoptotic signals to MM cells. Moreover, we demonstrate that SAS ([octa-O-bis-(R,R)tartarate ditellurane]), an immunomodulator Tellurium compound, is not only able of blocking the physical interaction between MM cells and fibronectin but is also capable of re-sensitizing the cells to the chemotherapeutic drugs. Finally, we show that this re-sensitization is coupled with the blocking of pAKT induction, in MM cells, by the MSC's. These results indicate that SAS may be useful in the treatment of drug resistant MM.
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Affiliation(s)
- Eti Zigman-Hoffman
- Bar Ilan University Mina and Everard Goodman Faculty of Life Sciences, Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.,Tel Aviv Sourasky Medical Center, Institute of Hematology, BMT Unit, Tel Aviv, Israel
| | - Benjamin Sredni
- Bar Ilan University Mina and Everard Goodman Faculty of Life Sciences, Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel
| | - Benjamin Meilik
- Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ella Naparstek
- Tel Aviv Sourasky Medical Center, Institute of Hematology, BMT Unit, Tel Aviv, Israel
| | - Boris Tartakovsky
- Tel Aviv Sourasky Medical Center, Institute of Hematology, BMT Unit, Tel Aviv, Israel
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25
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Jena BC, Mandal M. The emerging roles of exosomes in anti-cancer drug resistance and tumor progression: An insight towards tumor-microenvironment interaction. Biochim Biophys Acta Rev Cancer 2020; 1875:188488. [PMID: 33271308 DOI: 10.1016/j.bbcan.2020.188488] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/27/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022]
Abstract
The tumor microenvironment (TME) is a complex network of cellular organization consisting of fibroblasts, adipocytes, pericytes, immune cells endothelial cells, and extracellular matrix proteins. Besides communicating with each other, tumor cells are also involved in the tumor stroma interaction. Presently, most of the studies have focused on the contribution of TME in supporting tumor growth through intercellular communication by physical contact between the cells or through paracrine signaling cascades of growth factors and cytokines. The crosstalk between the tumor and TME has a pivotal role in the development of anti-cancer drug resistance. Drug resistance, be it against targeted or non-targeted drugs, has emerged as a major hurdle in the successful therapeutic intervention of cancer. Among the several mechanisms involved in the development of the resistance to anti-cancer therapies, exosomes have recently come into the limelight. Exosomes are the nano-sized vesicles, originated from the endolysosomal compartments and have the inherent potential to shuttle diverse biomolecules like proteins, lipids, and nucleic acids to the recipient cells. There are also instances where the pharmacological compounds are transferred between the cells via exosomes. For instance, the transfer of the cargoes from the drug-resistant tumor cells immensely affects the recipient drug-sensitive cells in terms of their proliferation, survival, migration, and drug resistance. In this review, we have discussed multiple aspects of the exosome-mediated bidirectional interplay between tumor and TME. Furthermore, we have also emphasized the contribution of exosomes promoting drug resistance and therapeutic strategies to mitigate the exosome induced drug resistance as well.
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Affiliation(s)
- Bikash Chandra Jena
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
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26
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Pietrobono D, Giacomelli C, Marchetti L, Martini C, Trincavelli ML. High Adenosine Extracellular Levels Induce Glioblastoma Aggressive Traits Modulating the Mesenchymal Stromal Cell Secretome. Int J Mol Sci 2020; 21:E7706. [PMID: 33081024 PMCID: PMC7589183 DOI: 10.3390/ijms21207706] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/01/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma is an aggressive, fast-growing brain tumor influenced by the composition of the tumor microenvironment (TME) in which mesenchymal stromal cell (MSCs) play a pivotal role. Adenosine (ADO), a purinergic signal molecule, can reach up to high micromolar concentrations in TME. The activity of specific adenosine receptor subtypes on glioma cells has been widely explored, as have the effects of MSCs on tumor progression. However, the effects of high levels of ADO on glioma aggressive traits are still unclear as is its role in cancer cells-MSC cross-talk. Herein, we first studied the role of extracellular Adenosine (ADO) on isolated human U343MG cells as a glioblastoma cellular model, finding that at high concentrations it was able to prompt the gene expression of Snail and ZEB1, which regulate the epithelial-mesenchymal transition (EMT) process, even if a complete transition was not reached. These effects were mediated by the induction of ERK1/2 phosphorylation. Additionally, ADO affected isolated bone marrow derived MSCs (BM-MSCs) by modifying the pattern of secreted inflammatory cytokines. Then, the conditioned medium (CM) of BM-MSCs stimulated with ADO and a co-culture system were used to investigate the role of extracellular ADO in GBM-MSC cross-talk. The CM promoted the increase of glioma motility and induced a partial phenotypic change of glioblastoma cells. These effects were maintained when U343MG cells and BM-MSCs were co-cultured. In conclusion, ADO may affect glioma biology directly and through the modulation of the paracrine factors released by MSCs overall promoting a more aggressive phenotype. These results point out the importance to deeply investigate the role of extracellular soluble factors in the glioma cross-talk with other cell types of the TME to better understand its pathological mechanisms.
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Affiliation(s)
| | - Chiara Giacomelli
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (D.P.); (L.M.); (C.M.); (M.L.T.)
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Gholipour E, Sarvarian P, Samadi P, Talebi M, Movassaghpour A, Motavalli R, Hojjat-Farsangi M, Yousefi M. Exosome: From leukemia progression to a novel therapeutic approach in leukemia treatment. Biofactors 2020; 46:698-715. [PMID: 32797698 DOI: 10.1002/biof.1669] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 06/13/2020] [Accepted: 06/16/2020] [Indexed: 12/14/2022]
Abstract
Exosomes, as small vesicles, are released by tumor cells and tumor microenvironment (cells and function as key intercellular mediators and effects on different processes including tumorigenesis, angiogenesis, drug resistance, and evasion from immune system. These functions are due to exosomes' biomolecules which make them as efficient markers in early diagnosis of the disease. Also, exosomes have been recently applied in vaccination. The potential role of exosomes in immune response toward leukemic cells makes them efficient immunotherapeutic agents treating leukemia. Furthermore, variations in exosomes contents make them beneficial to be used in treating different diseases. This review introduces the role of exosomes in the development of hematological malignancies and evaluates their functional role in the treatment of these malignancies.
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Affiliation(s)
- Elham Gholipour
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Sarvarian
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Samadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliakbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roza Motavalli
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hojjat-Farsangi
- Immune and Gene Therapy Lab, Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Aging Research Institute, Tabriz university of Medical Sciences, Tabriz, Iran
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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28
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Abbasi A, Pakravan N, Hassan ZM. Hyaluronic acid optimises therapeutic effects of hydrogen peroxide-induced oxidative stress on breast cancer. J Cell Physiol 2020; 236:1494-1514. [PMID: 32740942 DOI: 10.1002/jcp.29957] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/08/2020] [Indexed: 12/20/2022]
Abstract
Distinguishing the multiple effects of reactive oxygen species (ROS) on cancer cells is important to understand their role in tumour biology. On one side, ROS can be oncogenic by promoting hypoxic conditions, genomic instability and tumorigenesis. Conversely, elevated levels of ROS-induced oxidative stress can induce cancer cell death. This is evidenced by the conflicting results of research using antioxidant therapy, which in some cases promoted tumour growth and metastasis. However, some antioxidative or ROS-mediated oxidative therapies have also yielded beneficial effects. To better define the effects of oxidative stress, in vitro experiments were conducted on 4T1 and splenic mononuclear cells (MNCs) under hypoxic and normoxic conditions. Furthermore, hydrogen peroxide (H2 O2 ; 10-1,000 μM) was used as an ROS source alone or in combination with hyaluronic acid (HA), which is frequently used as drug delivery vehicle. Our result indicated that the treatment of cancer cells with H2 O2 + HA was significantly more effective than H2 O2 alone. In addition, treatment with H2 O2 + HA led to increased apoptosis, decreased proliferation, and multiphase cell cycle arrest in 4T1 cells in a dose-dependent manner under normoxic or hypoxic conditions. As a result, migratory tendency and the messenger RNA levels of vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), and MMP-9 were significantly decreased in 4T1 cells. Of note, HA treatment combined with 100-1,000 μM H2 O2 caused more damage to MNCs as compared to treatment with lower concentrations (10-50 μM). Based on these results, we propose to administer high-dose H2 O2 + HA (100-1000 μM) for intratumoural injection and low doses for systemic administration. Intratumoural route could have toxic and inhibitory effects not only on the tumour but also on residential myeloid cells defending it, whereas systemic treatment could stimulate peripheral immune responses against the tumour. More in vivo research is required to confirm this hypothesis.
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Affiliation(s)
- Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nafiseh Pakravan
- Department of Immunology, Medical School, Alborz University of Medical Sciences, Karaj, Iran
| | - Zuhair Mohammad Hassan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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29
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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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Abstract
Background and Objectives: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. In addition, nonmalignant cells in the tumor microenvironment play critical roles in all the stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation. Aim: This study aims to explore the concept of the tumor microenvironment by conducting a critical review of previous studies on the topic. Materials and Methods: This review relies on evidence presented in previous studies related to the topic. The articles included in this review were obtained from different medical and health databases. Results and Discussion: The tumor microenvironment has received significant attention in the cancer literature, with a particular focus on its role in tumor development and progression. Previous studies have identified various components of the tumor microenvironment that influence malignant behavior and progression. In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells. Conclusion: The tumor microenvironment harbors cancer stem cells and other molecules that contribute to tumor development and progression. Consequently, targeting and manipulating the cells and factors in the tumor microenvironment during cancer treatment can help control malignancies and achieve positive health outcomes.
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Affiliation(s)
- Borros Arneth
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, University Hospital of the Universities of Giessen and Marburg UKGM, Justus Liebig University Giessen, Giessen, Germany, Feulgenstr. 12, 35392 Giessen, Germany
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31
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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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Yu Y, Abudula M, Li C, Chen Z, Zhang Y, Chen Y. Icotinib-resistant HCC827 cells produce exosomes with mRNA MET oncogenes and mediate the migration and invasion of NSCLC. Respir Res 2019; 20:217. [PMID: 31606039 PMCID: PMC6790059 DOI: 10.1186/s12931-019-1202-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/27/2019] [Indexed: 12/26/2022] Open
Abstract
Background Icotinib has been widely used in patients with non-small cell lung cancer (NSCLC), and have significantly enhanced the overall survival rate of NSCLC patients. However, acquired drug resistance limits its clinical efficacy. Tumor cell-derived exosomes have been reported to participate in various biological processes, including tumor invasion, metastasis and drug resistance. Materials and methods In the present study, drug resistance was measured by MTT assay. Exosomes were extracted from the cell supernatant using ultracentrifugation and identified by exosomal marker. HCC827 cells were treated with exosomes derived from icotinib-resistant (IR) HCC827 to observe the invasion and migration of parent cells. The expression of exo-mRNA was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-PCR). In addition, 10 exo-mRNAs detecting from the plasma and bronchoalveolar lavage fluid (BALF) of NSCLC patients with icotinib treatment were used to establish a new drug resistant-warning formula. Results The oncogene MET into exosomes was identified from icotinib-resistant lung cancer cells, and this was also presented in exosomes in NSCLC patients diagnosed with cancer metastasis after icotinib treatment. The knockdown of MET in exosomes significantly decreased the ability of invasion and migration in HCC827 cells. Conclusion It was suggested that MET might be specifically package and transferred by exosomes to modify the invasion and migration ability of the surrounding icotinib-sensitive cells.
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Affiliation(s)
- Yiming Yu
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | | | | | - Zhongbo Chen
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Yun Zhang
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Yichen Chen
- Ningbo Institution of Medical Science, Ningbo, China.
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Tan HX, Cao ZB, He TT, Huang T, Xiang CL, Liu Y. TGFβ1 is essential for MSCs-CAFs differentiation and promotes HCT116 cells migration and invasion via JAK/STAT3 signaling. Onco Targets Ther 2019; 12:5323-5334. [PMID: 31308702 PMCID: PMC6615717 DOI: 10.2147/ott.s178618] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 04/17/2019] [Indexed: 12/12/2022] Open
Abstract
Background and purpose Colorectal cancer (CRC) frequently metastasizes to the liver, which involves the participation of multiple cytokines. Tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs) and tumor cells acts as an essential factor in cancer metastasis. Transforming growth factor β1 (TGFβ1) is a vital cytokine involved in migration and invasion of cancer cells. However, the underlying mechanisms remain unclear. In the present study, we aimed to investigate the role and molecular mechanisms of TGFβ1 in TME. Methods The conditioned medium prepared from colorectal cancer HCT116 and HT29 cells was used to culture mesenchymal stem cells (MSCs). The differentiation of MSCs to CAFs was detected by flow cytometry. The role of TGFβ1 in colorectal cancer cells metastasis was examined by wound-healing assay and transwell assay. And the activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway was measured by Western blot assay. Results TGFβ1 induced the differentiation of MSCs to CAFs and improved HCT116 and HT29 cells migration and invasion. Meanwhile, TGFβ1 also upregulated the phosphorylation of STAT3 and enhanced the nuclear localization of p-STAT3, which activated JAK/STAT3 signaling pathway. Conclusion TGFβ1 induced the differentiation of MSCs into CAFs and promoted the migration and invasion of HCT116 and HT29 cells, which depended on the activation of JAK/STAT3 signaling pathway.
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Affiliation(s)
- Hao-Xiang Tan
- Department of Gastrointestinal Surgery, Hunan Provincial People's Hospital, Changsha 410002, People's Republic of China.,Department of Gastrointestinal Surgery, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, People's Republic of China.,Department of Gastrointestinal Surgery, First Affiliated Hospital of Hunan Normal University, Changsha 410002, People's Republic of China
| | - Zhen-Bin Cao
- Department of Radiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, People's Republic of China
| | - Ting-Ting He
- Department of Pathology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, People's Republic of China
| | - Tao Huang
- Department of Gastrointestinal Surgery, Hunan Provincial People's Hospital, Changsha 410002, People's Republic of China.,Department of Gastrointestinal Surgery, First Affiliated Hospital of Hunan Normal University, Changsha 410002, People's Republic of China
| | - Cai-Ling Xiang
- Department of Gastrointestinal Surgery, Hunan Provincial People's Hospital, Changsha 410002, People's Republic of China.,Department of Gastrointestinal Surgery, First Affiliated Hospital of Hunan Normal University, Changsha 410002, People's Republic of China
| | - Yu Liu
- Department of Gastrointestinal Surgery, Hunan Provincial People's Hospital, Changsha 410002, People's Republic of China.,Department of Gastrointestinal Surgery, First Affiliated Hospital of Hunan Normal University, Changsha 410002, People's Republic of China
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Plava J, Cihova M, Burikova M, Matuskova M, Kucerova L, Miklikova S. Recent advances in understanding tumor stroma-mediated chemoresistance in breast cancer. Mol Cancer 2019; 18:67. [PMID: 30927930 PMCID: PMC6441200 DOI: 10.1186/s12943-019-0960-z] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 02/20/2019] [Indexed: 02/07/2023] Open
Abstract
Although solid tumors comprise malignant cells, they also contain many different non-malignant cell types in their micro-environment. The cellular components of the tumor stroma consist of immune and endothelial cells combined with a heterogeneous population of stromal cells which include cancer-associated fibroblasts. The bi-directional interactions between tumor and stromal cells therefore substantially affect tumor cell biology.Herein, we discuss current available information on these interactions in breast cancer chemo-resistance. It is acknowledged that stromal cells extrinsically alter tumor cell drug responses with profound consequences for therapy efficiency, and it is therefore essential to understand the molecular mechanisms which contribute to these substantial alterations because they provide potential targets for improved cancer therapy. Although breast cancer patient survival has improved over the last decades, chemo-resistance still remains a significant obstacle to successful treatment.Appreciating the important experimental evidence of mesenchymal stromal cells and cancer-associated fibroblast involvement in breast cancer clinical practice can therefore have important therapeutic implications.
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Affiliation(s)
- Jana Plava
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05, Bratislava, Slovakia
| | - Marina Cihova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05, Bratislava, Slovakia
| | - Monika Burikova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05, Bratislava, Slovakia
| | - Miroslava Matuskova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05, Bratislava, Slovakia
| | - Lucia Kucerova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05, Bratislava, Slovakia
| | - Svetlana Miklikova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05, Bratislava, Slovakia.
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Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova II. Therapy resistance mediated by exosomes. Mol Cancer 2019; 18:58. [PMID: 30925921 PMCID: PMC6441190 DOI: 10.1186/s12943-019-0970-x] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 02/21/2019] [Indexed: 12/21/2022] Open
Abstract
Therapy resistance can arise within tumor cells because of genetic or phenotypic changes (intrinsic resistance), or it can be the result of an interaction with the tumor microenvironment (extrinsic resistance). Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. They transfer therapy resistance by anti-apoptotic signalling, increased DNA-repair or delivering ABC transporters to drug sensitive cells. As functional mediators of tumor-stroma interaction and of epithelial to mesenchymal transition, exosomes also promote environment-mediated therapy resistance. Exosomes may be used in anticancer therapy exploiting their delivery function. They may effectively transfer anticancer drugs or RNAs in the context of gene therapy reducing immune stimulatory effects of these drugs and hydrophilic qualities facilitating crossing of cell membranes.
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Affiliation(s)
| | - József Dudás
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Sergej Skvortsov
- Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria.,EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Ute Ganswindt
- Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
| | - Herbert Riechelmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Ira-Ida Skvortsova
- Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria. .,EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria.
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Zhou X, Li T, Chen Y, Zhang N, Wang P, Liang Y, Long M, Liu H, Mao J, Liu Q, Sun X, Chen H. Mesenchymal stem cell‑derived extracellular vesicles promote the in vitro proliferation and migration of breast cancer cells through the activation of the ERK pathway. Int J Oncol 2019; 54:1843-1852. [PMID: 30864702 DOI: 10.3892/ijo.2019.4747] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 02/14/2019] [Indexed: 11/06/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been demonstrated to be involved in tumor progression and the modulation of the tumor microenvironment, partly through their secretome. Extracellular vesicles (EVs) are membranous nanovesicles secreted by multiple types of cells and have been demonstrated to mediate intercellular communication in both physiological and pathological conditions. However, numerous questions still remain regarding the underlying mechanisms and functional consequences of these interactions. The purpose of this study was to investigate the effects of human umbilical cord mesenchymal stem cell‑derived EVs (hUC‑MSC‑EVs) on the proliferation, migration and invasion of human breast cancer cells. We successfully generated and identified hUC‑MSCs and hUC‑MSC‑EVs which were used in this study. The results revealed that treatment of the MDA‑MB‑231 and MCF‑7 human breast cancer cells with medium containing hUC‑MSC‑EVs significantly enhanced the proliferation, migration and invasion of the cells in vitro. Treatment of the cells with medium containing hUC‑MSC‑EVs also reduced E‑cadherin expression and increased N‑cadherin expression, thus promoting the epithelial‑mesenchymal transition (EMT) of the breast cancer cells. Treatment of the breast cancer cells with extracellular signal‑regulated kinase (ERK) inhibitor prior to the interaction with hUC‑MSC‑EVs significantly reversed the enhanced proliferation, migration and invasion, as well as the EMT of the breast cancer cells induced by the hUC‑MSC‑EVs. On the whole, these data indicate that hUC‑MSC‑EVs promote the invasive and migratory potential of breast cancer cells through the induction of EMT via the ERK pathway, leading to malignant tumor progression and metastasis. Taken together, the findings of this study suggest that targeting pathways to reverse EMT may lead to the development of novel therapeutic approaches with which to combat breast cancer.
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Affiliation(s)
- Xiaohe Zhou
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Tao Li
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yufei Chen
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Nannan Zhang
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Pengli Wang
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yingying Liang
- Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Melissa Long
- Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Haoran Liu
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jian Mao
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Qiuyan Liu
- National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, P.R. China
| | - Xiaochun Sun
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Huabiao Chen
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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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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Mousavi-Niri N, Naseroleslami M, Hadjati J. Anti-regulatory T cell vaccines in immunotherapy: focusing on FoxP3 as target. Hum Vaccin Immunother 2019; 15:620-624. [PMID: 30633616 PMCID: PMC6605713 DOI: 10.1080/21645515.2018.1545625] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/01/2018] [Accepted: 11/03/2018] [Indexed: 12/29/2022] Open
Abstract
Anti- tumor vaccination elicits imperfect immune responses against tumor cells; that is related to the presence of suppressive obstacles in the tumor microenvironment. The main members of suppressive milieu of tumor are heteroogenous groups of immune cells in which regulatory T cell is a substantial component. Tregs express different immunomodulatory molecules such as FoxP3. Transcription factor, FoxP3, is a specific intracellular marker of Treg and crucial for Treg development. Therefore it is an attractive target for cancer treatment. This article reviews some recent anti-Treg vaccine focusing on FoxP3 to ameliorate anti-tumor immune responses. Among them, fusion vaccine of FoxP3-Fc(IgG) recombinant DNA vaccine and its accordant protein vaccine represents effective results.
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Affiliation(s)
- Neda Mousavi-Niri
- Department of Medical Biotechnology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Naseroleslami
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Jamshid Hadjati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Zhang X, Xu Y, Liu H, Zhao P, Chen Y, Yue Z, Zhang Z, Wang X. HIF-2α-ILK Is Involved in Mesenchymal Stromal Cell Angiogenesis in Multiple Myeloma Under Hypoxic Conditions. Technol Cancer Res Treat 2018; 17:1533033818764473. [PMID: 29656700 PMCID: PMC5912287 DOI: 10.1177/1533033818764473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stromal cells are proven to be likely induce the angiogenic response in multiple myeloma and thus represent an enticing target for antiangiogenesis therapies for multiple myeloma. Substantial evidence indicates that angiogenesis in multiple myeloma is complex and involves direct production of angiogenic cytokines by abnormal plasma cells and these B-cell neoplasia generated pathophysiology change within the microenvironment. In this study, we demonstrated that mesenchymal stromal cells cultured with U266/Lp-1 under hypoxic conditions resulted in an increased α-smooth muscle actin expression and high productive levels of both hypoxia-inducible factor-2α and integrin-linked kinase proteins. Moreover, inhibition of hypoxia-inducible factor-2α by Small interfering RNA (siRNA) in mesenchymal stromal cells decreased the protein levels of both α-smooth muscle actin and integrin-linked kinase after mesenchymal stromal cells cultured with U266 under hypoxic conditions. We further demonstrated that transfection of integrin-linked kinase-siRNA reduced the protein level of α-smooth muscle actin and attenuated angiogenesis in vitro by decreasing the attachment of Q-dot labeled cells and secretion of angiogenic factors. In conclusion, our research showed that mesenchymal stromal cells cultured with myeloma cells under hypoxia participated in the angiogenesis of multiple myeloma, which is regulated by the hypoxia-inducible factor-2α-integrin-linked kinase pathway. Thus, targeting integrin-linked kinase may represent an effective strategy to block hypoxia-inducible factor-2α-induced angiogenesis in the treatment of multiple myeloma.
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Affiliation(s)
- Xiaoying Zhang
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Cancer Hospital of Tianjin, Tianjin Medical University, Tianjin, China
- The authors contributed equally to this work
| | - Yinhui Xu
- Thoracic Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- The authors contributed equally to this work
| | - Hongbo Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- The authors contributed equally to this work
| | - Pan Zhao
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Cancer Hospital of Tianjin, Tianjin Medical University, Tianjin, China
| | - Yafang Chen
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Cancer Hospital of Tianjin, Tianjin Medical University, Tianjin, China
| | - Zhijie Yue
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Cancer Hospital of Tianjin, Tianjin Medical University, Tianjin, China
| | - Zhiqing Zhang
- Department of Neurology, The Fourth Central Hospital, Tianjin, China
| | - Xiaofang Wang
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Cancer Hospital of Tianjin, Tianjin Medical University, Tianjin, China
- Xiaofang Wang, Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Cancer Hospital of Tianjin, Tianjin Medical University, Ti-Yuan-Bei, Huan-Hu-Xi-Road, Tianjin 300060, China.
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Proteomic analysis of exosomes reveals an association between cell invasiveness and exosomal bioactivity on endothelial and mesenchymal cell migration in vitro. Clin Sci (Lond) 2018; 132:2029-2044. [PMID: 30219799 DOI: 10.1042/cs20180425] [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: 05/22/2018] [Revised: 08/02/2018] [Accepted: 08/13/2018] [Indexed: 12/20/2022]
Abstract
Ovarian cancer has resulted in over 140 000 deaths reported annually worldwide. This is often attributed to cellular changes in the microenvironment, including increased migration of mesenchymal stem cells (MSCs) and endothelial cells (ECs) to facilitate metastasis. Recently, the ability of exosomes to communicate signals between cells (and promote cancer progression) has been established. In the present study, we explored the effect of exosomes on cells present in the tumour microenvironment. Exosomes were isolated from ovarian cancer cells with different invasive capacity (high = SKOV-3 and low = OVCAR-3) by differential and buoyant density centrifugation and characterised using nanoparticle tracking analysis (NTA), Western blot, and EM. Exosome secretion was positively correlated with invasiveness of releasing cells. Proteomic analyses identified common and unique proteins between exosomes from SKOV-3 and OVCAR-3 with gene ontology analyses revealing that these exosomes are involved in the regulation of cell migration. Since the tumour microenvironment contains multiple cell types, including MSCs and ECs, we examined the effect of these exosomes on MSC and EC migration. Exosomes promoted MSC and EC migration in a time- and concentration-dependent manner. The effect of exosomes isolated from SKOV-3 on cell migration was significantly higher compared with exosomes from OVCAR-3. Thus, we suggest that exosomes from ovarian cancer cells contain a specific set of proteins that are representative of its cell of origin and the invasive capacity.
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Joshi BP, Hardie J, Farkas ME. Harnessing Biology to Deliver Therapeutic and Imaging Entities via Cell-Based Methods. Chemistry 2018; 24:8717-8726. [PMID: 29543990 PMCID: PMC6174085 DOI: 10.1002/chem.201706180] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 03/12/2018] [Indexed: 01/21/2023]
Abstract
The accumulation of therapeutic and imaging agents at sites of interest is critical to their efficacy. Similarly, off-target effects (especially toxicity) are a major liability for these entities. For this reason, the use of delivery vehicles to improve the distribution characteristics of bio-active agents has become ubiquitous in the field. However, the majority of traditionally employed, cargo-bearing platforms rely on passive accumulation. Even in cases where "targeting" functionalities are used, the agents must first reach the site in order for the ligand-receptor interaction to occur. The next stage of vehicle development is the use of "recruited" entities, which respond to biological signals produced in the tissues to be targeted, resulting in improved specificities. Recently, many advances have been made in the utilization of cells as delivery agents. They are biocompatible, exhibit excellent circulation lifetimes and tissue penetration capabilities, and respond to chemotactic signals. In this Minireview, we will explore various cell types, modifications, and applications where cell-based delivery agents are used.
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Affiliation(s)
- Bishnu P Joshi
- Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA, 01002, USA
| | - Joseph Hardie
- Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA, 01002, USA
| | - Michelle E Farkas
- Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA, 01002, USA
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Razmkhah M, Mansourabadi Z, Mohtasebi MS, Talei AR, Ghaderi A. Cancer and normal adipose-derived mesenchymal stem cells (ASCs): Do they have differential effects on tumor and immune cells? Cell Biol Int 2018; 42:334-343. [PMID: 29076586 DOI: 10.1002/cbin.10905] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 10/25/2017] [Indexed: 12/24/2022]
Abstract
Adipose-derived mesenchymal stem cells (ASCs) are known to have immunomodulatory properties through soluble factors or by direct cell-to-cell contact. This study aimed to assess the expression of HLA-G and IDO activity in breast cancer and normal ASCs and to see whether ASC is capable of modulating both tumor cells and immune system cells in vitro. ASCs were enzymatically isolated from 15 breast cancer patients and 10 normal individuals. Then they were cultured, and the impact of their conditioned media on the movement of the MDA-MB-231 breast cancer cell line was studied in wound healing scratch assay. Next, PBLs from the peripheral blood of normal individuals were separated and co-cultured with breast cancer and normal ASCs. PBLs proliferation and apoptosis were assessed using CFSE labeling dye and annexin V/7AAD staining, respectively. IDO activity and HLA-G protein expression in ASCs were examined using kynurenine assay and Western blotting, respectively. Tumor-derived ASCs, especially those from higher stages of breast cancer, have stronger effects on the proliferation and movement of MDA-MB-231 cells than normal ASCs (P-value < 0.05). Apoptosis in PBLs increased in the presence of ASCs compared to PBLs cultured alone (P-value < 0.05). In contrast, necrosis of PBLs decreased in the presence of ASCs compared to apoptosis in these cells (P-value < 0.001). Collectively, ASCs may have strategic effects on both tumor cells and cells of the immune system in the tumor microenvironment, resulting in tumor development, growth, and metastasis.
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Affiliation(s)
- Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Mansourabadi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Sadat Mohtasebi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdol-Rasoul Talei
- Breast Diseases Research Center (BDRC), Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Purnamawati P, Pawitan JA, Rachman A, Wanandi SI. Effects of umbilical cord- and adipose-derived stem cell secretomes on ALDH1A3 expression and autocrine TGF-β1 signaling in human breast cancer stem cells. F1000Res 2018. [DOI: 10.12688/f1000research.13609.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background: Nowadays, umbilical cord- and adipose-derived stem cells (UCSCs and ASCs) are the most common sources of mesenchymal stem cells (MSCs). As part of the tumor microenvironment, MSCs are known to communicate with cancer cells via their secretomes. Increased activity of aldehyde dehydrogenase-1 (ALDH1) has been widely used as a common intrinsic stemness marker in normal and cancer stem cells. Our study aimed to elaborate on the effect of UCSC and ASC secretomes on the expression of ALDH1A3, as one of the important variants of ALDH1, TGF-β1 and TGF-β receptor type I (TβRI) in human breast cancer stem cells (BCSCs). Methods: UCSCs and ASCs were cultured in serum-free α-MEM media under standard conditions for 24 hours. The conditioned medium (CM) containing secretomes of UCSCs and ASCs were collected and added 50% (v/v) to the cultured of human BCSCs for 72 hours. The mRNA expressions of ALDH1A3, TGF-β1, and TβRI were determined using quantitative Reverse Transcriptase Polymerase Chain Reaction (q-RT-PCR). Results: We found that CM of UCSCs significantly increased the ALDH1A3 expression of BCSCs in parallel with the increase of TGF-β1 and TβRI expressions. Conversely, CM of ASCs had no significant effect on the ALDH1A3 expression, but significantly decreased TGF-β1 and TβRI expressions of BCSCs. These results contradict our published data on ALDH1A1, which is another important variant of ALDH1, as well as data of the pluripotency markers OCT4 and SOX2 expressions. Conclusions: UCSC and ASC secretomes have different regulation on ALDH1A3 expression in human BCSCs, which may be related to the autocrine TGF-β1 signaling in modulating cell proliferation and stemness of BCSCs. Further studies are required to evaluate factors involved in the differential effects of UCSC and ASC secretomes that regulate ALDH1A3 expression in relation to autocrine TGF-β1 signaling and aggressiveness of human BCSCs.
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Feng H, Zhao JK, Schiergens TS, Wang PX, Ou BC, Al-Sayegh R, Li ML, Lu AG, Yin S, Thasler WE. Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation. Br J Cancer 2018; 118:353-365. [PMID: 29384527 PMCID: PMC5808030 DOI: 10.1038/bjc.2017.415] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 10/03/2017] [Accepted: 10/23/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Radiotherapy remains one of the cornerstones to improve the outcome of colorectal cancer (CRC) patients. Radiotherapy of the CRC not only help to destroy cancer cells but also remodel the tumour microenvironment by enhancing tumour-specific tropism of bone marrow-derived mesenchymal stromal cell (BM-MSC) from the peripheral circulation. However, the role of local MSCs and recruited BM-MSC under radiation were not well defined. Indeed, the functions of BM-MSC without irradiation intervention remained controversial in tumour progression: BM-MSC was previously shown to modulate the immune function of major immune cells, resulting in an impaired immunological sensitivity and to induce an increased risk of tumour recurrence. In contrast, it could also secrete various cytokines and possess anticancer effect. METHODS Three co-cultivation modules, 3D culture modules, and cancer organoids were established. The induction of cytokines secretion in hBM-MSCs after irradiation was analysed by ELISA array and flow cytometry. AutoMac separator was used to separate hBM-MSC and CRC automatically. Cells from the co-cultured group and the control group were then irradiated by UV-C lamp and X-ray. Proliferation assay and viability assay were performed. RESULTS In this study, we show that BM-MSCs can induce the EMT progression of CRC cells in vitro. When irradiated with low doses of ultraviolet radiation and X-rays, BM-MSCs show an anti-tumour effect by secreting certain cytokine (TNF-α, IFN-γ) that lead to the inhibition of proliferation and induction of apoptosis of CRC cells. This was further verified in a 3D culture model of a CRC cell in vitro. Furthermore, irradiation on the co-culture system induced the cleavage of caspase3, and attenuated the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase in cancer cells. The signal pathways above might contribute to the cancer cell death. CONCLUSIONS Taken together, we show that BM-MSC can potentially promote the effect of radiotherapy in CRC.
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Affiliation(s)
- Hao Feng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of General-, Visceral-, Transplantation and Vascular Surgery, University Hospital of LMU Munich, Munich 81377, Germany
| | - Jing-kun Zhao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of General-, Visceral-, Transplantation and Vascular Surgery, University Hospital of LMU Munich, Munich 81377, Germany
| | - Tobias S Schiergens
- Department of General-, Visceral-, Transplantation and Vascular Surgery, University Hospital of LMU Munich, Munich 81377, Germany
| | - Pu-xiongzhi Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Bao-chi Ou
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Rami Al-Sayegh
- Department of General-, Visceral-, Transplantation and Vascular Surgery, University Hospital of LMU Munich, Munich 81377, Germany
| | - Ming-lun Li
- Department of Radiation Oncology, University Hospital of LMU Munich, Munich 81377, Germany
| | - Ai-guo Lu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shuai Yin
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of General-, Visceral-, Transplantation and Vascular Surgery, University Hospital of LMU Munich, Munich 81377, Germany
- Department of General Surgery, State Hospital of Anhui Province, Hefei 230000, China
| | - Wolfgang E Thasler
- Department of General and Visceral Surgery, Red Cross Hospital, Munich 80634, Germany
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Wang K, Zhu X, Zhang K, Yin Y, Chen Y, Zhang T. Interleukin-6 contributes to chemoresistance in MDA-MB-231 cells via targeting HIF-1α. J Biochem Mol Toxicol 2018; 32:e22039. [PMID: 29341321 DOI: 10.1002/jbt.22039] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 12/18/2017] [Accepted: 12/27/2017] [Indexed: 12/15/2022]
Abstract
Chemoresistance is a critical challenge in the clinical treatment of triple-negative breast cancer (TNBC). It has been well documented that inflammatory mediators from tumor microenvironment are involved in the pathogenesis of TNBC and might be related to chemoresistance of cancer cells. In this study, the contribution of interleukin-6 (IL-6), one of the principal oncogenic molecules, in chemoresistance of a TNBC cell line MDA-MB-231 was first investigated. The results showed that IL-6 treatment could induce upregulation of HIF-1α via the activation of STAT3 in MDA-MB-231 cells, which consequently contributed to its effect against chemotherapeutic drug-induced cytotoxicity and cell apoptosis. However, knockdown of HIF-1α attenuated such effect via affecting the expressions of apoptosis-related molecules as Bax and Bcl-2 and drug transporters as P-gp and MRP1. This study indicated that targeting at IL-6/HIF-1α signaling pathway might be an effective strategy to overcome chemoresistance in TNBC therapy.
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Affiliation(s)
- Ke Wang
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine., Wuxi 214063, Jiangsu Province, People's Republic of, China
| | - Xue Zhu
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine., Wuxi 214063, Jiangsu Province, People's Republic of, China
| | - Kai Zhang
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine., Wuxi 214063, Jiangsu Province, People's Republic of, China
| | - Yongxiang Yin
- Department of Pathology, The Affiliated Wuxi Matemity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, Jiangsu Province, People's Republic of China
| | - Yu Chen
- Central Laboratory, The Affiliated Wuxi Matemity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, Jiangsu Province, People's Republic of China
| | - Ting Zhang
- Central Laboratory, The Affiliated Wuxi Matemity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, Jiangsu Province, People's Republic of China.,Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment Cancer Center, Nanjing Medical University, Nanjing 210029, Jiangsu Province, People's Republic of China.,School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu Province, People's Republic of China
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Geraili A, Jafari P, Hassani MS, Araghi BH, Mohammadi MH, Ghafari AM, Tamrin SH, Modarres HP, Kolahchi AR, Ahadian S, Sanati-Nezhad A. Controlling Differentiation of Stem Cells for Developing Personalized Organ-on-Chip Platforms. Adv Healthc Mater 2018; 7. [PMID: 28910516 DOI: 10.1002/adhm.201700426] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Revised: 06/01/2017] [Indexed: 01/09/2023]
Abstract
Organ-on-chip (OOC) platforms have attracted attentions of pharmaceutical companies as powerful tools for screening of existing drugs and development of new drug candidates. OOCs have primarily used human cell lines or primary cells to develop biomimetic tissue models. However, the ability of human stem cells in unlimited self-renewal and differentiation into multiple lineages has made them attractive for OOCs. The microfluidic technology has enabled precise control of stem cell differentiation using soluble factors, biophysical cues, and electromagnetic signals. This study discusses different tissue- and organ-on-chip platforms (i.e., skin, brain, blood-brain barrier, bone marrow, heart, liver, lung, tumor, and vascular), with an emphasis on the critical role of stem cells in the synthesis of complex tissues. This study further recaps the design, fabrication, high-throughput performance, and improved functionality of stem-cell-based OOCs, technical challenges, obstacles against implementing their potential applications, and future perspectives related to different experimental platforms.
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Affiliation(s)
- Armin Geraili
- Department of Chemical and Petroleum Engineering; Sharif University of Technology; Azadi, Tehran 14588-89694 Iran
- Graduate Program in Biomedical Engineering; Western University; London N6A 5B9 ON Canada
| | - Parya Jafari
- Graduate Program in Biomedical Engineering; Western University; London N6A 5B9 ON Canada
- Department of Electrical Engineering; Sharif University of Technology; Azadi, Tehran 14588-89694 Iran
| | - Mohsen Sheikh Hassani
- Department of Systems and Computer Engineering; Carleton University; 1125 Colonel By Drive Ottawa K1S 5B6 ON Canada
| | - Behnaz Heidary Araghi
- Department of Materials Science and Engineering; Sharif University of Technology; Azadi, Tehran 14588-89694 Iran
| | - Mohammad Hossein Mohammadi
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto ON M5S 3G9 Canada
- Department of Chemical Engineering and Applied Chemistry; University of Toronto; Toronto Ontario M5S 3E5 Canada
| | - Amir Mohammad Ghafari
- Department of Stem Cells and Developmental Biology; Cell Science Research Center; Royan Institute for Stem Cell Biology and Technology; Tehran 16635-148 Iran
| | - Sara Hasanpour Tamrin
- BioMEMS and Bioinspired Microfluidic Laboratory (BioM); Department of Mechanical and Manufacturing Engineering; University of Calgary; 2500 University Drive N.W. Calgary T2N 1N4 AB Canada
| | - Hassan Pezeshgi Modarres
- BioMEMS and Bioinspired Microfluidic Laboratory (BioM); Department of Mechanical and Manufacturing Engineering; University of Calgary; 2500 University Drive N.W. Calgary T2N 1N4 AB Canada
| | - Ahmad Rezaei Kolahchi
- BioMEMS and Bioinspired Microfluidic Laboratory (BioM); Department of Mechanical and Manufacturing Engineering; University of Calgary; 2500 University Drive N.W. Calgary T2N 1N4 AB Canada
| | - Samad Ahadian
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto ON M5S 3G9 Canada
- Department of Chemical Engineering and Applied Chemistry; University of Toronto; Toronto Ontario M5S 3E5 Canada
| | - Amir Sanati-Nezhad
- BioMEMS and Bioinspired Microfluidic Laboratory (BioM); Department of Mechanical and Manufacturing Engineering; University of Calgary; 2500 University Drive N.W. Calgary T2N 1N4 AB Canada
- Center for Bioengineering Research and Education; Biomedical Engineering Program; University of Calgary; Calgary T2N 1N4 AB Canada
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Wen Y, Guo Y, Huang Z, Cai J, Wang Z. Adipose-derived mesenchymal stem cells attenuate cisplatin-induced apoptosis in epithelial ovarian cancer cells. Mol Med Rep 2017; 16:9587-9592. [DOI: 10.3892/mmr.2017.7783] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 08/22/2017] [Indexed: 11/06/2022] Open
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Hill BS, Pelagalli A, Passaro N, Zannetti A. Tumor-educated mesenchymal stem cells promote pro-metastatic phenotype. Oncotarget 2017; 8:73296-73311. [PMID: 29069870 PMCID: PMC5641213 DOI: 10.18632/oncotarget.20265] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 08/04/2017] [Indexed: 12/22/2022] Open
Abstract
Multipotent mesenchymal stem cells (MSCs) are recruited into tumor microenvironment in response to multiple signals produced by cancer cells. Molecules involved in their homing to tumors are the same inflammatory mediators produced by injured tissues: chemokines, cytokines and growth factors. When MSCs arrive into the tumor microenvironment these are "educated" to have pro-metastatic behaviour. Firstly, they promote cancer immunosuppression modulating both innate and adaptive immune systems. Moreover, tumor associated-MSCs trans-differentiating into cancer-associated fibroblasts can induce epithelial-mesenchymal-transition program in tumor cells. This process determinates a more aggressive phenotype of cancer cells by increasing their motility and invasiveness and favoring their dissemination to distant sites. In addition, MSCs are involved in the formation and modelling of pre-metastatic niches creating a supportive environment for colonization of circulating tumor cells. The development of novel therapeutic approaches targeting the different functions of MSCs in promoting tumor progression as well as the mechanisms underlying their activities could enhance the efficacy of conventional and immune anti-cancer therapies. Furthermore, many studies report the use of MSCs engineered to express different genes or as vehicle to specifically deliver novel drugs to tumors exploiting their strong tropism. Importantly, this approach can enhance local therapeutic efficacy and reduce the risk of systemic side effects.
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Affiliation(s)
- Billy Samuel Hill
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), Naples, Italy
| | - Alessandra Pelagalli
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), Naples, Italy
- Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy
| | - Nunzia Passaro
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), Naples, Italy
| | - Antonella Zannetti
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), Naples, Italy
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Lee HY, Hong IS. Double-edged sword of mesenchymal stem cells: Cancer-promoting versus therapeutic potential. Cancer Sci 2017; 108:1939-1946. [PMID: 28756624 PMCID: PMC5623746 DOI: 10.1111/cas.13334] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/18/2017] [Accepted: 07/22/2017] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) derived from adipose tissue, bone marrow, cord blood, and other tissues, have recently attracted much attention as potential therapeutic agents in various diseases because of their trans‐differentiation capacity. However, recent studies have suggested that MSCs also appear to contribute to tumor pathogenesis by supporting tumor microenvironments, increasing tumor growth, and eliciting antitumor immune responses. Although some studies suggest that MSCs have inhibitory effects on tumor development, they are overwhelmed by a number of studies showing that MSCs exert stimulatory effects on tumor pathogenesis. In the present review, we summarize a number of findings to provide current information about the therapeutic potential of MSCs in various diseases. We then discuss the potential roles of MSCs in tumor progression.
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Affiliation(s)
- Hwa-Yong Lee
- The Faculty of Liberal Arts, Jungwon University, Chungbuk, Korea
| | - In-Sun Hong
- Laboratory of Stem Cell Research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Korea
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Yeh WL, Tsai CF, Chen DR. Peri-foci adipose-derived stem cells promote chemoresistance in breast cancer. Stem Cell Res Ther 2017; 8:177. [PMID: 28750689 PMCID: PMC5532814 DOI: 10.1186/s13287-017-0630-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/20/2017] [Accepted: 07/10/2017] [Indexed: 02/07/2023] Open
Abstract
Background Mesenchymal stem cells in tumor microenvironment can influence therapeutic responses in various types of cancers. For triple negative breast cancer, chemotherapy remains the mainstay of standard treatment. Our aim was to investigate the correlation between human adipose-derived stem cells (hAdSCs) and chemoresistance in triple negative breast cancer. Method Conditioned medium was collected from hAdSCs, which was isolated from breast cancer patients who had had breast mastectomy. The expression of selected CD markers was evaluated by flow cytometry to characterize hAdSCs. By array analyses of the secreted cytokines and chemokines of hAdSCs, we identified CXCL1 that mediated doxorubicin resistance and the expression of ATP-binding cassette transporters ABCG2 in TNBC. By microRNA microarray, the association between hAdSC-mediated doxorubicin resistance in TNBC was also revealed. Results Conditioned medium collected from hAdSCs elicited doxorubicin resistance and enhanced the expression of ABCG2, which is a transporter responsible for the efflux of doxorubicin. CXCL1 secreted by hAdSCs downregulated miR-106a expression in triple negative breast cancer, and resulted in ABCG2 upregulation and doxorubicin resistance. Conclusions Our findings suggest that CXCL1 secreted by hAdSCs elicits doxorubicin resistance through miR-106a-mediated ABCG2 upregulation in triple negative breast cancer. These findings provide a better understanding of the importance of adipose-derived stem cells in breast cancer microenvironment regarding to the development of chemoresistance and reveal the potential of discovering novel therapeutic strategies to overcome drug resistance in TNBC. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0630-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei-Lan Yeh
- Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Road, Taichung, 40402, Taiwan.
| | - Cheng-Fang Tsai
- Department of Biotechnology, Asia University, No. 500 Lioufeng Road, Taichung, 41354, Taiwan
| | - Dar-Ren Chen
- Comprehensive Breast Cancer Center, Changhua Christian Hospital, No. 135 Nanxiao Street, Changhua, 50006, Taiwan.
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